Introduction

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The Role of Transport Processes I in Biological Systems

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The functioning of cells, organs, and tissues requires the efficient delivery of nutrients and regulators of growth and other processes of function. Organisms control the concentrations of molecules in their tissues and organs. Consequently, specialized mechanisms regulate the movement of molecules to, across, and within cells. These mechanisms are the subject of this book. Many organs, such as the lungs, liver, and kidneys, are organized to enable the rapid exchange of molecules between the blood and tissues. In addition, various levels of biological organization-for example, the density of capillaries in various tissues and the size and strjicture of cells---can be explained, iii part, by the rates of transport of molecules from their sources to their sites of delivery. Alterations in transport processes are important factors in a number of diseases, such as atherosclerosis, cancer, and kidney diseases. Transport phenomena involve the integrated study of momentum, mass, and energy transfer, as well as the thermodynamics and kinetics of chemical reactions. For the bioengineer, a mechanistic understanding of transport processes is important for the characterization of physiological and cellular processes, the design and operation of a number of devices, and the development of new therapies. Examples of biomedical devices influenced by transport processes include kidney dialysis machines, heart-lung bypass machines, biosensors, and membrane oxygenators. Transport processes are critical in the removal of toxins from blood, the design of replacement tissues, and the delivery of drugs. Understanding and exploiting transPOrt processes will be necessary in the application of molecular medicine. For example, the methods for delivering gene therapies must exploit biological transport pathways in order to successfully deliver the gene, in a functional' form, to sites of action in the body.
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Chapter 1

Introduction 1.2 Definition of Transport Processes

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Because biological systems have evolved unique adaptations to regulate molecular transport, the development and analysis of biomedical engineering transport problems requires an understanding of cellular biology and physiology. In-this text, we focus upon descriptions of cellular and organ-level processes of transport, the formulation of the equations describing transport processes, and the solution of these equations for problems of interest to biomedical engineers.
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The field of transport phenomena is sufficiently far advanced that the basic processes can be characterized mathematically. The predictive capabilities of models are quite good, even for complex biological systems. Analytical and numerical solutions are available for many problems pertaining to biological function and the design of many technologies. Nevertheless, there are many important biomedical transport problems that have not been solved. Such problems frequently demonstrate the interrelationships among biological, chemical, and physical processes.

FIGURE 1.1 SOO-step random walk. The walk begins at coordinates x ~ 0, y ~ 0 denoted by the"." and ends in the upper right hand quadrant denoted by "X". The arrow represents the displacement.

1.2 I Definition of Transport Processes
x Two physical phenomena are involved in the transport of molecules: diffusion and convection. Diffusion is the random motion of molecules that arises from thermal energy transferred by molecular collisions. Convection is a mechanism of transport resulting from the bulk motion of fluids. The movement of energy and momentum in biological systems is influenced by these two mechanisms.

1.2.1 Diffusion
Collisions between molecules Occur trillions of times per second. Each collision results in the random motion of solute and solvent molecules. This random motion gives rise to diffusion, which OCcurs in gases, in liquid solutions, in membranes, and in the interstitial spaces of tissues. The speed at which a molecule diffuses in a fluid or membrane depends upon its size and shape, the temperature, and the fluid viscosity, a property that reflects the resistance to flow.
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, . f ndom molecular motion is that diffusing mol, A macroscopic conseque~ce 0 ra . t regions of lower concentration. f ' f higher concentranon 0 ecules move rom reglO~s 0 . t ation gradients The net movement 1 diff known as concen r I • These spatia I erences are '.' di tion per unit time is known as a flux. of molecules through a unit area III a given Iredc antity as the amount of the quanqu fl is d f d for any transporte , ,, In general, a ux IS e ne , d it may depend upon both posmon . inz th h it ea per unit time an I tity passing t roug a um ar f '(including heat) and momentum. and time. Fluxes can be defined mass, ener :noving cells. Plu~es have a magniIn addition, fluxes can be defined or groui~ 0 diffusion flux is proportional to the tude and direction and.are thus vectors. eI
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In spite of the random nature of these collisions, net motion of molecules results. The term random walk is used to describe the net molecular motion arising from such collisions. A small sequence of a random walk is shown in Figure 1.1. Each change in direction is the result of collisions between the molecule of interest and the fluid molecules.
Figure 1.1 shows the random movement of a particle from the position marked by the filled circle to the position marked "X". The' net movemen t between these two points can be characterized by the root-mean-square displacement (,2) 1/2 which is calculated from a large number of random walks. The root-mean-square displacement is thus a measure of the distance traveled by a diffusing particle. The relation between random walks and diffusion is discussed in more detail in Section 6.5. Random motion can be viewed macroscopically by observing the spreading of a dye droplet after it is added to water. Initially, dye molecules are close to the site of application. As time proceeds, the outer edges of the droplet become less distinct. Gradients in color appear, and the intensity decreases with distance away from the point of application of the dye. Eventually, the dye is uniformly distributed throughout the water.

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gradient of the concentration. iffusi fl d the concentration gradient (also The relation between ~he .dt ~s~on fiuX an tified in 1855 by Adolph Pick, " ationi was rst quan I ,I known as a constttuttue eq~.. Fi k' fii t law Fick's first law is used Wide y 'I' d IS known as lC s rs . fI a German physio ogist, an lOP' k developed his relation from care u diffusi in dil te so unons IC. in studies of I USlOn III I U ,h P '. 'I of heat conduction, which states ' d bIg Wit ouner s aw experimentation an. y ana 0, y the radient of temperature. • that the flux of heat ISproportlO:a~:~f . g fl to the concentration gradient is the The quantity that relates tel ..USlOn ux, .ref h lute and ,0 to the ' ffi· D here the subscnpt t re ers to t e so binary diffUSIOn cae jj, ion of erature and pressure. The magsolvent. The diffusion coeffiCl~nt IS a fun~tIon 0 tte~~olute and the medium through nitude of the diffusion coefficient depen s up,on'd (Table 1 1) The diffuf 1 ases liqui s or tissues 1; •• which diffusion occursor examp ed'g 'h 1 t"ve unimportance of intermolec' "1 tf r gases ue to t e re a I sion coefficient IS arges ,0 , d . Diff 'ng molecules travel distances d hI' I low ensity. I USl ular forces an t e re ative y , b f lliding with other molecules. Because much larger than the molecular Size e ore co I I

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,. .', ion of material roperries. Unlike a conservation relation, v.:hich lA constitutive equation IS a specific rela~lOn0 ifi PI fmaterials or a specific rang.e.of conditions. " ion applies to a specI c c ass 0 ., , F' k' is universal, a consntunve equatIOn, h diffusi 'dilute binary solutions, In practice, IC S For example, Fick's law is strictly applicable to, tel USlOnIn law has been used over a wider range of conditions.

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The magnitudes of various liquid viscosities vary over four orders of magnitude. For mixtures. m part becauseproreins Interact with the cytoskeleton as well as membrane Ii ids ~~~~. Density is a ma~erial property that characterizes .sen es I usron In. The protein diffusion coefficient within the cell cytoplasm IS about 1 X 10-7 cm2 S-1 A prot' diff f h d .2 ConvectionOne means of overcoming limits imposed by diffusion is to move molecules or cells of interest by fluid motion. Solute motion differs slightly from the local fluid motion because the solute molecules are also diffusing simultaneously. and composition. such as tissues. The density of a pure fluid varies with temperature and pressure.. Diffusion coefficients (cm2 S-I) Gases in gases Gases in liquids Small molecules in liquids Proteins in liquids Proteins in tissues Lipids in lipid membranes Proteins in lipid membranes 0. Gases have relatively low viscosities (Table 1. Shear stresses result from forces applied tangentially to a surface. and hence. effiCient process :vhe. If fluid motion is-slow relative to diffusion. the'tlensity is the ratio of the mass of the system to the volume of the system.1 p (crrr' 5-1) 0. Fick's law de ib diff . For example. Diffusion in membranes is further reduced. Stresses acting perpendicular (i. and the surface to which the force is applied. For a pure fluid.7 hours. transport by diffusion is 10 liquids than in gases. In c~lI n:embranes. then diffusion.2.0 1 o. whereas the viscosities of gases vary by less than one order of magnitude.be compressive or tensile. The stress depends upon the magnitude of the applied force. In complex structures.ot 10 0.2 . The fluid viscosity fI is a measure of the frictional resistance of a. which is less dense than water. When a molecule must be transported lar~e distances.~1 ··f I Gases Liquids Water Glycerol Blood 10--4 0. Gases and liquids flow following the application of forces such as gravity. The net motion of a fluid carries along solutes that are dissolved within it. if the fluid motion is fast relative to diffusion.des . 5-1) Density. the net fluid motion will be the dominant. Liquids are much more viscous and dense.relatIve to another. Further. these obstructions exert drag forces on dlffusmg molecules that slow their movement. however. em can I use rom t e e ge of the cel! to the center in about 2. the direction of the force. causing two contiguous parts of the material to slide relative to each other. p (gcm-3) Kinematic viscosity. The application of a shear stress and a pressure gradient can result in fluid motion.2. diffusion distances of molecules and other particles are greatly increased due to the presence of obstructions created by t~e e~tracellular matrix and cells.~OO-l. Effects of forces applied to a surface are characterized in terms of stresses (which have units of force per unit area).1 to 0. '. which helps propel the flow of blood through the circulatory system.2 p. The frictional force.002 ern) m diameter.will dominate in causing solute transport. Physically.5 1 X 10-7 to 7x 10-5 1 X 10-5 1 X 10-7 to 7x 10-7 1 X 10-7 to 7 X 10-10 1 X 10-9 1 X 10-10 to 1 X 10-12 o~ ~ol~cules in liquids.2). . the density is a function of temperature.ch s_rna~ler. One important exception is ice.than Its size. pressure. . mobility ~O. due to the presence of intermolecular forces. Diffusion is a ~ery rap~d. Pressure. solids are denser than liquids and liquids are denser than gases. or shearing forces. The effective diffusion coefficient incorporates the effects o~ increased diffusion distances and the drag forces exerted by the extracellular matrix and cells.1 ! .fluid to flow. p of the decreased. '.2 em thick is 27. v = p.5 seconds. relative to dif~uslOn m liquids. The nrne for the same protein to diffuse through a tissue only 0. Albert Einstein determined that the diffusion coefficl.veloping the theory of relativity. (g em-I Viscosity.2.025 1.with ~iquid molecules when it has traveled a distance that is mU. and a solute molecule diffusmg m a liquid colh.2 Definition of Transport Processes 5 TABLE 1. Generally.1) [1].~".1) is that the time required to diffuse mcrease~ with the square ~f the distance over which diffusion occurs. a typIc~l ~ellIs about 20 um (~0. However. is a compressive normal stress. diffusion becomes a very slow and inefficient process. normal) to a surface can . pressure.01 10 0.ent ISrelated to the mean square distance a molecule moves during a random walk (FIgure 1. OO~OOOtl_rnes slower .1) ?ne important result from Equ~tion (1. that must be applied in order to produce motion is proportional to the fluid viscosity.how closely molecules are arranged.1 1. Biological examples of shearing forces are those which occur in joints and in the eyelids.tIssues 1 the bl~ary dlf~uSlO? coefficient is replaced with an effective diffusion coefficient Def~' The binary diffusion coefficient characterizes the diffusion of one molecule . if . Convection is a mechanism of transport resulting from the bulk motion of fluids. For a random walk in two dimensions (x and y) he found that ' (1. By contrast.03 0. the viscosity is a thermodynamic function of temperature and pressure. protein diffusion is slower than lipid diffusion.e. TABLE 1. ~I~ Ilil' 4 Chapter 1 Introduction 1.n distances are small.means of transport.. ~rior to de.001 1.

define~ as the sum of the .3) and compressive stresses are negative.3. If a white blood cell with a diameter of 10 11mmoves at the speed of our hypothetical fish. When flow is turbulent. gases have a greater kinematic viscosity than some liquids (Table 1. This kind of transport IS discussed In derail in Section 7.y depends upon the velocity gradient. For example.3) The . All ofthes~ transport processes are important in biological systems. Even though this is a relatively high speed for a cell. The relations for rnomentum. the relative significance of viscous and inertial forces depends upon size. is ~nown as N~wtonJs law of viscosity and is another example of a constitutive relanon. and momentum be summanzed as the followmg general relation: FI. The kinematic viscosity is analogous to the diffusion coefficient (and ?as the. Stewart. the viscos~t.000. and air. transport.3. the viscosity depends upon temperature and pressure only. Consistent with the analogy between energy.3 v=!!:. When an applied force on a fluid in motion is removed. For mixtures. Flow can be characterized as laminar or turbulent. Another way to conceive shear stress applied to fluids is to note that the shear stress transports momentum to the fluid adjacent to the site of application of the shear stress [3]. The kinemat~c viscosity is a me~sure of the efficiency of momentum transport. the shear stress can also be represented as the momentum per unit area per unit time. The analysis of turbulent flow is more complex than that of laminar flow. cells.5. The change in velocity with time arises from a balance between viscous and inertial forces. stress. tensile stresses are positive (see Section 2. some time elapses before fluid motion ceases. L is a characteristic length and v is a characteristic velocity for the flow.. the relative ~ontributions of these forces vary among different fluids. some fluid is drawn along while the other layers -of the fluid resists this motion. is an an~logy am. The movement of momentum through the fluid can be regarded as analogous to diffusion. In fact. Viscous forces act to retard fluid motion. For steady laminar flow. One conceptual view of the mechanics of fluid motion is that the applied forces transfer momentum to the fluid. and inertia depends 'upon the mass or density. viscous forces dominate. a negative sign is not used in mechanics to relate the shear stress and velocity gradient. ~hus. and energy transport.2) Molecular transport mechanism Momentum Mass Energy Flux Shear stress Mass or molar flux Energy Gradient Velocity Concentration" Temperature Coefficient of proportionality Viscosity Diffusion coefficient Thermal conductivity Phenomena [3]. and an extracellular matrix-an interconnected network of proteins and proteoglycans. Because of molecular attractions.ong energy.1. momentum. For the most part. a quantity also known as the shea~ =: Mixtures do not follow Newton's law of viscosity. we adopt the convention used in mechanics. p (1. In order to render the flux a positive quantity in the direction of transport a negative sign is often applied. the shear stress is commensurate with a momentum flux a view developed by Bird. resulting in a velocity gradient. and momentum transport. (N m -2 [Pa] or dyne em ). which can 'For charged molecules. the velocity at any given location does not change with time.ux of qUantity) being transported Re \ = inertial forces/volume viscous forces/volume --- pv2/L pLv /-L . whereas inertial forces act to keep the Huid in motion. mechanics. from a greater to a lesser magnitude of the quantity being transported. the shear stress transports momentum to the fluid.2. such as polymer solutions and blood. Th:2 unit. flow inside the body is laminar. water. the Reynolds number also represents the ratio of momentum transport by convection to momentum transport by viscous diffusion [2]. Biological tissues consist of water. In spite of the analogy among mass. SInce a force equals the rate of change of momentum with time. mass.III! 6 Chapter 1 Introduction 1. same units) and characterizes the "diffusion" of momentum [2]. For these fluids.2.' There. the same amount of momentum IS transferred over longer distances in air than in water. It applies to a number of common fluids with a single component. As a result. One remarkable feature of fluid motion is that the character of the flow changes dramatically above a critical value of the Reynolds number.2. For simple fluids. and Lightfoot in their classic text Transpor. and more complex constitutive relations must be applied. which are proteins containing ~l . This relation. however. alcohol.2).s of shear stress and pressure are force per unit area. they also ~av~ low densities. As a result. the viscosity is the coefficient of proportionality between the shear stress and the velocity gradient. the Reynolds number is 5. Since the kinematic viscosity of ai~ is greater than the kinematic viscosity of water. Viscous forces are much less significant than inertial forces./-Lv1L2 (1. then the Reynolds number is 0. (1.6).negative sign in Equation (1. and energy are summarized in Table 1.2. the velocity fluctuates randomly due to the formation and dissipation of eddies of fluid at high energy. A dimensionless grouping of parameters known as the Reynolds number describes the ratio of inertial forces to viscous forces: . mass. transport is down an electrochemical gradient. Here. given by Equation (2. The net result is that the next fluid layer moves more slowly than the layer adjacent to the site of application of the shear.4.i . such as 2Note that. Although gases have low viscosities. For objects moving at the same speed. concentration gradient plus the potential field gradient. in. . mass.2 Defin ilion of Tra nsport Processes 7 The ratio of viscosity to density is known denoted by as the kinematic viscosity and is TABLE 1. for a fish 50 em long moving in water at the relatively slow speed of 1 em s-l. Because viscous forces are sensitive to viscosity.4) ( cc_(Gradient of qUantity) being transported .3) is used because transport occurs down a gradient-that is.

