Connective tissue

- Connective tissue : is the tissues that provides a matrix that supports and
physically connects other tissues and cells together to form the organs of the body.
The interstitial fluid of connective tissue gives metabolic support to cells as the
medium for diffusion of nutrients and waste products.

- It is the most abundant tissue in the body , almost every organ as a support of
connective tissue .

- Unlike the other tissues in which the cells are abundant , here the extracellular
matrix (ECM) is more abundant .

- Extra- cellular matrices consist of different combinations of protein fibers (collagen

and elastic fibers) and ground substance. Ground substance is a complex of anionic,
hydrophilic proteoglycans, glycosaminoglycans (GAGs), and multiadhesive
glycoproteins (laminin, fibronectin, and others).

- All connective tissues originate from embryonic mesenchyme, a tissue developing

mainly from the middle layer of the embryo, the mesoderm.

- In addition to producing all types of connective tissue proper and the specialized
connective tissues bone and cartilage, the embryonic mesenchyme includes stem
cells for other tissues such as blood, the vascular endothelium, and muscle.

CELLS OF THE CONNECTIVE TISSUES

Fibroblasts Adipocytes Macrophages and mononuclear phagocyte system

Fibroblasts :
- are the key cells in the connective tissues and the permanent resident here ,
produce and maintain most of the tissue’s extracellular components.

- Fibroblasts synthesize and secrete collagen (the most abundant protein of the body)
and elastin, which both form large fibers, as well as the GAGs, proteoglycans, and
multi adhesive glycoproteins that comprise the ground substance.

- They can be divided into :

- Active which is the fibroblasts :

- The active fibroblast has more abundant and irregularly branched cytoplasm,
containing much rough endoplasmic reticulum (RER) and a well-developed Golgi
apparatus, with a large, ovoid, euchromatic nucleus and a prominent nucleolus.
- The quiescent cell fibrocytes is smaller than the active fibroblast, is usually spindle-
shaped with fewer processes, much less RER, and a darker, more heterochromatic
nucleus.

- Their growth is influences by the local growth factors .

- They also involved in the wound healing and here they are called myofibroblasts .

- Adipocytes
- Adipocytes, or fat cells, are found in the connective tissue of many organs. These
large, mesenchymally derived cells are specialized for cytoplasmic storage of lipid as
neutral fats, or less commonly for the production of heat.

- Tissue with a large population of adipocytes, called adipose connective tissue,

serves to cushion and insulate the skin and other organs.

Macrophages & the Mononuclear Phagocyte System

Macrophages :
- Are phagocytic cells that are abundant in sites of inflammation have highly
developed phagocytic ability and specialize in turnover of protein fibers and removal
of dead cells, tissue debris, or other particulate material . Size and shape vary
considerably, corresponding to their state of functional activity.

- A typical macrophage measures between 10 and 30 μm in diameter and has an

eccentrically located, oval or kidney-shaped nucleus. Macrophages are present in the
connective tissue of most organs and are sometimes referred to by pathologists as
“histiocytes.”

- They have irregular surface with pleats, protrusions, and indentations, features
related to their active pinocytotic and phagocytic activities, and they have well
developed Golgi apparatus .
- They are derived from the monocytes cells that circulated in the blood and under
certain conditions they cross the vessels walls to enter the connective tissues where
they will differentiate and mature and become phagocytic cells , where they are
abundant in sites of inflammation.

- They are found in most organs and with other monocyte- derived cells, they
comprise a family of cells called the mononuclear phagocyte system.

- All of these macrophage-like cells are derived from monocytes, but have different
names in various organs, for example, Kupffer cells in the liver, microglial cells in the
central nervous system , Langerhans cells in the skin, and osteoclasts in bone.

- All are long-living cells and may survive in the tissues for months. In addition to
debris removal, these cells are highly important for the uptake, processing, and
presentation of antigens for lymphocyte activation.

- The transformation from monocytes to macrophages in connective tissue involves

increases in cell size, increased protein synthesis, and increases in the number of
Golgi complexes and lysosomes.

Mast cells :

- Are oval or irregular cells ,filled with dense basophilic granules , which display
metachromasia, which means that they can change the color of some basic dyes (eg,
toluidine blue) from blue to purple or red.

- They function in release of substances which are important in inflammation ,

immunity and tissue repair . They include the following :

Heparin, a sulfated GAG that acts locally as an anticoagulant

Histamine, which promotes increased vascular permeability and smooth muscle

contraction

Serine proteases, which activate various mediators of inflammation

Eosinophil and neutrophil chemotactic factors, which attract those leukocytes

Cytokines, polypeptides directing activities of leukocytes and other cells of the

immune system

Phospholipid precursors, which are converted to prostaglandins, leukotrienes, and

other important lipid mediators of the inflammatory response.
- They are numerous near small blood vessels in skin and mesenteries (perivascular
mast cells) and in the tissue that lines digestive and respiratory tracts (mucosal mast
cells); the granule content of the two populations differs somewhat.

- These major locations suggest that mast cells place themselves strategically to
function as sentinels detecting invasion by microorganisms. They are involved in
type of allergic reaction called immediate hypersensitivity reactions by releasing their
granules , and an example of that is the anaphylactic shock ( a sever allergic reaction
that can be fatal ). They are also originated from progenitor cells in the bone marrow .

Plasma cells :

- These are B- lymphocyte–derived, antibody-producing cells. These relatively large,

ovoid cells have basophilic cytoplasm rich in RER and a large Golgi apparatus near
the nucleus that may appear pale in routine histologic preparations , with spherical
eccentric nucleus , always present in the connective tissues , living 10-20 days .

- Each antibody specific for one antigen , which become harmless when bound to this
antibody (when it will be destroyed by phagocytosis ) .

Leukocytes :

- These are wondering cells between the blood vessels( passing between the
endothelial cells of the vessel wall) and the connective tissues beside macrophages
and plasma cells . This is increased during inflammation :

- A vascular and cellular defensive response to injury or foreign substances,

including pathogenic bacteria or irritating chemical substances , begins with the local
release of chemical mediators from various cells, the ECM, and blood plasma
proteins.

- These substances act on local blood vessels, mast cells, macrophages, and other
cells to induce events for example :
- increased blood flow and vascular permeability , entry and migration of leukocytes,
- and activation of macrophages for phagocytosis.

- Classically, the major signs of inflamed tissues include “redness and swelling with
heat and pain”). Increased blood flow and vascular permeability produce local tissue
swelling (edema), with increased redness and warmth.

- Pain is due mainly to the action of the chemical mediators on local sensory nerve
endings. All these activities help protect and repair the inflamed tissue .
- The leukocytes live for only hours or days and then they will undergo apoptosis and
will be removed to the lymphoid tissues .

Fibers

Are elongated structures that are proteins polymerized after secreted from the
fibroblasts . There are three types :

Collagen fibers Elastic fibers Reticular fibers

collagen and reticular fibers are formed both from collagen family of proteins , elastic
fibers from elastin proteins .

Collagens

- Are proteins forming sheets , fibers and networks and found in all connective
tissues , basement membrane of the epithelial tissues , external lamina of the
muscles , and nerves .

- It is the most abundant protein in the human body consisting about 30% of the dry
weight . It is the major product of the fibroblasts and secreted from other cells .

- There are 28 collagen types found in the vertebra . They are divided into :

- Fibrillar collagens : collagens I, II, III ,V,XI : big fibrils that can be seen by electron
and light microscopes , densely found in the connective tissues . Found in the
tendons , dermis and organ capsules .

- Network or sheet forming collagens: collagens VI ,X ,formed by the epithelial tissues

and the major components of the epithelia basement membrane and the external
lamina .

- Linking anchoring collagens :collagens VII, IX ,XII ,XIV are short link fibril collagen
to one another and to other components of the ECM , they also link the sheet
collagen and anchor the basal lamina to the reticular lamina in the basement
membrane .
ELASTIC FIBERS

- Are smaller than collagen I fibers , found in many organs especially those subjected
to regular bending and stretching . These fibers have rubber like properties and
found in the lung and in the walls of the blood vessels .