1. ThIS amplification of the SIgnal can enable the ligand to be effective even at low concentrations. Although diffusion is efficient at such length scales. . ~he mod~fied cytoplasmic side of the receptor is either directly or indirectly involved I~ c?emical reactions producing molecules that can exert a biological response within the cell: Suc~ a process of indirect action is known as cell signaling. Such foreI~n molecules . it ~inds to an antibody.5). product m~lecules. for a g~ven receptor molecule. diffusion can be quite rapid.8 Chapter 1 ----------------r~~d~~ __. The Darcy permeability represents the conductivity of the porous medium to flow and depends upon the detailed microstructure of the porous medium. they are transported mto the cell by a process in:o!ving the formation of vesicles derived from the plasma membrane. a constitutive relation known as Darcy's law. only a small number of structurally similar molecules can bmd to the receptor. the local motion of fluid is described by relationships sI~TIllar. molecules bound to cell membrane receptors exert their effects mdlrectly: Bmdmg of the molecule. For example.\ TABLE 1. \0 \~()(J il It' !t 'II! 10~1 10° I 'II ! "\ . because the rate of reaction depends upon the rate at which the reacting molecule is transported to the reaction site. The process requires energy from the cell and is known as active transport.4). v) L _ vL . thus. The antigenbound antibody then binds to cells of the Immune system via a portion of the antibody known as the Fc segment. .l i . In biological systems.__. Binding r~actions are used to selectively transport molecules into cells. which is a protein molecule of the immune system. Thus. The constant of proport~~nality is the ratio of the Darcy permeability to the viscosity. diffusion is most important for small molecules such as oxygen (Table 1. As distance increases... That is. Bin~ing reacti?ns p. This number is given by Mass transport by convection Pe = Mass transport by diffusion ( L2 = D.that bind to antibo. the dIffUSIOn time increases as the square of this distance.j )( Ilil. the average velocity represents the characteristic velocity. however. to the receptor produces a change tn the three-dimensional spatial organization of the portion of the receptor exposed to the cytoplasm. he average velocity o~ flui? moving through the tissue is proportional to the change m the pressure drop with distance.1 1. 0. When the Peelet number is much less than unity. For example.\ Convection is essential to transport larger molecules-such as proteins-and cells. Conversely.D. In many cases.3 Relative Importance of Convection and Diffusion :r 1. On the scale of t~e 'pores (e.1) ~)(tr<'\ I 1 where v is a characteristic velocity and L is a characteristic length. Over a scale much larger than the dImensIons of the matrix (e. One advantage of cell signaling IS that a single molecule can initiate a·reaction that pr~duces ~any. When hor~ones and proteins bind to receptors on the cell membrane.g. For a fixed-length scale and velocity. also known as a ligand. Some binding interactions can e~able cells to transport molecules against a concentration gradient. Such changes in structure are known as conformational ~hanges.. 10-100 urn).systems. Thus. diffusion is more rapid than convection. known as transporters.2. These interactions can be described with methods of chemical kinetics and equilibrium.01-:-10 urn). some reactions of membrane-bound proteins ~\.rovide a means of chemical recognition. Such reactions are said to be diffusion limited. Clearly.3.4 Quantity Proteins and nucleic adds Organelles Cells Capillary spacing Organs Whole body Source: From Ref. blood flow is very slow and oxygen is transported to local tissues by convection. Such a process ISreferred to as endocytosis. III!I! II Length scales in biological systems range over eight orders of magnitude (Table 1. The matrix provides structural rigidity to the tissue. At short distances.3 Transport by Binding Interactions !n addition to being affected by convection and diffusion. Introduction .. no single transport process can function efficiently over these lengt~ sca~es. Over the dimensiohs of a cell (10 pm). The immune system cells can now digest the foreign molecule or cell. One approach is to calculate the Peelet number. It IS porous. In the smallest blood vessels. which can then produce a biological response. and water can flow between the matrix molecules.g. Flow in tissues is examined in Chapter 8. selective transport.. diffusion becomes increasingly less efficient.3 Relative Importance of Convection and Diffusion 9 iii!":!'" !' I s~gnifica~t amounts of polysaccharides.. convection typically transports molecules over distances for which diffusion is too slow. and cell signal amplificerion. bind to ions and small molecules. blood transports oxygen bound to hemoglobin in red blood cells (known as erythrocytes) over large distances in the larger blood vessels of the body by convection. molecular transport is mfl. S~ch mteracnons are known as binding interactions and are specific. convection is the dominant mode of transport.uenced by no~co~alent interactions between two molecules. concentration gradients may still arise if the molecule reacts very rapidly relative to the speed at which it is transported to the reacting site. which represents the ratio of mass transport by convection to mass transport by diffusion. The significance of diffusion versus convection can be evaluated in two equivalent ways. Many weak interactIo~s betw~en binding molecules can produce a net interaction that is quite stable. Specialized molecules 10 the cell membrane. the relative importance of diffusion or convection varies with the specific situation. diffusion is highly efficient for internal transport. the relationship is different.to those applied to fluid moving in a tube. In so~e c~ses.:1. when a foreign molecule or cell enters the body. antibody binding enables the immune system to recognize and remove foreign molecules and cells. Because of the different length scales in biological. enabling them to pass across the cell membrane. ~il ~ III1 I: I Length scale (m) 10-8 10-7 10-6 to 10-6 10-4\~ lo·t.dies are known as antigens. .' (1. when the Peelet number is very large. . [4].

11"11 Cell Ipm 5 X 10 8 'l Ojrm 'IIr III 5X 5X 10-9 10-10 Note: For L 100 pm. 10-3 10-2 10-1 I Distance (ern) . phospholipids account for more than half of the lipid component of the plasma membrane. Proteins embedded in the cell membrane serve as the means to specifically transport these solutes and to transmit signals.\. The elapsed time for the delivery of these molecules is on the order of a few minutes. convection is slower than diffusion whereas f I p di ranees. and cholesterol accounts for 28% of the weight. t e time for convection is always equal to \. For proteins difs::~:rl(l~n p~ ~e3tob~oces.4 I Transport Within Cells In order to regulate the movement of molecules into and through cells. the nervous system uses electrical conduction of signals through transmembrane ion movement and the release of neurotransmitters.. export of proteins (Golgi apparatus). diffusion is efficient for distances on the order of 100 pm. An extensive network of membrane-hound vesicles transports proteins to and from the extracellular fluid and between organelles. requires a much faster response time than can be accomplished by convective transport through blood and diffusion in tissues. What follows is a summary of the mechanisms that exist to selectively transport and target molecules within the cell.2 Effect of distance on diffusion and convection times.67 Pe 0. ffi . diffusion is slower than convection. Endocytosis is the major mechanism to transport larger molecules that cannot permeate across the cell membrane.05 0. An alternative way of comparing the relative roles of diffusion and convection ISto compare the times required for a molecule to be transported b h The Peeler number is equivalent to computing the ratio of the Yd~fafc .1 Transport Across the Cell Membrane The cell membrane-or plasma memhrane-consists of lipids and proteins. I USlOntimes and convection times change with distance trans orted For short distances. specialized mechanisms have developed in cells to transport molecules efficiently. og.000 20 200 2. em. and cell division (nucleus). ri (td .~.. The lipids themselves are subdivided into three groups.<:1 '"<:1\ nb \'" 1'co oc on ria 1 mem rane) are of reactants to the membrane.000 150. C'.3 and Table 1. and if vII all molecules and particles.og pot t at s ow.'. Body movement." 2. hormones) that are transported through the blood is limited by the oxygen-delivery requirements.4 -Transport Within Cells 11 TABLE 1. Such molecules may he involved in cellular nutrition or in the transfer of ~gnals from the cell exterior to the cell interior.s Figure 1 2 span th fI f e cients s own III fusi . Ion gradients are maintained across cell membranes. or sma mo ecules such as gases.) . .-. The dynamic response of other molecules (e.000 Diameter 2 X 10 5 2 X 10-6 1 X 10-6 6 X 10-7 Diffusion time. By weight. 105~ -ill I ~ Convection. The diffusion co ffi ' ho .g.W"" I b" !II IIIII~ h dO.. In addition to diffusion.5 Oxygen Glucose Insulin Antibody Particle Virus Bacterium 180 6.000 20.. Chemical reactions lead to a decrease in the concentration of the diffusing molecule and reduce the distance over which diffusion is an efficient process.proc~ss.1 urn ". sufficient to meet normal demands. Sphingolipids account for 17% of the lipid weight.L2/ Dij) to t he time for convectIOn (t "" L/v) Figure 121's a I 1I usion time e Ih show h diffusi . \f'" . glucose. protein degradation (lysosomes). motor proteins can qury SOlutesover long distances. In addition.50 1. and cholesterol. The cardiovascular system uses convection to optimize oxygen delivery to the various organs.l X __ 10-4 em 5:"1 -~ Diffusion. ~""' I '-J<tl.g. Therefore. or urea. h urn s . ' . at speeds as high as 500 m S-1.e range 0 va ues or proteins and small solutes...".. L2/Dil (s) Pe Lv/D" 5 50 100 167 Diffusion time (s) 0. sphingolipids. transport is governed by interactions of solutes with specialized proteins. 0-6 1 cm2 5 -1 tIl . this distance is about the normal spacing between capillaries in many tissues.000 L/~ = 100 s for \ .4. The cells of higher animals are complex structures consisting of many organelles (Figure 1.000 200. Much of the organization of cells is a result of the need to regulate the transport of molecules between the cell and extracellular fluid and between the cytoplasm and various organelles. phospholipids. Phospholipids and sphingolipids are amphipathic molecules-containing both hydrophilic and hydrophobic !~I FIGURE 1. Interestingly. Transport within cells is highly regulated and complex.10 Chapter 1 Introduction 1.h elusion ' diff 1.6) that perform specialized functions such as protein synthesis (endoplasmic reticulum). ' or onger ISoften (e. The distance at which transport by the two processes becomes e ual i l~vers~ly related to the diffusion coefficient.0 1. ~r dime~sionls on the order of the size of a c:lI ~r . the reaction of oxygen with enzymes on the mit rmute d by t. however. Cells use the energy of the 'ions to drive chemical reactions and to transmit information.!2- 102 101 10° 10-1 10-2 10-3 S E:: Q) 1.

Lysosome is an organelle that contains proteolytic enzymes at a low pH and is involved in protein hydrolysis. the regulated transport of Ions and molecules across the cell. ions. Cholesterol increases the rigidity of the . dissolved gases. keratins. There is a greater concentratl~n?f negatively charged lipids on the cytoplasmic side. These molecules enable membranes to fold and form vesicles.I~. the attachment of cells to other cells or to the extracellular matrix. Ribosomes are macromolecular complexes involved in the translation of RNA to protein. The two nonP?lar hydrocarbon tails reside in the interior. and the transmission of signals from the extracellular fluid to the cell interior. Protein channels and receptors permit selective transport. Lipid metabolism occurs in the smooth endoplasmic reticulum. The cytosol plus all organelles except the nucleus is called the cytoplasm. and vimentin) that provide structural support for the cell and regulate movement of proteins and organelles. Although some proteins can diffuse freely within the plasma membrane.II I. Transfer RNA (tRNA) transports amino acids to the ribosomes.4 Transport Within Cells 13 ~--------- Plasma membrane TABLE 1. Mitochondria are organelles that generate energy from glucose and oxygen. Both lipids and prot~ins contain charged sugar groups (referred to . the lipid composition of an organelle differs from the compositions of the membranes of other organelles. thereby preventing direct interaction between lysosomal contents and the cytoplasm. Proteins serve many important functions ~n the binding of molecules from the extracellular fluid. Endoplasmic Reticulum is an extensive membranous network in contact with the plasma membrane. which spa~ the membrane. FIGURE 1. eukaryotic cells have a nucleus and organelles. many are segregated into distinct regions. where ribosomes are assembled.3 \ Coated pit with receptors I 1'1 [J II:. The rough endoplasmic reticulum contains ribosomes bound to the membrane and is the site of protein synthesis.4).4) and charged polar and hydrophIh~ h~ad groups (the spheres attached to the squiggly lines in Figure 1.ospholipids and sphingolipids consist of long chains of nonpolar and hydroph??lc hydrocarbons (the squiggly lines in Figure 1. Vesicles containing proteins fuse with lysosomes.n:embran~ and ?ecreases the permeability of the phospholipids. the growing peptide chain moves into the endoplasmic reticulum. to another protein. Source: Adapted from Ref. [5J. "'"!I '!~I I:' II" !. Actin microfilarnents are involved in cell motility and muscle contraction. The polar po. The lipid comPOSltlO?S on either ~Ide of the pla~n:a membrane are different. regions. Ph. During translation of RNA into proteins.' "] J results from protein-protein interactions in the membrane and protein binding to the cytoskeleton. tubulin. showing the major organelles. proteins. Microtubules are involved in nuclear division and cell mitosis.. RNA synthesized in the nucleus binds to ribosomes.rtIOn of phospholipids and sphingolipids is on the outer portion of the membrane. The polar portion of cholesterol is also directed toward the exterior of the membrane. Vesicles bud from the Golgi and fuse with the plasma membrane or the membrane of other organelles. which is used in various metabolic reactions. Communication between the nucleus and the cytoplasm occurs through pores. and the cytoskeleton. The lipid composition of plasma membranes varies among cell types and species. The lipids can diffuse f:eely within the plane of the plasma membrane but cannot easily move from one Side of the membrane to the other. small polar molecules. Peripheral proteins are present on only one SIde . in contact with extracellular or intracellular water. The lipid membranes are impermeable to larger biological molecules. Golgi Apparatus is a membranous network involved in protein secretion and organelle formation. Also present within the nucleus is the nucleolus. Proteins for export are secreted into the endoplasmic reticulum. Mitochondria store energy in the form of adenosine triphosphate (ATP). which transport molecules into the cell from the extracellular fluid or from receptors present in the cell membrane. I Schematic of a mammalian eukaryotic cell. Microtubules are polymers of tubulin that interact with the proteins kinesin and dynein to selectively transport ~olecules and org~nelles within cells.12 Chapter 1 Introduction 1. which consist of a protein complex that controls both the movement of proteins that regulate DNA transcription to messenger RNA (mRNA) and the transport of RNA from the nucleus to the cytoplasm. Note: Prokaryotic cells have no nucleus or organelle. The cytosol consists of water. The endoplasmic reticulum is the site of synthesis of proteins and lipids found in the plasma and organelle membranes. Ili" Cytoskeleton represents networks of filamentous proteins (actin.I'! !I "11" 11: 1 I '. J:i . or peripheral proteins.6 Plasma Membrane consists of a lipid bilayer containing proteins that separates the cell from the external environment. This segregation I lil'~. The lipid bilayer is permeable to gases and small nonpolar molecules.. Intermediate filaments provide structural suJ3'portfor the cell. Cytosol is the intracellular fluid in which all organelles reside.of the plasma membrane. either partially embedded in the plasma membrane or linked ~o the molecule's polar group or. are classified as either transmembrane proteins. Th~ proteins m cell membranes. Nucleus contains DNA in the form of chromosomes bound to proteins known as histones. thereby releasing their protein contents.' ' Coated Pits and Vesicles are specialized regions of the cell membrane containing clarhrin and other proteins. In contrast. where it undergoes conformational changes and chemical modifications. Similarly.