Reticular fibers

- Found in delicate connective tissue of many organs, notably in the immune system,
reticular fibers consist mainly of collagen type III, which forms an extensive network
(reticulum) of fibers.

- Reticular fibers produced by fibroblasts occur in the reticular lamina of basement

membranes and typically also surround adipocytes, smooth muscle and nerve fibers,
and small blood vessels.

- Delicate reticular networks serve as the supportive stroma for the parenchymal
secretory cells and rich microvasculature of the liver and endocrine glands.

- Abundant reticular fibers also characterize the stroma of hemopoietic tissue (bone
marrow), the spleen, and lymph nodes where they support rapidly changing
populations of proliferating cells and phagocytic cells.

Ground Substance

- The ground substance of the ECM is a highly hydrated (with much bound water),
transparent, complex mixture of three major kinds of macromolecules:

- glycosaminoglycans (GAGs), proteoglycans, and multiadhesive glycoproteins.

Filling the space between cells and fibers in connective tissue, ground substance
allows diffusion of small molecules and, because it is viscous, acts as both a
lubricant and a barrier to the penetration of invaders. Physical properties of ground
substance also profoundly influence various cellular activities.

(GAGs) Also called mucopolysaccharides , the largest and most common is the
hyaluronan (hyaluronic acid) which is synthesize directly in the ECM by an enzyme
found in the cell membrane of many cells .

- Hyaluronan forms a viscous, pericellular network which binds a considerable

amount of water, giving it an important role in allowing molecular diffusion through
connective tissue and in lubricating various organs and joints. Other GAGs are
smaller and bound to the proteins and synthesized in Golgi apparatus like dermatan
and heparan sulfate .
Proteoglycans

- Consist of core proteins attached to sulfated GAGs . Like glycoproteins, they are
synthesized on RER, mature in the Golgi apparatus, where the GAG side-chains are
added, and secreted from cells by exocytosis.

- Unlike glycoproteins, proteoglycans have attached GAGs which often comprise a

greater mass than the polypeptide core. The commonest one is the perlecan , which
is the key proteoglycan in the basal membrane.

- Another example is aggrecan which bind to hyaluronan which found in large

amounts in the cartilage . In developing and mature connective tissues GAGs and
core proteins sequester many growth factors which are used during tissue repair .

Multiadhesive glycoproteins :

- All have multiple binding sites for cell surface integrins and for other matrix
macromolecules.

- The adhesive glycoproteins are large molecules with branched oligosaccharide

chains and allow adhesion of cells to their substrate.

- Examples are laminin, fibronectin , which are important for cell adhesion and
migration in ECM.

Water :

- Water in the ground substance of connective tissue is referred to as interstitial fluid

and has an ion composition similar to that of blood plasma.

- Interstitial fluid also contains plasma proteins of low molecular weight that pass
through

- the thin walls of the smallest blood vessels, the capillaries. Although only a small
proportion of connective tissue proteins are plasma proteins, it is estimated that as
much as one-third of the body’s plasma proteins are normally found in the interstitial
fluid of connective tissue because of its large volume and wide distribution. Two
factors are important in the movement of the water :

- The hydrostatic pressure of the blood caused by the pumping action of the heart,
which forces water out across the capillary wall

- The colloid osmotic pressure produced by plasma proteins such as albumin, which
draws water back into the capillaries
 TYPES OF THE CONNECTIVE TISSUES

Connective tissue proper:

According to amount of the collagen fibers , they divided also in :

Loose cutaneous Dense cutaneous Reticular tissues Mucoid tissue

Loose cutaneous :

- Also called areolar tissue, the loose connective tissue typically contains cells,
fibers, and ground substance in roughly equal parts

- The most numerous cells are fibroblasts, but the other types of connective tissue
cells are also normally found, along with nerves and small blood vessels.

- Collagen fibers predominate, but elastic and reticular fibers are also present. With at
least a moderate amount of ground substance, delicate consistency , flexible and not
resistant stretch .

Dense connective tissues :

- Dense connective tissue has similar components as loose connective tissue, but
with fewer cells, mostly fibroblasts, and a clear predominance of bundled type I
collagen fibers over ground substance.

- The abundance of collagen here protects organs and strengthens them structurally.
The tissue here according to the arrangement of the fiber bundles can be divide into :
- Dense irregular connective tissues : in which the fiber bundles are randomly
arranged and examples of that are the deep dermis layer of the skin and the capsule
of most organs.

- Dense regular connective tissues:

- Consists mostly of type I collagen bundles and fibroblasts aligned in parallel for
great resistance to prolonged or repeated stresses from the same direction , and the
best examples are the : tendons ,aponeurosis and the ligaments.

- Here the bundles are dense parallel with little amount of ground substance and few
blood vessels , inextensible and white in color with fibrocytes in between and
cytoplasmic folds also , and some of the elastic ligaments have elastic fibers beside
the collagen fibers.

- They are covered with layer of irregular dense ct continuous with adjacent muscles
and bones . And since the vasculature is poor here , so the repair process is slow.

Reticular tissues :

- Here the tissues are characterized by abundant amount of collagen III , support
many cell types and also known as reticulin and is formed by modified fibroblasts
called reticular cells , which are associated and partially covered the fibers.

- The loose disposition of glycosylated reticular fibers provides a framework with

specialized microenvironments for cells in hemopoietic tissue and some lymphoid
organs (bone marrow, lymph nodes, and spleen).

- The resulting cell-lined system creates a meshwork for the passage of leukocytes
and lymph.

- Macrophages and dendritic cells (also in the mononuclear phagocyte family) are
also dispersed within these reticular tissues to monitor cells formed there or passing
through and to remove debris.

Mucoid Tissue

- Mucoid (or mucous) connective tissue is the principal component of the fetal
umbilical cord, where it is referred to as Wharton’s jelly.

- With abundant ground substance composed chiefly of hyaluronan, mucoid tissue is

gelatinous, with sparse collagen fibers and scattered fibroblasts.

- Included among the fibroblastic cells are many mesenchymal stem cells,. Mucoid
connective tissue is similar to the tissue found in the vitreous chambers of eyes and
pulp cavities of young teeth.
skin

- Skin is the largest body organ , account for 15-20% of total body weight and in adult
it account for 1.5-2 m2 of the surface area , sometimes it is called the integument or
the cutaneous layer.

- the skin is composed of epidermis : epithelial layer of ectodermal origin.

- And dermis : a mesodermal connective tissue.

- In the irregular junction of the two layers we have dermal papillae, with invaginating
epidermal ridges.

- Epidermal derivatives are : hair , nails ,sebaceous and sweat glands . Beneath the
dermis lie the subcutaneous tissues which is a loose connective tissue bind the skin
to the underlying tissues.

Functions
- Protective : it is a physical and mechanical barrier against thermal insults , friction
and pathogen , melanin pigment protect against UV radiation ,and a permeability
barrier against excessive uptake or loss of fluids.

- Sensation : it is part of protection , since it’s protect against thermal or cold insults.

- Thermoregulatory :a constant body temperature is maintained here.

- Metabolic : skin cells synthesize vitamin D . Excess electrolytes removed via sweat
and energy stored in the subcutaneous layer as fat.

- Sexual signaling : pigmentation and hair are involved in the attraction between the
sexes.

- Any defect in these functions can lead to serious problems , like atopic eczema,
leprosy and sweat retention syndrome

Epidermis
- It consist mainly of stratified squamous epithelia , cells mainly are keratinocytes ,
with three less cells : melanocytes (pigment producing) ,Langerhans cells(antigen
presenting ) and Merkel cells(tactile cells).

- According to the epidermis the skin is divided into thick in the palms and the soles
and thin elsewhere in the body , the thickness varies from 75-150micrometer for thin
skin to 400-1400micrometer for thick skin , also it differ according to the site.