The transport of large peptides and proteins into cells involves receptor-mediated endocytosis. As discussed in Chapter 7. ~ave high pe~meability across lipid bilayers. Since transport occurs by the binding of solutes to earners.. Due to the differences in the polarity and s~r~c~ure. respectively) that are involved in the binding molecules and ill mtracellular signal generation. urea) have ~uch lower pe~meablhty across lipid bilayers. which are transmembrane proteins that are classified as either earners or channels. Other carriers transport two solutes in the same direction (symporters) or in opposite directions (antiporters). Some carriers. diffusion across the lipid bilayers is more complex than It IS ill SImple fluids such as water [6].0-. Consequently. Carrier-mediated transport produces a no~IInear relano? between the rate of transport and concentration (Figure 1. Ions an? .. Hydropho~ic molecules. glucose. The ligand binds reversibly to its receptor on the cell surface. and they are selective for specific ions. . The molecule binding to the receptor is often referred to as a ligand... Surprisingly. . transport is affected by the electrical potential and concentration gradients. such as ethanol. mechanically. referred to as coated Pits. Transport by Receptor-Mediated Endocytosis. contain binding sites for receptors. ~t high concentrations.. with a dissimilar solute. For charged molecules. are known as uniporters and transport a single solute...4 10 20 Transmembrane channel protein 30 40 Concentration (fJ-M) 50 Schematic of a section of the cell plasma membrane. Several features distinguish carrier-mediated transp~rt from sl~ple dIffUSIOn(see Chapter 14). sodium. Such regions. allowing the solutes to diffuse through the proteins. the perme~blhty IS proport1~n_al to the solubility of the molecule in organic solvents. via a structurally similar solute or noncompentIvely.g. 1.. The rate of transport through channels can be as much as a -rhousand times faster than transport rate by carriers. ' 3Transport of uncharged molecules is in the direction of the concentration gradient. Ion channels playa major role in regulating transmembrane electrical potentials.S Comparison of carrier-mediated transport and diffusion across cell membranes. transport can occur only in the direction of thevelectrochemical gradient. Interest~ngly.sport can be blocked competitively.f The required eIlergy often derives from the hydrolysis of the molecule adenosine triphosphate (ATP)~ coupled with the transport. . N2. coupled with ion transport down an electrochemical gradient. tr~n. Channel proteins transport ions. Saturation arises because the carrier sites become occ~pIed as fast as they appear. of Lipid bilayers are model membranes that exhibit limited permeability to molecules. Some receptors diffuse over the cell surface until they Contact a region of the membrane that contains the protein clathrin on its cytoplasmic side. uncharged polar molecules.--------------------~~~==~~ I ~II . The transport of a solute against an electrochemical gradient. 0 0. the rate of transport becomes independent of concentration In a p~ocess known as saturation. Channels can be opened (or gated) electrically. or chemically. such as the glucose carrier that is present on many cells. 0 (]) ~ ~ 5 0 filaments FIGURE 1. as glycolipids ~n? glvcoproteins.g. and CO2) and small organic mole. Small polar solutes (e. such as gases (Oj. and amino acids) have low permeabilities across lipid bilayers and are transported across cell membranes by t~ansport proteins.Ility across lipid bilayers. water exhibits a relatively high permea.5). of the membrane.. Transport can be energy independent if the solutes are transported down an electrochemical gradient. Alternatively. active transport may be involved if the transport Occurs against an electrochemical gradient.. does not involve AIP hydrolysis and is referred to as secondary active transport. § b <.b. these two processes generate an electrochemical gradient. ~he per~eabIiIty of anesthetic gases correlates with the solubility of the gases In the.cules...s~all polar molecules (e. Channels enable transport by providing hydrophilic pores through which solutes move (see Chapter 14). u: 25 20 15 10 1. interfacial polar head groups of the lipid bilayers. III "'·ill· I' !I'I ~i" I . Solutes bind to the carrier protein and are carried across the membrane due to a conformational change of the molecule. Transport across chann~ls occurs when hydrophilic pores open within the proteins. For small..4 Transport Within Cells FIGURE ! 14 Chapter 1 Introduction 15 Phospholipid Receptor Cholesterol Peripheral protein Glycoprotein 30 . The Channel Transport~ I Carrier-Medl~ted Tran~port. These channels are critically important in electrically condUctive cells such as nerve and cardiac cells.. The channels are in either an open or a closed state. The lipid membranes are virtually Imp~r~eable to I~ns.

in order to perform specialized functions. Solutes in the extracellular fluid are also internalized during vesicle formation. The vesicle fuses with secondary Iysosomes. diffuse through the cytoplasm. A number of membrane proteins (e. they dissociate from the carrier. The organelles and cytoskeleton offer barriers to diffusion. For example. Ql ] u + + til V I I Ii I i 3: . and bind to receptors in the nucleus or the cytoplasm...g. which catalyzes the formation of cyclic adenosine monophosphate (cAMP) from ATP. are synthesized at ribosomes attached to the endoplasmic reticulum. where it undergoes another round of binding and internalization. Q o '" "§ -<t. the proteins undergo modifications and are sorted. known as endosornes. Ions may associate nonspecifically with charged molecules or bind to specific sites on proteins.. increasing the time for molecules to reach them. such as steroid hormones. This hormone-protein-DNA complex can then regulate the expression of genes. forms a continuous network... 00 I 17 . (Models of receptor-mediated endocytosis are considered in Chapter 11. Polar hormones and drugs exert a number of actions by binding to receptors on the cell surface. In addition.4. 1· • . The cascade of reactions enables tight control of the various steps and amplification of signals. and vitamin D. relaying signals generated at the cell surface to various sites within the cell. the rates of binding and reaction are limited by the rate of diffusion in the cell membrane. Within newly formed vesicles.2 Transport Within the Cell Many small molecules enter the cytoplasm and then diffuse to various parts of the cell. the pH decreases and the protein dissociates from its receptor. For example. The receptor is recycled to the cell surface.. Q. Newly synthesized proteins that are secreted from the cell are transported in vesicles by a pathway known as exocytosis. the calcium ion serves as a second messenger.) 1.6). the clathrin coat dissociates. This process is much less efficient than receptor-mediated endocytosis.. 1. retinoids. Small and hydrophobic hormones. bind to carrier proteins. Within the Golgi apparatus. destined for secretion or insertion into regions of the membrane. which.. hormones can stimulate signaling by activating a protein found on the cytoplasmic face of the membrane known as a G-protein (Figure 1. For some signaling molecules. these second messengers can stimulate cell division or regulate specific genes and subsequent protein synthesis.16 Cha prer 11 ntroduction ~i I ligand-bound receptor binds reversibly to an adaptor protein in the coated pit. The receptor-hormone complex enters the nucleus and binds to DNA. In turn. Once within the coated pit. After the vesicle separates from the plasma membrane. which transport these hormone molecules across the cell membrane. The cascade of events produces an amplification of the initial signal. The signaling process involves the activation of the enzyme adenylate cyclase. the ligand-receptor complex is internalized by the continuous formation of coated vesicles 50-150 nm in diameter. This binding event initiates a cascade of biological reactions that affect cell function. Within the cell. wherein the protein portion is degraded to its constituent amino acids or is used in subsequent metabolic reactions. The proteins then move into the endoplasmic reticulum. calmodulin) bind calcium and serve as stores for that element. the calcium ion can be transported inrothe endoplasmic reticulum and stored there. A large number of signaling pathways exist that can positively Of negatively regulate ion transport and generation of other second messengers. together with the Golgi apparatus. Proteins. The vesicles fuse with the plasma membrane and release their contents into the extracellular fluid.

For example. vesicles containing neurotransmitters fuse with the end of the synapse. Epithelial cells line the cavities of organs such as the intestines.functions are unclear. The apical surface has a large number of membrane folds known as microvilli. ". 7) [7]. Endothelial cells line all blood vessels and Lymph vessels. lateral.~--~~~~-.7. including epithelial cells. Following stimulation by electrical signals in nerve axons... which is connected to other epithelial cells via tight junctJo~s. The spaces between the membranes in tight junctions contain three different transmembrane proteins that form continuous linkages surrounding the cells.. communicating junctions. cuboidal. Gap junctions consist of 2. which is in contact with the extracellular space between the epithelium and blood ~essels. and anchoring junctions. !qr " I Outer leaflet of . liver. Variations in gap junction permeability among cells are due.. or adjacent to each other. These axons are needed to transmit electrical signals over long distances. and apical surfaces can be described.000 daltons. columnar. and act as selective permeability barriers between fluid on different sides of cells.. Epithelial cells are present at tissue interfaces. the exchange of solutes. Tight junctions are the principal determinants of the transport of small molecules between epithelial and.8). their. and secretory glands.. which provide a large surface 'Y'e<l. The proteins forming connexons can rotate to dose the pores in the presence of a small number of calcium ions or a high pH. known as axons. ---------. Two major types of cells regulate the transport of molecules within and between tissues: epithelial cells and endothelial cells. exhibit gap junctions.and the lateral side. The connections involve transmembrane proteins linked to the cytoskeleton. stomach. 19 I: Nerve cells can have very long appendages. The cells have a definite orientation. Like all epithelial cells. A second set of junctions involves intermediate filaments. intestines. The membrane properties differ on the surfaces that are exposed to the intestinal lumen and to the blood capillaries (known as polarity) in order to regulate nutrient transport to the blood (Figure 1. The various types of epithelia with a transport function are listed in Table 1. and basal.5. in different cell packing and orientation geometries (e. There are two types of communicating junctions: gap junctions and synaptic junctions.. These cells serve a number of fllnctions. _ plasma membrane Tight junction proteins I FIGURE 1. These proteins are also linked to the cytoskeleton. _ . including those in the stomach. The number of such linkages influences the degree to which transport between cells is limited. The permeability of tight junctions can be controlled by a number of stimuli that alter the interaction of the cytoskeleton with tight junction proteins. In some epithelial cells. Introd uction 1. to differences in connexon structure. are considered polarized. in part."where they interact with channels on the target cells..5 prn s-1. These channels transiently open. Anchoring functions connect cells to the extracellular matrix or other cells. depending on the cell location.5 Transcellular Transport . Since diffusion is inefficient over such distances and convection does not occur.7 Schematic of the arrangement of the tight junction. including secretion and absorption. 1. kidneys.JJ. Neurotransmitters rapidly diffuse across the small gaps between the nerve ending and target cells. endothelial cells (Figure 1...i. allowing ions to enter. lungs.g. which faces the intestinal lumen.. The result is transmission of electrical impulses along the nerves or the activation of muscular contractions. 1. adberens junctions afe linked to the cytoskeleton protein actin and can be found in the cell-cell adhesion belt and in cell-matrix focal contacts. which interact with microtubules and provide directed motion at speeds as high as 3-4. Epithelial cells are typically bound together in sheets. the~e cells consist of an apical side.5.: 1~~I=-.. a basal side. these motor proteins also serve to maintain the position of organelles. The hydrolysis of ATP provides the energy to drive the motor proteins. ~ells with membranes that provide different functions. 18 Cha prer 1 ----------------_. Connexons permit transcellular transport of electric currents and solutes with molecular weights less than 1. The openings form a channel connecting two cells by means of a complex of protein molecules known as connexons. The mechanism of transport in the space between cells involves a finely developed network of junctions. 1.2 Epithelial C~!ls .. In smaller cells. alone. Although many cells. Epithelial cells that line the interior of the small intestine regulate nutrient transport into the body.to 4-nm-wide openings between two cells. tight junctions enable the passage of specific ions. The cell membrane in each of these regions has a specialized function. and squamous).5 I Transcellular Transport The movement of molecules between tissues must be finely regulated for the optimal concentration to be reached in the cells and to prevent the accumulation of toxic molecules.1 Junctions Between Cells The junctions between cells can be divided into three types: occluding or tight junctions. and lungs.Ij. Synaptic junctions are specialized forms of connections that nerve cells make with other nerve cells or muscle cells. proteins and organelles are transported via microtubule motor proteins.

spleen. Cells involved in absorption brush border of intestine striated duct cells of exocrine glands gallbladder epithelial cells brush border of proximal tubule of kidney distal tubule cell of kidney epididymal cells 2. Continuous endothelia are found in all of the major blood vessels and capillary beds of the brain. These cells often rest on a thin layer of extracellular matrix known as the basal lamina. Fenestrated endothelia are present in the capillary beds of endocrine glands and kidney glomerulus. Discontinuous endothelia are present in the liver. [8].20 Chapter 1 Introduction TABLE 1. Occasionally. Their underlying extracellular matrix may be exposed to the capillary lumen. Lumen of small intestine Microvillus Glucose Na+ .5. Except for the capillary endothelia in the brain. In addition. © 1984 by the American Physiological Society. much like epithelial cells. and agents that cause vessels to dilate or constrict 1.10). or another cell type may be positioned between the endothelial cells. and discontinuous (see Chapter 9). Cells with an internal barrier function type I pneumocyte-lines air spaces of lungs duct cells of glands and exocrine organs glomerular epithelium collecting duct cells of kidney Specific carriers transport glucose and amino acids from the intestinal lumen into the epithelium. muscles. The energy for the transport comes from the movement of Na+ down an electrochemical gradient.to the extracellular fluid passively by means of a umporter. The junctions between cells permit the passage of molecules as large as 2 n01. Continuous endothelial cells make adherens junctions with the extracellular matrix. A prominent feature of continuous endothelia is an extensive number of vesicles. The ~ndothelium (e) overlays a basal lamina (bl) and muscle cells (m) and exhibits a vesicle (va) III contact with the basal lamina.9). The tight junctions of these cells are not as extensive as those found in epithelial cells. Molecules are transported across the endothelium in several ways. heart. and lungs (see Figure 1. The lining is called the endothelium and it regulates transport. Solute transport between epithelial cells is blocked by the presence of tight junctions. very leaky junctions are qbserved. Discontinuous endothelia are not connected to each other.5 TransceUuJarTransport 21 1. Shown in Figure 1. fenestrated.) grom . The fenestrae (from the Latin word for window) are openings in the plasma membrane between the capillary lumen and the underlying tissue or basement membrane (Figure 1. In' order to maintain low Na+ concentrations within cells an ' enzyme k nown as N a+IK +-ATPase hydrolyzes one ATP to adenosine diphosphate (ADP) and drives three Na + out of the cell and two potassium ions (K+)into the cell. endothelial cells regulate coagulation and the adhesion of leukocytes.9 I I' Glucose "~l___ 1 A continuous endothelial cell type from a vessel in the rat diaphragm. Junctions similar to those found in continuous endothelium connect fenestrated endothelial cells. glucose is transported. On the basal ~urface. the fenestrae contain a diaphragm that may serve as a molecular filter.3 Endothelial Cells Endothelial cells line all blood vessels. Ref. Vesicles are present throughout the endothelial cell (vc). These are not transient structures.. These endothelial cells are connected to each other by a system of gaps and tight junctions. and bone marrow. e I Schematic of a portion of an epithelial cell sheet showing directed transport of glucose from the intestinal lumen into the tissue.8 is a glucose symporter that moves glucose and sodium ions (Na+) from the lumen of the intestines into the cell.8 o Epithelial cell ADP II FIGURE 1. and the plasma membrane remains continuous.7 1. the junctions of continuous endothelial cells are permeable to solutes as large as 2 nm in radius. FIGURE 1. Used by permission of xford University Press. In some cases. There are three types of endothelial cells: continuous.

and regulation. as a result of infection.6. Alterations in transport across endothelium are important in a number of diseases. In addition.) Urea synthesis Metabolism of toxins Filtration of plasma Removal of urea and waste products Water reabsorption Maintenance of plasma volume and blood pH Kidneys 1'1 1. organs that have interrelated and coordinated functions ate grouped together into organ systems. Used by permission of Oxford University Press. solely of one type of celt since they require a blood supply and innervation for communication. [8]. (From Ref. In edema. and produces clots following injury to blood vessels. The fenestrae (arrowheads) are neal the peripheral portion of the endothelial cel!s (e). Organ or organ system . [ps) pericapillary space. The distance traveled by vesicles is about 1 urn. An important function of a number of organs and organ systems is the transport of molecules for growth. alterations in fluid transport across the kidney glomerulus can significantly affect kidney function. brmgs waste products to the kidneys for filtration. to an alteration in the permeability of arterial endothelium to proteins. lymphoid. vesicles have been observed to fuse. In fenestrated endothelium. muscle. (bl) basal lamina. atherosclerosis is due. Edema can arise from elevated blood pressure or damage to the endothelium.6 Chapter 1 Introduction Physiological Transport Systems 23 TABLE 1. fluid accumulates in the extracellular space of tissues. albumin. repair. the liver. and the reproductive system. Examples include the digestive system. blood vessels. transports molecules and cells of the immune system to sites of infection. creating equilibrium between concentrations in plasma and the subendothelial space. 1 Respiratory system Cardiovascular system Delivery of oxygen from [he lungs to the blood and transport of carbon dioxide in the opposite direction Transport of oxygen within red blood cells Removal of carbon dioxide Delivery of antibodies and cells of immune system to sites of infection Thrombosis and hemostasis Digestion and absorption of nutrients Carbohydrate storage and release Cholesterol metabolism and lipoprotein metabolism Synthesis of plasma and transport i' Gastrointestinal Liver tract synthesis and (e.6"1 Physiological Transport Systems Most animals are composed of highly organized arrangements of cells known as tissues ~nd organs. the respiratory system. and the kidneys. and connective tissue IS]. nutrition. many proteins can pass through fenestrae. The major types of tissue are nerve.II also increase the junction permeability.22 1. . In turn. The follOWing discussion focuses upon five organs and organ systems that have signifiCant transport functions: the cardiovascular system. blood transports nutrients and hormones to various organs. © 1984 by the American Physiological Society. many cells of a similar type are needed to perform a specific function and are grouped together in a tissue. Organs are tissues grouped in an organized fashion to perform specialized functions. Tills-process can occur in the fluid phase or by the binding of macrom~lecules to receptors on the endothelial cell surface. Although vesicles can transport low-molecular-weight molecules. 1. and communication (Table 1. (ep) epithelial cell. forming transient channels. for example. nourishme~t. blood.111 1· . the gastrointestinal tract. These changes in permeability involve coordinated interactions between the cytoskeleton and junction proteins [9]. Tissues themselves are not composed The cardiovascular system consists of the heart. In another condition. in part. the vesicular pathway accounts for a small fraction of the transport of water and of small solutes. and blood.8).g. Often. the respiratory system.8 Examples of org'!~l ~nd Organi~y~tems wlth'!ransport Transport functions Fu-:ac:tions. proteins transferring) Synthesis and export of molecules for tissue energy metabolism FIGURE 1."epithelial.1 Cardiovascular System 1. Finally.Example of fenestrated endothelium. Macromolecules are also transported across endothelium by vesicles. (I) vessel lumen. (c) transendothelial channel. The primary function of the cardiovascular system is to transport oxygen from the lungs to th~ tissues. [rnv] multivesicular body. In addition.10 . summarizing the transport functions and the relations between anatomy and physiology.

.the arterial wall are ated wlthtn the adventitia. Aorta . each with an atrium and a ventricle. while venous blood has low oxygen concentrations. The beating of the heart is under neural and hormonal control.leaves the heart through arteries and returns via veins. and extracellular ~a~rix. The C entttla IS a layer of loose connective tissue. I I l I I I ~ Stomach and spleen Intestines Kidneys Trunk and legs i I Mesenteric arteries Renal arteries . 'During vigorous exercise. Valves separate the atria and ventricles and maintain flow in one direction.. arterial blood is oxygenated.24 Chapter 1 Introduction 1. such that their heart rate mcreases only 50%-75%.the heart receives blood from the venous system and pumps it to the lungs (Figure 1. and fibroblasts. that is.. FIGURE 1. the atria contract. the cardiac output (CO. IJ I I Portal vein . the left ventricle is more muscular than the right ventricle. . The arterial system transports blood from the heart to the tissues.tissue that transports blood (Figure 1.12 Diagram of the heart showing the four chambers.11). The ventricles fill until the ventricular pressure exceeds the pressure on the arterial side. it needs to generate a higher pressure.-- Right atrium Pulmonary artery Right ventricle . In order to reduce backflow. Blood. valves exist between the ventricles and blood vessels and between the atria and ventricles. During training..measured in liters) and the heart rate (HR. I. valves. Because the left side of the heart pumps blood to all of the body except the lungs. I iliac arteries Simplified schematic of the blood flow distribution throughout the body. The cardiac output is the amount of blood per minute that flows from the heart. The stroke volume also changes with exercise. The atria and ventricles beat sequentially. The venous system transports blood from the tissues to the heart. I 11 J Tricuspid valve Ii. forcing blood into the ventricles.- Coronary arteries :1. 'I ~ I r I 1 stroke volume (SV. Relaxation of the cardiac muscle causes the atria to fill. Blood vessels consist of endothelium. Collagen. l " ~ 1 Lungs Pulmonary vein Vena cava 1.1... The aortic and pulmonary valves then open. The media consists of extracellular matrix and smooth muscle cells beneath the internal elastic lamina. When the ventricular pressure exceeds atrial pressure. the media. the heart rate can rise to 150 beats per miqute.axa~ion of the smooth muscle cells regulate the blood vessel diameter. where it is pumped to the body.1 II! 111. present in the extracellular matnx. Thus. measured in liters per minute) is the product of the = SV X HR.1 Superior vena cava Inferior vena cava !~ Hepatic vein W I Head and arms Brain Liver Brachiocephalic artery Carotid arteries Celiac artery r Left atrium Left ventricle Vena cava FIGURE 1. lo~PllIarie~a~d lymphatic vessels supplying the outer portion of.. (1. and veins leading into and arteries leading away from the heart.1) The cardiac output in r~sting individuals is about 5 L min'". and the adventitia. CO 1 II!II 'I I I I I . smooth muscle cells. Blood then passes into the left side of the heart.. and blood flows toward the organs. providing structure and elasticity to the ~essel. Arteries consist of three layers: the intima. The atria receive blood from the body. measured in beats per minute).6.11 I . Once full.. The heart is a four-chambered pump consisting of muscle. elastin and glycosaminoglycans. The stroke volume is the amount of blood ejected during each heartbeat. Except for the pulmonary artery and vein. I The right side of. athletes ~re able to increase their stroke volume substantially.6 Physiological Transport Syst~ms 25 I Ii II . are responsible for the mechanical behavior of the blood vessel. and the resting-heart rate is between 60 and 72 beats per minute. The microcirculation consists of smaHblood vessels in which solutes and solvents are exchanged with the tissue. Contraction :~~ rel.12).. The system of blood vessels is divided into three main parts. and the cardiac output can increase to as much-as 25 L min-I. the atrioventricular valves close. It is divided into left and right parts. The intima comprises the endothelium and a layer of extracellular matrix consisting of proteoglycan and collagen. smooth muscle cells. Consequently. The ventricles pump blood to the organs.

10 Total (%) 45-53 15 10-12 8-11 10-12 4-5 Region Small arteries Arterioles Capillaries Venules Veins Total (%) 15 50 20 5 10 fa = CO X R. :Il About 85% of the total vascular resistance occurs in the small arteries. . known as edema. Thisfluid accumulation. blood p~. The medial layer consists of one or two sublayers of smooth muscle cells. Veins are exposed to lower pressures th~n arteries and have thinner walls than arteries. increasing heart rate. Edem~ can occur in many kinds of tissue.lOtic pres~ure. This net pressure difference causes fluid flow from the capillaries into. variations in blood pressure due to the heartbeat are much smaller (30-70 mmHg). have a limited ability to contract or dilate. For blood to pass ~hr~ugh smaller capillaries. In resting individuals.'il II i~. These vessels consist of a single layer of endothelial cells and a thin basement membrane. Arterioles control arterial blood pressure by contraction and relaxation of smooth muscle cells. Neurotransmitters transmit the signal generated by t1:~ nerve to the effector cell." with the time-averaged artenal pressure typically equal to 95 mmHg. the lymphatic system is unidirectional. by an osmotic pressure difference arising from a difference in protein concentration within the blood and the interstitial space (often referred to as colloid osmotic pressure or oncotic pressure). which operates in a loop. During exercise. Consequently. Arterioles can relax 60%-100% and constrict as much as 40%-50%. the largest pressure drop in the circulatory system occurs between the small arteries and the end of the capillary endothelium. Capillaries are sites where fluid and mass are transferred between the blood and the tissue. his mnervation is responsible for maintaining blood pressure. collagen. heart rate. The norepinephrine binds to receptors.6. Veins are thin-walled vessels that receive blood from venules and transport blood to the right side of the heart. In ~ nu~ber of disea~es. Due to a small pressure difference. Correspondingly. can arise from damage to the lymph vessels. Two types of nerves control heart function: sympathetic nerves.as adrenergic receptors. and parasympathetic nerves. The mean arterial pressure Pais the product of the cardiac output (CO) and the resistance (R) offered by the blood vessels of the circulatory system. Although the flow of interstitial fluid in each tissue is quite low. Large arteries contribute negligibly to vascular resistance. while ~here is a significant increase in flow to skeletal muscle and the heart.The s~ructure of the vascular system is adapted to its function.) Parasympathetic nervous stimulation of th~ heart resu ts rn the release of the neurotransmitter acetylcholine. that is. .9).9 Region Small veins and venules Large veins Lungs Heart Systemic arteries Capillaries TABLE 1.10). the red cells must deform and proceed through the tubes m single file. Because of the absence of smooth muscle cells. such as hemorrhage. which consist of an endothelial cell layer and a single layer of smooth muscle cells. TABLE 1. The lymph vessels connect to two main vessels that drain into the venous system. Typical blood pressures range ~etween 80 and . and elastin. ' Blood leaves capillaries and flows into uenules. or a decrease in colloid osn. This volume can decrease in response to injury. Sympathetic nervous stimulation of t ll heart results in the local release of norepinephrine from the synapses of nerve ~e Is. Pulmonary edema. i I ~I ~I II . blood volume.w----.0133 X I 4Blood pressure is typically reported as mmHg.lC~ stimulate the heart. cell (s nne IS a neurotransmitter-a molecule released at the connection of a nerve cell to a muscle ynapse). Unlike the circulatory system.0133 106 gYJ) cm-z) equals 760 !P. (Receptors to which epinephrine and norepinephrine bind are no~n.J. capillaries. ~n elevation of the capillary pressure or capillary permeability. X (1. in part. which binds to receptors to redUce heart rate and conduction velocity.6 Physiological Transport Systems 27 II Il '~I Iii I I I'l I. the net drainage into all of the tissues amounts to several liters per day. organs involved in nutrient and fluid exchange. unlike arterioles. blood flow to the brain is maintained constant. .ig. A pressure of 1 atm (=1.2) 105 Pa=1. Capillaries are typically 2-6 urn in radius. which slow down the heart.'~ !I I I . I. The blood-flow distribution to organs varies widely and is significantly altered during exercise (Table 1). 5Noreplneph" . and carbon dioxide levels. arteries have a high content of smooth muscle cells. there is a local accumulation of fluid in the interstitial space. arterioles. oxygen levels. and capillaries (Table 1. A hydrostatic pressure difference between the capillary blood and the tissue is offset. skeletal muscle. ~h. the flow to digestive organs is reduced dramatically. Blood pressure. Because of the Importance of the brain. and hence cardiac output are under neural and hormo~al control. which can anse from mitral stenosis or heart failure can severely impede breathing.120 mmHg during the cardiac cycle.the tissue and enhances convective transport of macromolecules in the interstitial space. fluid leaving the tissues is collected by a system of lymphatic vessels. conduction veloc~y. Venules are exposed to pressures between 10 and 16 mmHg and serve as reservoirs for blood. These vessels undergo radial dilations of 10%-15% during each cardiac cycle. and contractility. In the smaller arterioles. The arterial system IS a high-pressure and high-flaw-rate system. This distribution is essential for the efficient transport of oxygen and metabolites. About one-third of all the blood in a resting individual is stored in venules (Table 1. and the brain receive the greatest amount of blood flow..1).!!!..j "I I: 26 Chapter 1 Introduction 1.