- The epidermis is a vascular , it receive it’s nutrients and O2 from the dermis .
- The human epidermis renewed every 15-30 days according to the age , site and
other factors .

- From the dermis upward the epidermis consist of four layers:

1- Basal layer (stratum basalis)
2- Spinous layer (stratum spinosum)
3- Granular layer (stratum granulosum)
4- Stratum lucidum
5- Stratum corneum

1- Basal layer (stratum basalis) : a single layer of cuboidal or columnar cells with
intense mitotic activity , it contain the progenitors for all epiderma layers and a niche
for the hair follicles.

- It rest on the basement membrane of the dermoepidermal junction connect to it by

the hemidesmosomes and to each other by the desmosomes . The keratinocytes here
contain the skeletal keratin and as the cells move upward it’s amount increase until it
become half the protein in the superficial layers.

2- Spinous layer (stratum spinosum): polyhedral cells contain nuclei and nucleolus
and it is the thickest layer in the epidermis ,

- the cells actively synthesize keratin and above the basal layer still some cells may
divide , and this layer may called the stratum germinativum and these cells contain
tonofilaments and numerous desmosomes and this layer is thickest in the areas
where there is more friction like in the sole of the foot with abundant tonofilaments
and desmosomes .

3- Granular layer (stratum granulosum) : 3-5 layers of flattened cells undergoing

keratinization ( the terminal process of differentiation ) and the cells here contain
keratohyalin granules(non membrane masses contain many proteins associated with
the keratins of the tonofilaments )

- and they also contain lamellar granules (contain lipids and glycolipids) , these
undergo exocytosis producing lipid rich impermeable layer around the cell and with
keratinization , form barrier to the penteration by most foreign materials.

4- Stratum lucidum : only found in thick skin , thin translucent layer of keratinocytes ,
nuclei and organelles lost and the cytoplasm consist of keratin packed in the matrix.

5- Stratum corneum : 15-20 layer of squamous keratinized cells , the fully keratinized
or cornified cells called squames continuously shed at the surface as the as the
desmosomes and the lipid rich envelopes break down here.
Melanocytes

- Are specialized cells of epidermis found in the basal layer and in hair follicles ,
neural crest derived migrate in the embryo to this area , one cell for each 5-6 basal
keratinocytes ( 600- 1200/mm2 of skin),

- they produce a brown or black pigment called eumelanins , and in the red hair it is
called the pheomelanin , the cells are pale rounded shape attached by
hemidesmosomes to the basal layer but not the keratinocytes have cytoplasmic
extensions passing through the basal and spinous layer.

- Melanin in these cells synthesized from the tyrosine into different types of melanin
linked to structural proteins and accumulate into vesicles then become mature
granules the melanosomes,

- these accumulate into the keratinocytes and before keratinization , they absorb the
sunlight , protecting the DNA of the living cells from the ionizing ,mutagenic effects of
the UV light.

- Keratinocytes contain melanin more than the melanocytes , the two form epidermal-
melanin unite , the density of which is similar in all individuals , but , in people near
the equator , the melanocytes are more to protect against the sun,

- while in for example north Europe , UV radiation is less and the need for the vitamin
D is more , the keratinocytes are lighter allowing UV penetration and vitamin D
production.

- Defects in the melanin formation can cause diseases like vitiligo and albinism

- Melanocytes can normally proliferate in the skin to produce moles or benign

melanocytic nevi , if there is change in the size or appearance , this may indicate
dysplastic changes and may progress to malignant melanoma and this may penetrate
basal lamina , the dermis and invade blood and lymphatic

Langerhans & Merkel

- Langerhans cells are monocytes derived cells , form 2-8% of epidermal cells , seen
clearly in the spinous layer , have cytoplasmic processes extend between the
keratinocytes , they bind process and present antigens to the T-lymphocytes ,

- so microorganisms can’t penetrate the skin without alerting these cells , this is part
of skin adaptive immunity .