Within cells. This sequence of dlvldmg airways continues for 23 generations (Figure l. mature in the bone marrow.60 5. and removes carbon dioxide. disso. where they complete their immune function. platelets bind rapidly to the extracellular matrix and release a number of molecules that promote the coagulation of blood cells and clotting proteins. At a site of infection.00 0. and muscles (diaphragm). and proteins. acetylcholine binds to cholinergic receptors to produce vasodilation. I I~ I Sympathetic nervous stimulation of most arteries. At the lower blood-plasma concentrations of oxygen in tissues. and chemical reaction. Once the monocytes are inside the tissue.] is bound to hemoglobin.75 0. eosinophils.80 Percent Of cardiac output 24 19 13 Percent of cardiac output I 4 21 9 10 100 0. Respiration involves the intake of oxygen through the nose.6. These adhesion receptors. B cells reside in the spleen and lymph nodes and release antibodies that bind to molecules (antigens) that are present on pathogens (viruses.65 4 3 4 85. all working in a coordinated fashion to regulate ?reathing. Molecules that dilate or constrict blood vessels also alter the permeability of the endothelium to water and macromolecules [9].10 0. The metabolism of oxygen produces ATP by a series of coupled reactions. (Models of adhesion and the role of transport processes are discussed in Chapter 12. Selectins bind rapidly to their counter-receptors.0 from Ref.25 1. each of wtich diverges into two bronchioles. Red cells.ungare involved in warming and humidifying the air. First. Sympathetic nerves that release acetylcholine also innervate skeletal muscles. These molecules bind to counter-receptors on endothelium and cause the leukocyte to stop rolling and become firmly arrested. the gas exchange units.90 L min"! 1. Cells and molecules of the immune system are transported from sites of generation through the cardiovascular system to sites of infection. and neutrophils).2 Respiratory System The respiratory system delivers oxygen to tissues. The local release of molecules that cause blood vessels to dilate (vasodilators) or constrict (vasoconstrictors) influences the flow through the vessels. diffusion. capillary bed.known as integrins. v . _ Cells of the immune system reach sites of infection via a sequential adhesion process (12\. lungs. . The trachea terminates I~t~ two bronchi.I~ 28 Chapter 1 Introduction 1. Over somewhat longer times. This initial contact causes the leukocytes to slow down and begin rolling. which then bind to antibodies bound to antigens and ingest foreign molecules or cells by phagocytosis.50 0. known as alveoli. and veins releases norepinephrine. A clot is an aggregate of red cells. platelets" and the protein fibrin. and foreign molecules). Because of its low solubility in plasma. Convective transport through the blood carries t e oXygento tissues. venules.) .30 0. Further interactions between integrins and their receptors cause the leukocytes to migrate between endothelial cells and enter the tissue. nervous system. When portions of the extracellular matrix are exposed to blood after injury or damage to the endothelium. T cells can bind to antibodies that are in turn bound to antigens. Neutrophils respond more rapidly. except for T cells. Beginning at the 15th generation of bronchioles. which is an oxygen-carrying protein :V1thm red blood cells. bind to counter-receptors on leukocytes. Platelets produce clots following damage to blood vessels. Blood flow in the microcirculation is under local regulation. The upper airways of the I. The formation and growth of blood clots involves interplay among convection. blood and consists of water. I I' 1. In skeletal muscle.40 1. ~igen participates in the conversion of glucose to chemical energy in the for~ ~f blo~d~he carbon dioxide produced by these reactions diffuses from the tissues into e riquiid phase 6Plasma is th 0 f .11 Bloo~ Flow Distribution Region Digestive system Renal Brain Heart Skeletal muscle Skin Others Cardiac output Source: Adapted during Rest and Heavy Exercis4_! Rest Heavy exercise Lrnin"' 0.75 1. chemicals produced by the pathogejis. Vessels respond rapidly to an increase or decrease in arterial or venous pressure and passively adjust local blood pressure toward the value present before the perturbation.60 0. T cells mature and form subclasses in the thymus and migrate to the lymph nodes [11]. [10). chemical signals from the pathogen or other immune system cells cause the monocytes to transform into macrophages.6 and bound to hemoglobin. ATP provides chemical energy for many biochemical reactions.00 22.lv~din ~lasma. most of the oxygen I~ bloo. white cells ibasophils. sugars.13b).20 0. monocytes invade a site of infection. appear. T cells and B cells respond to pathogens over periods of days to weeks. arterioles. The binding of selecrins to their receptors activates a second class of molecules on leukocytes. subsequent breakage of bonds as the bonds are stressed.Transport Systems 29 TABLE 1. expressed on the endothelial cell surface. or the pathogens themselves. The respIratory system consists of the nose. Gas exchange occurs in the lungs (Figure 1. Smooth muscle cells in blood vessels contract when stretched and relax after the stress is removed. trachea. yeast. Oxygen exchange erween the air and blood occurs in the alveoli. where it is metabolized. Oth~r functions of the respiratory system include the regulation of blood pH. monocytes.5 2 0. Capillaries Surround each alveolus.10 25. a process that involves the rapid formation and. mast cells. bacteria. blood flow changes 'in response to various stimuli. followed by conbectlve transport of the oxygen to the larynx and the lungs. larynx. Oxygen is transported in blood. diffuse to the endothelial cells and stimulate those cells to make proteins. OXygen dissociates from hemoglobin and diffuses into tissues and cells.6 Physiological. and platelets form and. ions. amino acids.13a).I3-adrenergic receptors and causes vessels to contract. As a result. invading a site of infection and ingesting bacteria by a process known as phagocytosis. which binds . an initial adhesive contact occurs Involving specialized sugar molecules on both endothelial cells and leukocytes known as selectins. lymphocytes.5 100.

14 is the oxygen partial pressure at which 50% of the sites on hemoglobin have bound oxygen. . Under normal conditions. bl .I~ 30 Chapter 1 Introduction 1. p reac~lon rate is greatly accelerated by the enzyme carbonic anhydrase. and the pulmonary vein (PV). Under normal conditions. The quantity Pso shown in Figure 1. The oxygen-hemoglobin dissocianon Curve is altered by number of environmental changes. lout 10 Yo IS dissolved at low levels in plasma. one bronchus (B).osecells. there is no cooperatl.. The oxygen partial pressure.4 X 10-6 mol L-1 mml-Ig"..Myoglobin binds oxygen very strongly (Pso = 5.3-~iphosphogylcerate. .". Although jhe r-ed-cellnW!Ilbrane a . The fractional saturation is the relative amount of heme groups bound to molecular oxygen. S is the average f~actional saturation of hemoglobin.8 o ''= o:l Brolnd~~~~{ ~~~ 4 I Bronchioles H + -------~~=~f-----~-----~ l i l~ 12 ___ lZ 19 .2 ~ <a .m = 26 mmHg under normal conditions. Although disthe c~rbon dioxide reacts wah water to form bicarbonare IOn (HC03-) and H+.a phenomenon known as the Bohr effect.6.blood is then I. f Becauseoxygen partial pressures are low in the placental circulation (50 mmHg).L_ ___________ ~~ .2 Terminal _QWDcmQ~~__ ~~ Respiratory bronchioles -~~~~~~~~~----7~·_~--. Ab Car~o~ di?xide is present in three forms within blood (Figure 1. the maximum partial pressure of oxygen in air (21 mol%) is 159. Further.14 Oxygen-hemo~lobin and oxygen-myoglobin dissociation curves. .ar =Z:..I~I " < o!'L' -. and Het is the hematocrit.13 (a) Cast of a human lung.3 mmHg) at the low oxygen partIal pressures that appear in muscle during heavy exercise. or 2.. hemoglobin saturation is about 70%. Po .4 0.. used with permission.ent In the plasma a~ blcarbon~te Ion. ~here p. At 37"C.6 Physiological Transport Systems FIGURE 1. which .. .. ~~alhemoglobin exhibits an oxygen-hemoglobin saturation curve in which Pso is Shiftedtoward a I. Alveolar sacs (a) (b) ~~~~. in materna I blood.4) .. the pulmonary artery (PA). The fractional saturation is given by the following expression and is plotted in Figure 1. Reduced pH is important in the normal release of oxygen and in the binding of carbon dioxide to hemoglobin in tisSues..6 mrnl-Ig.14..14). solved ISpres. In the presence of any of these factors. As a result. Arterial blood ranges from 95 to 100 mmHg pressure and is about 95%-97% saturated. Another 60% of car b di OXIe ~n. Myoglobin is a protein that is present in muscle tissues and that contains a Slng~e.is t~~S~ntf In re~ cells. Since myoglobin contains only one heme group. '. Pso for oxygen binding to hemoglobin is 26 mmHg. Although bicarbonate is produced in red cells.. Even at these partial pressures. 00 d i on id .. only about oner 0 the bicarbonate remains "Yithil1th. HHb is the oxygen solubility i~ hemoglobin solutions. 'I (L6. . The solubility of carbon dioxide in p as mais.15) [14). IP )2. 0. and oxygen partial pressure in the pulmonary artery is typically 38 mmHg.more than 20 times the solubility of oxygen in plasma. Oxygen partial pressures in tissues are about 40 mmHg. ~ _~f'. .3) where Hoz represents the oxygen solubility in plasma.. the solubility of oxygen in plasma is 1. 31 1 _~r~:~e~ ~ __ j_ _1 (~~}~: Branch ~e:~~ation e 0.ower value. The curve can shift toward higher values for Pso by a decrease in pH or by an increase in temperature. u o:l .6' so O2 (1. the volume fraction of red blood cells.) The oxygen-hemoglobin dissociation curve is often reported as a function of the partial pressure of oxygen in the gas phase (Figure 1. carbon ~ioxide.. [13). (b) Schematic of the organization of [he airways in the human lung..8 u.heme group.6 1 + (p. The total concentration of oxygen in .vlty. is related to the oxygen concentration in blood Co 2 ' ~ through the formula (1.~====1i Jl 0023 -t-" where CHb is the total concentration of heme groups in red blood cells. (From Ref. _ S= (PO)PSO)2.6.5) FIGURE 1."]1. the hemoglobin content in fetal blood exceeds t at . o 50 100 150 -4 Oxygen Partial Pressure (mmHg) ______________ ----1§ . fetal blood has greater oxygen content than maternal blood.. showing the trachea (T). oxygen IS more easily liberated: from hemoglobin.

dealgas law. On equating the net gas flow into the alveolus. ~ns .-I I. across thin epithelial cells. because the layer is thin and these gases are soluble in the lipids of the cell membrane. and arteriolar blood. which is the volumetric flow rate of InSpIred air entering the alveoli. The lungs are an efficient system for gas exchange. oxygen diffuses through a surfactant film on the inner alveolar surface. (HbOz)4 represents the fully oxygenated hemoglobin molecule. The net transport of gas between the lung and the blood vessels is obtained by applying a mass balance on the alveoli and capillaries (Figure 1. VALV is the p~oduct of the ~lveolar volume. (a) Pco2=40rnrnHg FIGURE 1. Caly. Bicarbonate is one of several ions influencing the pH within the red cell. the capillary surface area is slightly smaller (Figure 1. an area equivalent to the size of two tennis courts! At 115 m2. affects oxygen-hemoglobin binding.. Carbon dioxide binds to uncharged amine groups (-NH2) to form carbamates. due to the increase in cardiac output. known as perfusion.16). and.f 32 Chapter 1 Introduction 1. which exchanges one bicarbonate ion. venula~ blood. with the net flow of gas between the arteriolar and venular ends of the capillary. blood travels farther along the length of alveolar capillaries before it is fully oxygenated.. The remaining 30% of the carbon dioxide in blood is bound to a modified form of hemoglobin in red cells.te[eaving the alveolar capillaries. alveoli.. across the capillary endothelium. The alveolar volume equals the difference between the volume of ~7srred air minus th~ dead volume. The adult lung consists of 300 million alveoli that occupy a surface area of 130 'm2. refer to the gas C. blood is completely oxygenated within one-third of its passage through the alveolar capillaries (Figure 1. Under resting conditions.6) :vhe~e VALV is the alveolar ventilation rate. the blood-flow rate increases. mulp ed by the breathing frequency (breaths per minute]. in turn. which.16 1. Nevertheless.16).6. blood is cornpletelyoxygenated befo. across a nal'~0':Y: extracellular matrix. 40 mmHg venular ~~~~~======================~Po2=100nunHg -------. these carbamates account for a small fraction of those present in blood. and the concentrations Cf. Except during a disease. \ . The transport of oxygen and carboll'dioxide across the iayerso] and matrix is rapid. for one chloride ion. between the plasma and the interior of the red cell.1 S Schematic of transport and major reactions of oxygen and carbon dioxide with hemoglobin (Hb) in red blood cells.16). respect~e1r The gas phase concentrations can be obtained from the partial pressure using : e I.. finally. ~I l Hi I is permeable to bicarbonate ion. transport is enhanced by a transmembrane transport protein.oncentrationin the inspired air. known as ventilation.6. .38mmHg PcOz'" 46 mmHg PC02 = . and the capillary volume is 194 mL [15]. Although carbamates can also form with plasma proteins.0 Oxygen and carbon dioxide exchange across the alveolar capillaries . In order to reach the blood. Q is the blood-flow rare through the lungs and equals the cardiac output. the resulting mass balance is (1.carbon dioxide. Equation (1'. During exercise. o Relative Distance along Pulmonary Capillary (b) FIGURE 1.6 Physiological Transport Systems 33 Tissue CO2 Plasma CO2 HC03- Red blood cell Inspired air +H 2 0 carbonic anhydrase H2C03 Cl- Cl- HC03- + H+'" I arteriolar p02". and C. As a result.6) applies to Oxygen. Cy. Carbamate formation is enhanced by the conformational change that occurs upon the dissociation of oxygen from hemoglobin. 0 ~----~~--------------------------_. between the interior of the red cell and the plasma. or other gases used to measure perfusion and ventilation. the diffusion of oxygen across the alveoli does not limit the transport of oxygen into blood.

The enzyme catalyzes the formation of carbon dioxide from bicarbonate. The inner surface of the intestine contains folds. Although the net change in carbo I! dioxide concentration is 6 mmHg.·A number of specialized types of epithelial cells line different portions of the stomach and then release hydrochloric acid. The end result is a 300-fold increase in surface area.. The small intestine is about 7 m long and consists of the duodenum (0.. The presence of the enzyme carbonic anhydrase on pulmonary capillary endothelium facilitates this exchange and limits the need to transport bicarbonate back into the red cell [16]..' In the oral cavity. In the lumen of the small intestine. and the surface of those epithelial cells facing the intestinal lumen contains many finer folds. Ion transport is often linked to protein or sugar transport. The combination of the large surface area of the villi and the abundant capillary network results in greater surface area for transport into the blood. Each of these folds contains another set of folds. Below the surface of the villi is an extensive network of capillaries. in the cell membrane. and ions are transported across cell membranes in energy-dependent processes by carrier proteins. .6.6 Physiological Transport Systems 35 ~. and rectum. Food can reside in the stomach for periods ranging from several minutes to a few hours.. breakdown. jejunum (2. enzymes. The system includes the oral cavity. " [. The stomach can hold as much as 1 L of food.5-3 m).17). and for small polar molecules.. ii I . liver. FIGURE 1. . The irregular surface of the stomach provides the mechanical means to disrupt and mix food.17 Schematic of the surface area of the inner intestinal mucosal surface. gastrointestinal tract. Pancreatic enzymes are involved in the breakdown of proteins. and triglycerides. small and large intestine. concentration gradients favor the transport of oxygen from the lung alveoli to the blood and the transport of carbon dioxide from the blood to the lung alveoli (Figure 1. I The digestive system is involved in the intake. The high concentrations of monosaccharides. osmotic gradients and passive diffusion drive water transport across epithelium. carbohydrates. and lipid-soluble drugs are absorbed in the stomach. which are typically several hundred microns long. food is first broken down and dissolved by chewing and by enzymes present in the saliva. Multiple layers of smooth muscle cells provide coordinated contractions to mix and move food through the stomach. alcohol.3 Gastrointestinal Tract i ') i " !. with ._ " '"'~ "". A layer of mucus protects epithelial cells from the highly acidic pH of the stomach. which ~re subsequently transported across the epithelial membrane. Bicarbonate in plasma rapidly reacts with water to form carbon dioxide.. transport the nutrients across intestinal epithelium. due to the greater solubility of carbon dioxide in plasma and the formation of bicarbonate ions. and triglycerides near the microvilli increase the rate of transport of these molecules across the epithelium..if' I 34 Chapter 1 Introduction 1. that increase its surface area about fourfold (Figure 1. amino acids. transport. and polynuc1eotides into their constituents. Transport across epithelial cell membranes occursby diffusion for lipid soluble n:olecules. the small change in carbon dioxide partial pressure can produce a significant release of carbon dioxide to the lungs. sugar and amino acids are transported first to the liver. fats. and metabolism of food and the removal of waste products.fatty acid triglycerides are emulsified by bile acids and diffuse across the epithelial cell membranes. water. II When blood enters the lungs. where the acids are neutralized..5 pm long and 0. it enters the duodenum. 4cm Portion of small intestine 1. known as microvilli. and store and remove waste products. known as villi.25 m). such as alcohol. . termed rugae. In CO?trast. amino acids. The primary functions of the small intestine are absorption and secretion. The teeth break food particles into smaller particles by grinding. absorption. Microvilli provide additional surface area to transfer mass across the cell membrane. After entering the blood. which are typically 0. Although a significant amount of water is removed from the digested food and secretions. Each cell contains several thousand microvilli. rT • 'Microvilli Epithelium Blood \ Blood epithelial cells. proteins. monosacchandes. stomach.1 urn in diameter. and the stomach stores the food and breaks it down further through the actions of digestive enzymes. gallbladder. These components are then absorbed in the jejunum by transport across the intestinal mucosa. As a result. Proteins.16). and pancreas. hydrolytic enzymes break down carbohydrates. After food leaves the stomach. and proteins. and fats to monosaccharides. the capacity of blood for carbon dioxide is about twice as large as the capacity of blood for oxygen [14]. The surface of the villi is covered. and ileum (4 mi. The gastrointestinal tract consists of the esophagus.. Although most absorption occurs in the small' intestine. Food moves sequentially through the small intestine in about three to four hours. These functions require the coordinated action of the gastrointestinal tract with all of the organs of the digestive system. The function of the gastrointestinal tract is to break down food. Fats are eventually transported to the liver in the form of large lipid particles called chylomicrons.