- Excessive action of Langerhans cells can produce a condition called allergic

contact dermatitis which is allergic response caused by contact to a substance .
- Merkel cells or epithelia tactile cells are mechanoreceptors for sensing gentle
touch , abundant in areas like the fingertips and the bases of some hair follicles ,
attach to the keratinocytes by desmosomes and originate from the basal layer of
epidermis but lack melanosomes ,

- instead they have granules concentrated in areas where they contact the afferent
nerve fibers in the basal layer and light touch will cause release of neurotransmitters
and initiation of sensation in that area.

Dermis

- Is a layer of connective tissues connect the epidermis to the sub cutaneous tissues,
reach it’s maximum thickness in the back(4mm) , on the surface there are the dermal
papillae , there is always basement membrane between the dermis and the stratum
basale through which nutrients diffuse to the epidermis , it contain two layers

- Thin papillary layer include dermal papillae , type I and III collagen fibers ,
fibroblasts ,mast cells dendritic cells and leukocytes , and fiber of type VII collagen
insert in the basal lamina binding the dermis to the epidermis.

- Reticular layer is thick irregular connective tissues , mainly type I collagen and
fewer cells , also there are elastic fibers ,making the skin elastic and between the two
fibers abundant proteoglycans in dermatan sulfate.

- Between the two layers lies the subpapillary plexus for nutrition and
thermoregulation and also the dermis is richly innervated.

- Stretch marks, also known as striae, are a form of scarring on the skin with an off-
color hue. Over time they may diminish, but will not disappear completely.

- Stretch marks are caused by tearing of the dermis during periods of rapid growth of
the body, such as during puberty or pregnancy.

- vascular birthmark is a discoloration of the skin that is caused by blood vessels that
don't form correctly. They are present at birth or appear shortly after birth.

- Lymphoedema is a long-term (chronic) condition that causes swelling in the body's

tissues. It can affect any part of the body, but usually develops in the arms or legs. It
develops when the lymphatic system does not work properly.

- Urticaria, also known as hives, is an outbreak of swollen, pale red bumps or plaques
(wheals) on the skin that appear suddenly -- either as a result of the body's reaction
to certain allergens, or for unknown reasons. Hives usually cause itching, but may
also burn or sting .
- Leprosy is an infectious disease that causes severe, disfiguring skin sores and
nerve damage in the arms, legs, and skin areas around the body.

Subcutaneous tissues & sensory receptors

- Subcutaneous tissues is a loose connective tissues containing adipocytes vary in

number and size according to the region and nutrition , connecting the skin to the
underlying organs making the skin possible to slide over them . It is richly vasculized
making rapid intake of insulin and other injected drugs.

- Diverse sensory receptors found in the skin including simple without covering to
more complex sensory fibers enclosed by glia and delicate connective tissue
capsule , the unencapsulated receptors include :

Merkel cells Free nerve ending Root hair plexuses

- The encapsulated receptors respond rapidly to the stimuli on the skin and they are :

- Meissner corpuscles are numerous in the fingertips ,palms and the soles and
decrease with age , they initiate stimuli to light touch .

- Lamellated (Pacinian) corpuscles found deep in the dermis and hypodermis ,

specialized for coarse touch ,pressure and vibration , also found in connective
tissues of deep organs like the rectum and the urinary bladder (pressure sensation).

- Krause end bulb fund in the skin of penis and clitoris sensing low frequency
vibration.

- Ruffini corpuscles stimulated by stretch and twisting of the skin .

Hair

- Are elongated keratinized structures formed in the epidermal invaginations the hair
follicles , the color ,size ,shape and texture vary according to the age , genetic and
region of the body.

- All the skin has hair except the palms , soles ,lips ,glans penis ,clitoris and the labia
minora .

- Hair growth had growth and rest cycles and the growth not the same in all regions .

- Growing hair follicle has hair bulb , in the base of which insert a dermal papilla
contains capillary network , keratinocytes continuous here and they form the matrix
of the hair root and the hair shaft.
- The keratin here is harder and mare compact.

- The hair especially thick ones had central medulla and cortex around it and cuticle
cover the cortex , also it has internal and external root sheaths and there is a glassy
membrane separating the follicle from the dermis . To the hair follicle attached.