Smaller molecules are transported across fenestrae without significant resistance. and iron ions. zinc. and phospholipids [19]. The hepatocytes form a two-cell layer between sinusoids.18. This arrangement is important for the receptor-mediated uptake ofproteins and. The polarized surface of hepatocytes enables them to perform important metabolic and transport functions [18]. Some residual digestion occurs. a different view of the functional unit of the liver has emerged. The basal surface of hepatocytes is in contact with sinusoidal blood through fenestrae and the extracellular space. the activity function is organized around a repeating structural unit that performs the basic functions of that tissue. triacylglycerols.gh the urea cycle. albumin) by the hepatocytes.I II·. Food waste may reside in the large intestine for times ranging from hours to days. cholesterol and lipoprotein metabolism. Blood flows from the hepatic artery or portal vein through the sinusoids to the central vein. Kupffer celis are present adjacent to and beneath endothelial cells. I b Ii. which terminate in the bile duct. Because the liver processes molecules from food and the body. The classical view of the functional unit of the liver is the lobule (17]. Sinusoids from different lobules have interconnections. and sugar molecules from the intestines and other ~rgans and produce glucose. Based upon recent studies of the structure and function of the 'liver. synthesis of vitamlOSand retinoids. A conical segment of the classic lobule. Hepatocytes process amino acids. fatty acids. and lipids are transPOrted across the apical surface into the bile canaliculus. The sinusoids are analogous to the capillaries found in other tissues. removes toxic molecules from the blood. Located on the basal surface are receptors for amino acids. but the inner surface of the large intestine lacks the large surface area that the small intestine possesses. Kupffer cells are resident macrophages and account for about 15% of liver cells.36 Chapter 1 Introduction 1. it has a dual blood supply. In a number of different kinds of tissues. ~: I FIGURE 1. The hepatocytes perform the major metabolic and synthetic functions of the liver and account for 60% of the liver cells.6 Physiological Transport Systems 37 The primary functions of the large intestine are the absorption of fluids and the storage of feces. immunoglobulin A. Cholesterol is important for cell memr~nes and for myelin in nerves. Sinusoidal endothelial cells contain numerous fenestrae that are 100 nm in diameter. The remaining 20% of blood flow comes from the hepatic artery. Cholesterol is transported to the body tissues in the form of very-low-density ~po~roteins (VLDLs) and low-density lipoproteins (LDLs). lies between the endothelial cells and hepatocytes.6. and it is a precursor of steroid hormones and bile ~Clds. known as the space of Disse. a hexagonal-shaped region bounded by the terminal branches of the hepatic artery and the portal vein (Figure 1. and contributes an important immune function. 1. The major functions of hepatocytes are energy metabolism.' II ! Central vein I. Fat-containing cells are found in the space of Disse. represents the functional unit and is termed the hepatic microvascular subunit. Excessive levels of these molecules may be . glucose. The fenestrae appear to prevent the passage of large particles. I The liver synthesizes most of the cholesterol needed by the body and regulates asma cholesterol and lipoprotein levels. and the state of oxygenation and metabolic function may vary within and between lobules.18). Between the hepatocytes. Bile is selectively secreted from the apical surface. In turn. As a result. The cytoplasmic side of this surface also contains molecules involved in formation and fusion of vesicles wiih the plasma membrane. The basal surfaces are exposed to high levels of circulating metabolites and proteins. and metabolism of copper..18 Schematic of a region of a hepatic lobule.. The liver consists of six cell types. the alveoli of the lungs and the villi of the intestines perform the basic functions of their respective organs. such as that shown in Figure 1. For example. acetoacetate. LDLs and highenSlty lipoproteins (HDLs) return cholesterol to the liver. The portal vein transports 80% of the blood to the liver and carries blood from the intestines.4 liver The liver processes metabolites from the small intestine and the body. Cytoskeletal proteins surrounding the fenestrae regulate the fenestrae diameters in response to various stimuli. bile collects in the bile canaliculi. The liver lobules also contain lymphatic vessels and nerves.g.release of synthesized molecules (e. The liver endothelium is not continuous. Endothelial cells represent 20% of all liver cells and provide a barrier function regulating the entry of molecules to the hepatocytes. hepatocytes modify molecules that are not normally synthesized or used by the body. Bile acids. In the process of detoxification. small molecules present in the space of Disse are probably in chemical equilibrium with the blood plasma. The lateral surfaces contain tight junctions that connect hepatocytes with each other and limit the transport of molecules between the hepatocytes. A thin layer of extracellular matrix. bile synthesis and se~retion. hepatocytes remove excess nitrogen and synthesize the essentIal amino acid arginine. These Kupffer cells are in direct contact with endothelial cells. Epithelial cells account for 3%-5% of liver cells and line the bile ducts. detoxification. hrou. Hepatocyte Endothelium . and a number of metabolic proteins. a branch of the celiac artery. The remaining cells of the liver are the fat-storing cells and the pit cells.

a = RPFv + QU.6). The fenestrae permit unrestricted solute transport across the endothelium. a process known as ultrafiltration. Enzymes involved in these reactions are concentrated in the liver. A net pressure. 1.2 million nephrons. The kidneys receive blood from the renal arteries.6. Transport processes in the kidney are discussed in detail in Chapter 14. the molecule would mix with fat in fat tissue and remain for long periods of time. which merge ~nto the renal vein.6 0.000 mmole day"! (glucose) (urea) 800 mmole day"! 933 mmole day"! ~ '1 The kidneys are responsible for the removal of waste products such as urea for fluid and ion balances. asma ow in the artery and vein. The glomerulus consists of a layer of fenestrated endothelium lining the capill~ry surface. a' basement membrane. These charged groups appear to playa role in the charge selectivity of the membrane.4 0.p ro anes equals the mass excreted in urine. negatively charged molecules are filtered to a lesser extent than are uncharged molecules of the same size. The extent to which ions and water are reabsorbed is summarized in . A variety of diseases of the kidney result in protein in the urine.To m~ximize reabsorption of fluid and solutes by the blood.!It . The kidneys contain 1. a condition caused by a change in filtration due to an alteration in either the charge or the size selectivity of the glomerular membrane. TABLE 1. ultimately forming interlobular arteries. Kidney function is summarized here. As a result. The kidneys account for about 0._g FIGURE 1. .200 mmole day-l 720 mmole day"! 270 mmole day'? 4. there is a countercurrent flow of blood in the capillaries and ~e tubules. a significant fraction of the ions and water and most glucose and ammo acids are transported from the tubule to the peritubular . or proteinurea.5 Kidneys 25.0 nm are transported across the membrane to a limited extent. The fraction filtered equals Cfler.25 L min "}. . [20]. ~ ~ u ro kid A mass balance summarizes the overall exchange of solutes and water in the II ney. The glomerulus is highly selective with respect to molecular size as shown in Figure 1. Between the regions where the epithelial cells contact the membranes (termed foot processes) are narrow gaps through which solute and fluid are transported. where Cf is the solute concentration in the glomerulus and er is the solute concentration in the afferent arterioles.5 nm are filtered across the membrane 1 . Filtration of the blood plasma and reabsorption of water and ions remove waste products and balance fluids. The frequency of these openings decreases with the size of the opening..12 Molecule H2O Na+ K+ Ca++ HC03- Filtration rate Excretion rate 1.CVRPPV = CUQu J l l' (1. In contrast. respectively.19 Fraction of solute filtered across the glomerulus as a function of molecular radius.5 mmole day'? 467 mmole day'? Ii . there are some openings between matrix molecules that allow larger molecules to penetrate.difference between the capillary and glomerulus causes fluid and small solutes to flow across the glomerulus.320 mmole day-I 18. where solutes are reabso~bed by active and 'passive transport across the epithelial cells to the blood. able 1. One important function of hepatocytes is to convert lipophilic molecules to a water-soluble form for removal by the intestines or kidneys. Essentially. 0 2. The arteries branch repeatedly. RPF of theIn the proximal ~ubule. Blood from the interlobular artery passes through glomerular capillaries.~II III II' 1.5 and 3. limiting the passage of large solutes.6 Physiological Transport Systems 39 harmful.1 i ~ I cr C6HI206 CO(NH2h Source: Adapted from Ref. Because solutes are flowing the mass balanc e can b e written as ' caRPFa . The membrane also is charge selective: positively charged molecules pass through the membrane more easily than do uncharged molecules of the same molecular radius. and a layer of epithelial cells (podocytes) (See Figure 14. The glomerular basement membrane is 300 nm thick and consists of collagen and negatively charged proteoglycans.. respectiVe! y. . Molecules with radii less than 1. without any restriction. Large flow rates are needed in order to filter blood efficiently. C'" IS t h e concentration m the unne..2 c . The processes of filtration and reabsorption occur in the nephron the functional unit of the kidney. Otherwise. Solutes with molecular radii between 1.6. Urine from many nephrons enters the collecting ducts and flows Into the bladder. Blood leaves the nephrons through the interlobular veins.44 L day-I 150 mrnole day-l 100 mmole day"! 5 mmole day'? ~ mmole qay-I 150 mmole day'? 0. but receive 25% of the cardiac output (1. the mass entering the capillaries minus the mass leaving the capil0.38 Chapter 1 Introduction 1. and RPFa andRPP . Urea and other waste products are concentrated in the filtrat~.2 C 0 '. and for the regulation of the blood pressure. The outer surfaces of the epithelial cells are coated with sialic acid.7) P:: . i are the rates of renal pI fl .12. a negatively charged sugar group. The filtrate flows from the glomerulus to the tubule network. ![ j!' 180 Lday"" 1.5% of the body weight..0 Molecular Radius (nm) ~ where Cf and Ci are the concentrations of the solute i in the renal artery and vein.5 3.. which are branches of the abdominal aorta.19. The network structure of the membrane is not uniform. Water IS passively transported to maintain an osmotic balance.

heart failure. Thus. The LOL macromolecule is composed of a hydrophobic core of trigylceride and cholesterol. The mechanism by which plasma cholesterol influences the initiation and progression of the disease is poorly understood. and protein. In the distal tubule. The release of vasodilators is a good example of paracrine regulation. the mechanism of how the disease begins and progresses is poorly understood. Na+ and CI. each of molecular weight 250. Systemic regulation can occur through the release of molecules from one type of cell that are utilized by another type of cell. the affinity of the neurotransmitter for the receptor is low. Complications arising from atherosclerosis (heart attack.g. possibly due to the alteration of endothelial cell function and monocyte transport by arterial fluid dynamics. acetylcholine release affects the speed of muscle cell contractions. The lipids present in atherosclerotic lesions are derived primarily from lipoproteins. These molecules are released by endothelium in response to local changes in blood flow or other agents and act on nearby smooth muscle cells. Treatment. Paracrine regulation involves molecules with short biological half-lives. elevated' plasma cholesterol. Synaptic transmission involves the release of neurotransmitters from nerve cells upon effector cells and is relatively rapid..limiting the distances over which the molecules can be active. Complications of the disease are the leading cause of death in the United States and many other developed countries. many disease processes result from alterations in transport pathways. • A quantitative analysis of transport processes is essential to the understanding of normal physiological and cell biological processes. In addition. The major route of transport across normal en~Otheliumis believed to be endocytosis.g. and stroke) are the leading cause of death in the United States.000.ions in the lower portion of the proximal tubule. In normal vessels. smooth muscle cells. The LDL receptor does not appear to play a significant role in LOL transport. Atherosclerosis is characterized by the formation of lesions in the arterial intima consisting of lipids.reabsorption continues with little transport of water. For long-term regulation. These molecules are transported through blood to their effector sires. we see how transport processes apply in the development of devices or therapies that use biomolecules and cells. lactate. hormones are secreted by various tissues of the endocrine system (e. I i I . Then. Although a number of risk factors have been identified (e. and Device Development I liil" -A .40 Chapter 1 Introduction 1. which actively maintains low sodium concentrations within the cell. The driving mechanism in all of this transport is the Na +fI(+-ATPase. LOLs form in the blood as a result of the actions of the 'pases that modify the lipids of VLOLs. As a result. and for platelet aggregation. The apoprotein B molecule is entwined around the lipid and binds specifically to recep~?rs On the cell surface. lesions protrude into the lumen of the artery. In the loop of Henle. cholesterol esters._ ~" . the symporters and antiporters function by transporting the ions down an electrochemical gradient. 1.7 Application of Transport Processes in Disease Pathology. . I j to "I. Canada. Lesions first appear around arterial branches or in highly curved arteries. When fully developed. surrounded by phospholipid. Further. which contain a network of tight junctions that permit transport of water and Na + and 0. Apoprotein B in the LOL molecules is essential for the receptor-mediated recognition of LDLs on the liver and peripheral tissues. hypertension.6 Integrated Organ Function ::. Finally. Oxidized lipoproteins can damage endothelium and lead to the unregulated accumulation "of cholesterol within macrophages. and uniporters transport ions. cells can release signaling molecules that act on the cells secreting the molecules. .. For example.. A variety of antiporters. The binding of immune system cells to each other and to cells in various tissues is a good example of such interactions. along with glucose. we describe how transport processes contribute to the development of atherosclerosis. known as apoprotein B. Treatment.!Il 1. because the endothelial cells are exposed to high concentrations of LOLs in the plasma. fibrous tissue. cations are transported between cells. / " . reducing the number of LDL receptors on the 1. resulting in thrombosis or embolism.6. although water is not. First. so that the release step does not produce a significant time delay. thyroid and adrenal glands). Understanding these mechanisms could produce new therapies to treat the disease prior to the onset of clinical symptoms. or phosphate. reducing blood flow or causing platelets to adhere to the arterial wall.1 Transport Processes and Atherosclerosis Atherosclerosis is a disease of the large and midsized elastic and-muscular arteries. and diabetes). Diffusion distances are very short. from the tubule lumen into the epithelial cells. Treatment often involves delivering a local agent to a site of disease or injury. amino acids.. Characteristic features of early atherosclerotic lesions are lipid-filled macrophages and the presence of extracellular lipids. and macrophages. Hormone binding initiates a cascade of signaling events within cells that affect cell function. and-Europe. Lipoproteins from patients with coronary artery lIisease show an increased susceptibility to oxidation. symporters. the arterial endothelium presents a significant barrier to the entry of LDLs into the arterial wall. In order to limit the response. Oxidation of lipoproteins appears to playa' significant role in the progression of lesions. Numerous epidemiological studies have demonstrated a correlation between plasma cholesterol levels and the risk of atherosclerosis. regulation can occur as the result of one type of cell binding to a second type. we examine the role of transport processes in a variety of therapies used in treating cancer. This section provides examples of the variety of roles that transport processes play in the progress and treatment of disease. .7. Sodium ion reabsorption and hydrogen ion excretion continue by a similar mechanism. LDLs are the major carriers of cholesterol in the blood. for smooth muscle contraction. transport of lipoproteins into the arterial wall and their subsequent metabolism play an important role in the initiation and progression of atherosclerotic lesions. and Device Development 41 capillaries. plasma proteins.7 'rJII L u I Application of Transport Processes in Disease Pathology. Alternatively. I I: The functions of tissues are regulated locally or systemically. Systemic regulation occurs via synaptic transmission and the endocrine system.J "I L. Such autocrine regulation is important during development. The protein consists of two structurally similar units.