- the arrector pili muscle a smooth muscle extend from the mid fibrous sheath to the
dermal papillary layer , in cold it cause the hair to be in erect position to bring worm

- Hair growth has three cycles :

1- Anagen a long period of mitotic activity and growth.

2- Catagen a period of arrested growth and hair bulb regression

3- Telogen a long period of inactivity in which the hair may be shed

- By the end of these phases and begin of the new cycle , the epidermal stem cells
near the pili muscle produce the progenitor cells for matrix of new hair.

- The hair growth in the face and pubis influenced by sex hormones and begin at
puberty.

- Loss of hair producing baldness or alopecia which can be partial(areata) or

complete(totalis) result from complex. Combination of genetic and hormonal factors.

- Reversible alopecia occur during cancer chemotherapy causing disrupt in the

function and the structure of the hair follicles.

Nails

- Are hard plates of keratin on the dorsal surface of the each distal phalanx , the
proximal part called the nail root with a fold of skin called cuticle or eponychium , it
has also a nail plate bound to bed of epidermis and nail bed which contain the basal
and spinous epidermis.

- The nail root form the nail matrix in which the cells divide , move distally and
keratinized like the hair , the growth in the is 3mm/month for fingernails and 1mm/mo
for toenails .the distal free end called the hyponychium.

Skin Glands

- Sebaceous glands are embedded in the dermis over most areas except palms and
soles , in average of 100/cm2 of skin , but in the face and the scalp 400-900/cm2 .
- They are branched acinar glands empty in the upper portion of the hair follicle
forming the pilosebaceous unite , in hairless areas like the penis , clitoris eyelids and
nipples , the ducts open directly on the epidermal surface.

- The glands here are holocrine and secret sebum a complex mixture of lipids
hydrolyzed by bacterial enzymes after secretion and it is increased after puberty and
under control of testosterone in male and ovarian and adrenal androgen in female . It
has weak antifungal and antibacterial effects.

- Sweat glands are long epidermal invaginations embedded in the dermis , have two
types

- Eccrine sweat glands are widely distributed , mostly in the sole (620/cm2) and
allover the body there are 3 million glands(equal to a mass of a kidney) producing
10L/day in response to different stimuli like increased temperature during exercise or
thermal stress , so it is a thermoregulator.

- The secretory part has three cell types : clear cells which secret the sweat and they
are the connect between the blood and the gland ,dark cells secret glycoproteins with
antibacterial activity and myoepithelial cells contract to move the secretions into the
duct.

- The ducts cells absorb Na to prevent excessive loss . When secreted the sweat
evaporated cooling the skin and the blood in the area . These gland eliminate
nitrogenous products and excess salts.

- Apocrine sweat glands in fact they are merocrine and not apocrine(as their
secretions undergo exocytosis ) , and confined to the axillary and perineal regions.

- their development and function not complete till puberty as their development
depend on the sex hormones.

- Their secretions may contain protein rich product , slightly viscous which initially
odorless but may later acquire a distinctive one due to bacterial activity.

- They are supplied by adrenergic supply while the eccrine by cholinergic fibers .

- Hyperhidrosis is a condition characterized by abnormally increased sweating, in

excess of that required for regulation of body temperature.

- Although primarily a physical burden, hyperhidrosis can deteriorate quality of life

from a psychological, emotional, and social perspective.

- Hidradenitis suppurativa (HS), also known as acne inversa, is a long-term skin

disease characterized by the occurrence of inflamed and swollen lumps.
- These are typically painful and break open, releasing fluid or pus. The areas most
commonly affected are the underarms.

Skin Repair
- Skin has good ability for repair . The cutaneous wound healing take many steps:

1- The blood vessels in the cut coagulate and release growth factors and , the
macrophages and the neutrophils remove the debris and bacteria this is the
inflammation which take 2-3 days .

2- Epithelialization occur by migration of the epidermal basal cell layer coming

beneath the blood clot (which will become scar) and sometimes come from the bulge
of the hair follicles.