Currently.20. altering their normal metabolic function and reducing the barrier function of junctions. Both receptor-dependent and receptor-independent pathways are involved. and the molecules are internalized. As a result of convection.7. The efficiency of delivery 00 . transmural pressure differences. Adhesion molecule expression is further increased by local fluid dynamics. binding to the matrix.. smooth muscle cells metabolize LDLs. chemotherapy acts in the body by I hng the dividing cells. it is the concentration at all tar~e~. Elevated LDL concentrations stimulate the expression of adhesion molecules on endothelial cells. Macrophages do not have receptors for LDLs themselves. : ~xL~ i '~~ FIGURE 1. there is a localized accumulation of lipoproteins in the intima. radiation therapy. • L~L· • -. the scavenger receptors are not. the extracellular matrix composition and charge."" _: Oxidatione z: l=<ell Ilk Activated macrophag~ Cell death replication Schematic of events leading to macrophage accumulation and foam cell formation.". the sites that are . C~ IVery is also an important issue in new approaches to cancer treatment (see apter 15). highly lesion-prone areas are adjacent to lesion-resistant ones.. patients have to kil ~reated with chemical drugs. LDLs accumulate within the vessel wall at sites of elevated permeability. The modified forms of LDLs bind to these scavenger receptors.20 M"WP:::~:-. When tumors have already ~etastasized {l. The initiation and progression of the disease are influenced by monocyte transport to and accumulation· within the vessel waH..) Adherent monocytes migrate between the endothelial cells and enter the tissue.predisposed to the formation of lesions are fairly consistent in individuals. Accordingly. and chemotherapy. making rupture of the plaque likely. As the disease progresses. The cause of the transient permeability is not known. Endothelial cell junctions become transiently leaky and allow the entry of macromolecules..In any approach based on therapeutic agents.. Over a period of years. The fenestrated internal" elastic lamina between the intima and the media may serve as a transport barrier. regional variations in permeability may explain the predisposition for plaque formation in specific locations.. which gives Blood \' Intima. rather. more than 1. liver. possibly as the result of oxidation. '. resulting in excessive accumulation of foam cells. Cytokines and oxidized LDLs stimulate endothelium. However. as well ashy the transport of LDLs and its subsequent chemical modification and metabolism. 1. the physical and chemical properties of these agents. A possible sequence of events is shown in Figure 1. macrophages remain. Normally.e. However. Receptors on blood monocytes bind to these adhesion molecules. some vital normal tissues (e. if the plasma cholesterol remains high and LDLs continue to accumulate in the vessel wall. .42 Chapter 1 Introduction 1.500 cancer patients died each day and about 1. Often.. However. Many factors affect the rate of transport of macromolecules within the arterial wall. the process acts as a positive feedback loop. surgery and radiation therapy are used only for patients with a few large tumors in the body. The major approaches to cancer treatment are surgery. In studies with cholesterol-fed animals. the macromolecular surface charge.I~. Atherosclerotic plaques generally form in characteristic regions of the circulatory system. the permeability of the endothelium has not altered as the disease begins. a clot forms-occluding the Vessel and leading to a heart attack or stroke.45 million new cases Were diagnosed.:P'O<L. and cellular metabolism in the media. and the macromolecular binding to extracellular matrix constituents and cell surface sites. If the underlying risk factors are not removed. j l~ . diffusion. disseminated) to many locations in the body. Firm binding of the monocyte to the endothelium provides a resistive force that balances the shear forces produced by blood flow. and b?ne marrow) are also damaged (luring the treatment.. . When the plaque interior is exposed to blood. Treatment. In 2007. The permeability of the arterial endothelium is 10-100 times greater than that of the surrounding regions.g. Hence.7 Application of Transport Processes in Disease Pathology. The accumulation of cholesterol by these scavenger receptors is unregulated. although indirect evidence suggests that the local fluid dynamics may playa role. Among them. which can vary .*. they have receptors for modified forms of LDLs. the de IVery of therapeutic agents in solid tumors is critical..SItes that determines therapeutic efficacy in cancer treatment. Binding of LDLs to the matrix may increase the likelihood that the LDLs are chemically modified by oxidants within the arterial wall. intestine. Increased LDL accumulation appears to be due to either binding to the extracellular matrix or accumulation within macrophages that have invaded the tissue. there is ~ett Interest in developing more effective means to deliver drugs into tumors. macrophages perform their scavenger function. and leave the tissue. remove foreign material. the cells a foamy appearance due to the lipid particles within the cells. '. Within the media. such as the macromolecule size and concentration.. possibly due to the release of chemicals known as cytokines from rnacrophages or to the oxidation of LDLs.2 Transport Processes and Cancer Treatment Cancer is the second leading cause of death in the United States [21]. Because the plaques result from the metabolism and accumulation of cholesterol within the arterial wall. the permeability of the endothelium does increase. (The transport and binding processes involved in leukocyte adhesion are discussed in Section 12.Transmigration. Although the LDL receptors are regulated by cholesterol consumption.4. and Device Development 43 '1 IIII II! Ilil! Iii cell surface. and macrophages accumulate lipid deposits. As a result. Following the elevation of plasma cholesterol levels (hypercholesterolemia). these macrophages release enzymes that weaken the vessel wall.. the cells are given the name foam cells. . l I . Regions of arteries where lesions develop exhibit increased endothelial permeability to macromolecules.

The capsule must be sturdy in order to prevent rupture and release of cells. Determining local distributions of drugs and genes within a tumor or around a microvessel is important in understanding whether the drug concentrations around all tumor cells are higher than threshold levels that are required to kill tumor cells.. difficulties persist in providing sufficient numbers of cells to replace normal cell function. and the cell level (-10 11m). viral or nonviral vectors in gene therapy. The details of some of these transport phenomena are discussed in Chapter 15. So~e assist devices (e.22). Studies with animals show that microencapsulated pancreatic islet cells. drug and gene delivery to rumor cells can be studied at four different length scales (Figure 1.Artificial Organs. the peritoneum). The solid curves in (b) represent tumor vessels. a number of assist devices have been developed. whereas the kidney dialysis machine is used if the kidneys stop functioning. and liver. obtaining enough cells. These three approaches hold much future promise. One approach involves growing cells in a biodegradable scaffold and implanting the tissue Construct.I!n' . Barriers to intracellular transport include the plasma membrane. principles that govern intracellular and extracellular transport are also discussed in other chapters. the cytoskeleton. various strategies are employed to enhance their entry H I!JIi " I I! t: I (b) (a) FIGURE 1. interstitial transport. artery. (d) represents a tumor cell with a nucleus.7. . There are two concentric cylinders in (c). and the nuclear envelope. the membrane of vesicles in cells. then transport in tumor cells becomes important.S}. A pressure difference across the fiber. but many fUHdamental scientific and engineering issues remain to be addressed. heart-lung ma~hines. If targets of drugs and genes are inside tumor cells or inside the nucleus. some researchers are developing hybrid devices that consist of cells and synthetic material. limiting their immunological rejection. which may serve as a bridge between organ failure and organ transplantation. ) " I. The inner cylinder represents a microvessel and the outer cylinder represents the region in tumor tissues that receives nutrients' from this microvessel. the growth and spatial localization of each type must be regulated. When multiple cell types are needed. anticancer agents can be oxygen in radiation therapy. bladder. and art~ficial~idneys. One approach is to microencapsulate cells in a polymeric material and inject them into various cavities (e. The growing knowledge about intracellular organization and communication creat~s new opportunities to treat a variety of diseases in which signaling pathways ar~ disrupted or altered. Tissue-engineered skin is available now for the treatment of burns and leg ulcers. molecular 10 0gy.Treatment. Other assist devices being lieveloped include the bioartificial kidney and artificialliver [24]. the tissue level (-1 ern). . The capsule prevents immune rejection and permits the use of nonhuman animal cells. maintaining differentiated cell function.21 Schematic of drug delivery to tumor cells at four different levels: (a) the body level (-1 m). transvascular transport. ~aterials science.7 Applicationof Transport Processesin DiseasePathology.forces the flow of plasma across.21): the body level (-1 m). 44 Chapter 1 Introduction 1. and Tissue Engineering Sincethe 1960s. Tissue engineering involves the growth of cells to replace the functions of damaged organs and tissues [22J.the fiber and cells. which keeps the cells isolated. The whole-body distribution of drugs and genes must be analyzed in order to understand which organs are targeted by these agents. Upon implantation. and intracellular transport.. and (d) the cell level (-10 prn). It is a challenge to facilitate drug and gene transport across these barriers. The open circles in (a) represent solid tumors. an adequate blood supply must be developed for the cells to survive. cells from the kidney ?r liver are coated onto one surface of a hollow fiber reactor. While the machine is quite efficient at removing low-molecular-weight waste products (see Section7. and transport processes. and using or not using stem cells. Important issues for in vitro culture include providing an adequate nutrient supply. Short of creating a complete tissue or organ that functions like the original organ. patients on dialysis suffer long-term health problems because only part of the kidney function is replaced. mechanical analysis. the microvessellevel (-0. ~. can provide very good control of blood glucose levels.'·Asa result. Within them (Figure 1. The capsule size is limited by the metabolic demands of the ceIls. il 1 from small molecules to cells. Tissues that are actively studied are skin. Such treatments involve the delivery of genes and promoters or Inhibitors of signaling pathways.01 em). (c) the microvessel level (-0. Because these molecules are not normally transported across cell membranes. Addressing these issues will ~:q~ire knowledge of cell biology. cytotoxic drugs in chemotherapy. ! I' 1. including circulatory support devices. The presence of the cells prOVides metabolic functions that are not achieved by simple filtration. oxygen~tors. transport across the plasma membrane of cells. " dl ~ .3 Transport Processes. heart-lung machines) are used III surgery or intensive-care umts. "I il~1~'.g. photosensitizers in photodynamic therapy.'I~'" . For example. The development of engineered tissues is affected by nutrient and growth factor transport [23].g. The.sedevices are extracorporeal. In general. cartilage. which secrete insulin. although an artificial kidney [25J could in principle replace dialysis.. The delivery of therapeutic agents may involve tumor microcirculation. (b) the tissue level (-1 em).01 em). . and DeviceDevelopment I .' 4S i !~!ll! ~". and effector cells or vaccines in immunotherapy.

uch greater than ulll. reactions of glucose metabolism in the mitochondria of cells [26].1 What differences would you expect to observe between a random walk of a molecule in a gas and a random walk of a protein molecule in water? 1.6 Why is edema jn the legs often seen in patients with chronic hypertension? .levels of carbon dioxide are less than 40 mmHg. the..3.. result in the formation of a complex that does not chemlca.] FIGURE 1.1. © 2002..~ 46 Chapter 1 Introduction -1. 1. diffusing molecules pass through an endothelial or epithelial layer and then diffuse into tissue. In such cases. the membrane IS t e imiring resistance. Nonco~a ent Illteract~ons.9 How might living at high altitudes affect oxygen uptake and what adaptations might occur? I kmL Bi = = __ Mass transfer by diffusion through tissue Deff' Mass transfer across a cell layer (1. transport? 1. It usually undergoes a chemical transformation. ' b After a molecule reaches a site of action.ty." II .overall speed at which a p:oce~s occurs eq~als the rate of this step. applying alternating electrical fields cell membrane (a process known as electroporation). Often..3 and 10. II" !. the rate-l irniting step is the slowest step in the sequence (see Sections 10. . (2) calcium ion.~ I. (Reprinted with permission from Ref. If the tissue is the m t e "" ' h li major resistance.lIy change either of the molecules.. When the product is formed as the result of a sequenc~ of reactions. Comparing timescales can provide useful information about the Importance of various transport and reaction steps.8.e. (3) ethanol.8 How does the Bohr effect influence the oxygenhemoglobin dissociation curve? 1. 1 j i I I I I . (1) oxygen. This is done using dimensional analysis. it is important to know the relative contribution of the endothelium and tissue to the diffusive resistance. If the intrinsic reaction dynamics are very rapid. For example. known as a reaction. The rate of reaction can be enhanced by decreasing the characteristic length if t~e process is limited by diffusion or by increasing the fluid velocity if the process is limited by flow ..l ri ii ~j into cells. or it inte~a~ts throughnonspecific f?rces to generate a biological signal. of the molecules. One of the most commonly used approaches in modeling transport and reaction processes is the identification of the rate-limiting step. however. include using viruses.. Consequently.and Reaction Processes .he nssu es occurs . !'i]! f I I· . I' I 1. what is the dominant mechanism of 1. The formation of complexes can produce changes III t?e conformation or three-dimensional structure. These conformational cha~ges canthen initiate additional noncovalent interactions or covalent bond formation.9 Questions ~ 47 11 Schematic of flow circuit for extracorporeal artificial liver. What effect should hyperventilation have upon blood pH? 1.1) . and D ff is the effective diffusion coefficient. A senes of uon I' . diffusion and convection often occur in conjunction with specialized cellular transport processes and chemical reactions. glucose IS Important III ~he OXidative phosph~ryla. If. As indicated in the preceding survey of cell biology and organ transport physiology.. Bi is I?. This cascade of reactions can produce biological signals leading to alterations in cell function. then the rate at which a reaction occurs will be affected by the rate at which the molecules are delivered to the reaction site.. . . 1. j. Identifying the rate-limiting step can simplify the reacrion model significantly. then BI IS much I~ss than ~nIty. H I Patient I I Hepatocyte bioreactor I. A cUFrent engineers is to develop a mechanistic and quantitative routes into the cell.5 Why does the blood flow distribution ous organs shift during heavy exercise? to the vari- 1. the arterial. or protein synthesis. chemical reactions transfers the energy in glucose to ATP.4 Explain how each of the following passes from the extracellular fluid into cells. Explain why an increase in hydrogen ion concent~atlOn would shift the oxygen-hemoglobin dissociatIOn Curve to the right. and (5) growth factors. L is the distance over which diffusion .1 ." I .22 k is the permeability of the cell layer. Such strategies to transiently disrupt the linking drugs to molecules challenge for biomedical understanding of transport deliver drugs and genes. American Association for the Advancemenr of Science. I . (4) glucose.9 I QUESTIONS 1..!_. replication.2 If the Peclet number for the transport of a drug in tissue is 0. in order to develop efficient ways to 1.8 Relative Importance of Transport I . One of the tasks facing the bioengineer is to quantify the relative contribution of each of the different processes to the overall transport process.----~------------------~~~~-----.7 During hyperventilation. I'j. [24].4).I . The Biot number (Bi) is a dimensionless number that is a measure of the relative resistances of each process and is defined by .. however. and internalized by receptor-mediated endocytosis. Reactions that are sensitive to the rate of transport are known as transport-limited reactions.

The number of bronchi N equals 2z.0 4~6 19.33 seconds..116 0.99 0. 1.47 0. The difference in carbon dioxide (at standard temperature and pressure) between arteries and veins in the lung is 2. Calculate the volume of blood and the surface area of the vessel wall in each order of vessels and the cumulative volume and surface area from order 1 to order 11.95 0.14 Order" Mean diameter (mm) 18.10 Problems 49 1. 1.519 31. 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 6 lus and in the renal vein.6 3.4 The alveolar epithelium. and lung capillary endothelium are typically 1 prn thick.0 7.3 2.486 5.6 Morphometric data of a human lung are shown in Table 1. (b) What does this result indicate about the endothelium as a barrier to LDL transport? .4 5.662 9.10 I PROBLEMS 1.13).073 0.0 7.5 o 1 2 3 \4 5 " 7 .2 The solubility of oxygen in plasma at 37°C is 1. basement membrane.27 cm ' per 100 crrr' for plasma carbon dioxide and 1. 0.5 3.3 2.6 0.0 122 8.43 0.260 11.41 Mean length (mm) 120. (a) How large a distance between capillaries would be needed for convection to influence oxygen transport to tissues? (b) Based upon reported values for the distance between capillaries.13.4 4.8 The permeability of normal rabbit arterial endothelium to low-density lipoproteins (LDL) is 5 X 10-9 em S-l.122 0.810 1.080 Mean vessel length (mm) 0.7 Using the data in Table 1. 1. .54 0.45 for men and 0. [14].433 0. do you think that convection is an important mechanism for oxygen transport in tissues? 1. determine (a) the fraction of water filtered across the glomerulus. and microvilli in the small intestine? Why are these structures absent in the large intestine? 1.12 Why does drinking a cup of coffee often result in increased production of urine? 1. . Determine the fraction of oxygen in solution and that bound to hemoglobin in arterial and venous blood.0 1.7 2. Under resting conditions.10 What is the function of folds. and the alveoli are the airways of order 23.1 The oxygen diffusion coefficient in tissue is about 1. and the pulmonary artery IS of order 11.40 for women.720 4.024 0.7 9.925 774 202 49 12 4 1 1.13 Mean vessel diameter (mm) 0.1 X 10-5 cm2 s-l. [28]. (a) Determine the Biot number.7 10. i 1. and calculate the cumulative volume and surface area from order a to order 23.. 'The trachea is called the airway of order 1.45 for men and 0. hemoglobin binding with oxygen reaches a steady state (i. 1. :lill 1.3 5. .66 0.1~ and a renal artery flow rate of 125 L min-I.5 2.e.lary? Source: Adapted from Ref.41 1. Calculate the volume of air and the surface area of the bronchial system in each order of airway. The heme concentration in red blood cells is 0. TABLE 1.5 0. For simplicity.14 How does the transport of nutrients affect the development of tissue-engineered blood vessels in the research laboratory? TABLE.74 0.352 0. The fluid filtration velocity is typically 1 urn s-l. .83 0. 1.7 0.870 25.09 0. (b) the renal vein flow rate.13 In what ways can alterations in transport processes affect the growth of tumors? 1.000 Order" 1 2 3 4 5 6 7 8 9 10 11 vessels 300.875 1.190 14. it does not change with time) in about 0.5 Data for the dimensions of the branches in the pulmonary arterial network are shown in Table 1.14 (see also Figure 1.736 2.3 1..41 0.45 0. The blood volume fraction (hematocrit) is typically 0.510 2.4 X 10-6 mol L-t mml-Ig'".600 8.11 Describe how the structure of the liver permits efficient exchange of molecules between the hepatocytes and blood.262 0. The diffusion coefficient of LDL in the rabbit arterial wall is 1 X 10-10 cm2 S-I.3 Compare the amount of oxygen taken up by blood and the amount of carbon dioxide released by the blood as blood passes through the lung capillaries.6 12.3 1.192 0.9 3.358 97.17 0.98 crrr' per 100 crrr' for red-blood-cell carbon dioxide.. The rabbit aorta thickness is 150 pm. "The smallest arterioles are vessels of order 1.6 4.0203 mol L-1 = 4CHb [27].48 Chapter 1 Introduction 1.65 1. where z is the order.54 1.044 0.8 2. villi. assume that the solubility in red blood cells equals the solubility in plasma.000 '\ ! .82 0. 1.6 6. The sodium ion concentration in the' blood entering renal arteries is 150 mM. The blood volume fraction (hematocrit) is typically 0.59 0.86 1. Is oxygen diffusion across the alveolus a significant factor in the time required for the hemoglobin to oxygenate as it traverses the capiL. and (c) the concentration of sodium ion leaving the glomeru- Source: Adapted with kind permission of Springer Science + Business Media from Ref.40 for women.533 0.519 2.

M. and Simionescu. and a respiratory volume of 0. Biomed. 386-400. 41-102.33 X 10-6 M mrnHg -1.... pp. R..77-95. E. A common method to determine the glomerular filtration rate is to add a low molecular weight sugar. "Design of airways and blood vessels considered as branching trees. and HHb is 1. Lewis. Funke. Roberts. 1656-1670. Inc. 1. 1997. Equation (1. D. (b) During exercise.. 1975. S. Cancer Facts & Figures 2007. R. 3. Rev. the cardiac output can rise to min"! from a resting level of 5 L min-to The heart rate of a well-trained athlete might rise from 60 beats . et al." Science.121-142. 4. D. Biomechanics: Motion. Molecular Biology of the Cell. 1633-1642. and Englard. where 4CIib is 0. Y.J. salveolar oxygen partial pressure at 105 mmHg. For an oxygen pressure drop in the lungs of 30 mmHg. 10... W is work." in The Biomedical Engineering Handbook.8 40 100 25 15 100 Note that oxygen in blood is present in red blood cells bound to hemoglobin and freely dissolved in the red cell and the blood plasma. the rate of oxygen removal from the lung venules for the following conditions: inspired air containing oxygen at 21 % partial pressure. pp. 1994. Boston: Little. Fung.000 feet above sea level) the barometric pressure drops to 485 mmHg.. New York: John Wiley and Sons. 1997. editors. "Molecular architecture of tight junctions. determine the oxygen uptake rate for a respiration rate of 20 breaths per minute. and Tanner. editor." in The Lung: Scientific Foundations. determine the oxygen consumption rate VOz under rest and exercise conditions. editors. Groebe. New York: Worth Publishers. 11. Springer. pp. "Carbon dioxide transport. New York: Raven Press. 189-214. 13. 1. Jamieson. R. Humes. G.. 1. 20. S.." in The Liver: Biology and Pathobiology.of the concentration in urine to the concentration in plasma. Bethesda: American Physiological Society. 3d ed.50 Chapter 1 Introduction 1. 2002. Lehninger.]. Strain.3 Pa (1 Pa =I N m-2). the respiration rate rises to 30 breaths per minute and oxygen demand increases to 4 L min-to The partial pressure of oxygen in the pulmonary artery declines to 20 mmHg but remains at 100 mmHg in the pulmonary vein.4). H. 1994. 323-364. et al. is typically 0.. Flow. editors. Bray. Seitter. Transport Phenomena. pp. pp. 1993. Investigations on the Theory of the Brown- 2.11 References 51 1. R. S..." in Section 2: The Cardiovascular System. editors.. at an altitude of 3. r. Ltd.08206 L atm mol"! K-t and 1 atm = 760 mml-Ig. L Arias. A. R. Mitic. M.. Einstein. Crystal. 1005-1009.15 L). where P is power. Michel. "Design and morphometry of the pulmonary gas exchanger. L Arias. 1998. Biochemistry.. Ltd. 19. 2007... 27. Physiology.48:pp. Probstein. Alberts. 2004.. A. 17.M. pp. 16. editors. Bird. E. M. 1997.. Rest Pulmonary blood flow (L min-I) Arterial P O2 (mmHg) • Exercise Venous Po I (mmHg) 5.12 At elevated altitudes. New York: Cambridge University Press. 1995. Klocke. 30: pp. and Growth. 106 Mrnrnl-Ig'". pp.. Tissue Engineering: Principles for the Design of Replacement Organs and Tissues. Louis: Mosby Year Book. Biotechnol.. Boca Raton: CRC Press. 3d ed. McCuskey. 1984... For example. the hematocrit or volume fraction of red cells..40 for females. 3d ed. 2002. and Deamer.. R. 60: pp... 12. respiration rate of 10 breaths per minute. et aI.15 14. E.. Eggington and H. Determine the glomerular filtration rate using a urine production rate of 1 mL min ". 1. to the blood 'and measure its concentration in the blood and urine.14 Use the data in Table 1.. 1992.650 m (close to 12. American Cancer Society. G. K. and Lightfoot. New York: Raven Press. Crystal. Estimate the oxygen saturation in venous blood if the hematocrit rises to 0.N. M.. inulin. R. Assume that T = 37°C and R = 0. A. Eng. "Gas transfer' and transpo t" . pp.. P = W{ = f J Pad V. and Tanner. Hoffman and J." Nature. 743-785. 1995. 295: pp. "Tissue engineeringcurrent challenges and expanding opportunities. What would the ratio be if the solute were transported along with water? The glomerular filtration rate is an important measure of kidney function. "Energy metabolism.125 g mL -1. 2002.. 28.11. Hubbard.6. L. New York: Garland Publishing. R. Physiol. 0.. the hematocrit or volume fraction of red cells.33 X 10-6 M mmHg-1.45 for males and 0. N. 1147-1157. and Weitzel.56 L per breath. 1994. E. W. Physicochemical Hydrodynamics. Lightfoot. Using the results from Problem 1.A.. 1990.. 26. H02 is 1. E. et al..001 g/mL and the concentration in urine was 0.346: pp. 1. and {is heart rate in beats per second. "Membrane permeability barriers to ionic and polar solutes.. The plasma concentration of inulin was found to be 0. the blood flow rate can rise to 25 L min-I. Membr... and Scott. and Naughton." in Section 14: Cell PhYSIology.10 (a) Determine 7. Simionescu. E. Oxford Uruversiry Press. 1999. Weibel. R. 1061-1071 Rhoades. 22. and urea to determine the ratio. Ltd. editors. 451-455.T. Hct. K. Hct.. 1956. Inulin is not reabsorbed. "Hepatocyte surface polarity. 231-252. 18. Philadelphia: LippincottRaven Publishers. New York: Raven Press.. D." Nat... J. 1-17. T. "Replacement of renal function in uremic animals with a tissue-engineered kidney.. Ross." in The Lung: Scientific Foundatl?nS. J. editors.. "Cellular immunology.. 2d ed. Stress. 21.0203 M. and Neuberger. Saltzman. V. Philadelphia: Lippincott-Raven Publishers. A." in The Lung: Scientific Foundations. Furth." Ann. 1009-1014. Volume IV: Microcirculation. 24. et aI. determine the fraction of the metabolic energy used to pump blood through the body..D.. "Ultrastructure of the microvascular wall: Functional correlations. L Arias. w. G. L. 1994. tan Movement. "The ro'le ~f mass transfer in tissue function. S.A. K+.11 25 L During exercise.45. Ogunrinade. L. III Medical Physiology. "The hepatic microvascular system.. G. Brown and Company. editors.9 For the following data.6. pp. B.. 23. editor. Assess the power of the left side of the heart for the athlete and the sedentary person." in The Liver: Biology and Pathobiology. Make sure that your units are consistent.0203 M. 1997.. pp.. The total concentration of oxygen in blood is given by Equation (1. Berne. Inc. the body adapts to the reduced barometric pressure to extract sufficient oxygen to permit normal metabolic functions and do work.6. 17: pp. HOI is 1. Kameya. New York: Oxford University Press. A. glucose. New York: Springer-Verlag. Weibel. W.. IEEE Press. New York: Dover Publications. and Watson.650 kcal per day. et al. "Factors important in modeling oxygen supply to red muscle. Renkin and C.. 1999. Paula. New York: Oxford University Press." Ann. and Anderson. "Adhesion receptors of the immune system. is typically 0. 1990. whereas the heart rate of a' sedentary person might rise from 72 beats per minute to 125 beats per minute and the mean arterial pressure may rise from 100 to 150 mmHg. R. Raff." in Oxygen Transport in Biological Systems.. Griffith." Curro Top.3) relates the partial pressure (mmHg) to the concentration in plasma and the total concentration of oxygen in blood is given by Equation (1. 1.4) where 4CHb is 0. G.12 for Na+. 1089-1106. V is the ventricular volume." in The Liver: Biology and Path 0 biology. 9. St. pp. Fuchs. S. Barr.50 X 10-6 M mml-Ig'". 425-434. Crystal. J. S. Philadelphia: LIppincott-Raven Publishers. blood flow rate of 5 L min-I.. The alveolar volume equals the difference between the respiratory volume and the dead volume (0. "A bioartificial Iiver=state of the art. 5. 25. Boston: Little. Boston: Butterworths." Science. Determine the respiratory volume and oxygen consumption rate if the alveolar concentration of oxygen and dead volume are unchanged. R. Buffington. Stewart.13 The basal metabolic rate for a resting individual is about 1. Medical Physiology. Note: 1 mmHg = 133. 1989... Brown and Company. 1. 1995. Rhoades. Bronzino. and HHb is 1. 295: pp. editors. and Truskey.L.G. 1.11 I REFERENCES 1. J. and Levy.S.50 X per minute to 105 beats per minute and the mean arterial pressure may rise from 100 to 130 mmHg. 2002. "Effect of fluid shear stress bn the permeability of the arterial endothelium. Mackay. Inc. Atlanta: American Cancer Society. Determine the volume of blood ejected during each heartbeat (stroke volume) and the peripheral resistance for an athlete and a sedentary person. 15. Pa is the mean arterial pressure.60 and the partial pressure of oxygen blood is at a partial pressure equal to 98% of the alveolar leveL 6.

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