3- Granulation tissues replace the clot , then this tissues will undergo remodeling ,
the collagens and the fibroblasts are more initially here than the surrounding forming
a scar.

- Excessive scar formation called keloid (are firm, rubbery lesions or shiny, fibrous
nodules, and can vary from pink to the color of the person's skin or red to dark brown
in color.

- A keloid scar is benign and not contagious, but sometimes accompanied by severe
itchiness, pain, and changes in texture. In severe cases, it can affect movement of
skin.
 Nervous system
- The human nervous system is the most complex system in the body , it is is formed
by a network of many billion nerve cells (neurons), all assisted by many more
supporting cells called glial cells.

- Each neuron has hundreds of interconnections with other neurons, forming a very
complex system for processing information and generating responses .

- Nerve tissue is distributed throughout the body as an integrated communications

network.

anatomically divided into two parts :

1- Central nervous system 2- Peripheral nervous system

1- Central nervous system : consisting from the brain and the spinal cord.

2- Peripheral nervous system : consisting from cranial, spinal and peripheral nerves
conducting impulses from and to the CNS ( sensory and motor ) and ganglia
(aggregations of neurons outside the CNS.

Neurons

- They are the functional unites in both the CNS & PNS ,and most of these cells
consist of:

- The cell body (also called the perikaryon or soma) which contains large euchromatic
nucleus with prominent nucleolus , the cytoplasm contain polyribosomes and highly
developed RER (high activity for the production of cytoskeletal and and secretion and
transport proteins )

- these areas called Nissl bodies (their amount vary according to the activity of the
cell) , Golgi apparatus found only in the cell body and the mitochondria found in the
axon terminals .

- Both the body and the processes contain microtubules , actin filaments and
intermediate filaments which are formed by the neurofilaments or the neurofibrils.

- The dendrites, which are the numerous elongated processes extending from the
perikaryon and specialized to receive stimuli from other neurons at unique sites
called synapses.

- typically short, small processes emerging and branching off the soma , are the
principal signal reception and processing sites on neurons.
- The large number and extensive branching of dendrites allow a single neuron to •
receive and integrate signals from many other nerve cells ,dendrites become much
thinner as they branch, with the filaments and microtubules predominating in these
distal regions.

- In the CNS most synapses on dendrites occur on dendritic spines, which are
membrane protrusions along the small dendritic branches ,and serve as the initial
processing sites for synaptic signals and occur in large numbers, estimated to be on
the order of 10 for cells of the human cerebral cortex.

Axons

- The axon ( axis), which is a single long process ending at synapses specialized to
generate and conduct nerve impulses to other cells (nerve, muscle, and gland cells).

- Axons may also receive information from other neurons, information that mainly
modifies the transmission of action potentials to those neurons ,their length vary
according to the function reaching 1 meter in the foot muscles and large cell bodies
and they originate from axon hillock in the perikaryon , where here the
axolemma(axon plasma membrane ) generate the action potential , and the cytoplasm
called axoplasm ,

- and here in this region after receiving the excitatory or inhibitory stimuli , the
decision is made to send or not send the nerve impulse

- Nerve impulse or action potential is an electrochemical process spread along the

axons by diffusion of the Na and K ions in and out of the axoplasm.

- According to the number of processes , neurons can be divided into :

1- Multipolar. 2- Bipolar 3- Unipolar or Pseudounipolar 4- Anaxonic neurons .

- So the nerve fiber is an axon and myelin sheath which covers the axon and increase
the conduction velocity , and functionally the nerve fibers can be divided into :

- Sensory or afferent fibers receiving stimuli from receptors allover the body .

- Motor or efferent nerve fibers sending impulses to the affecter organs like the
muscles and the glands .

- Somatic nerve fibers under voluntary control and typically innervate skeletal
muscle .

- Autonomic nerve fibers control the involuntary or unconscious activities of glands,

cardiac muscle, and most smooth muscle.
- 99% of adult neurons have interneurons , ie the cells have relationships with each
other forming circuits , and these cells either multipolar or anaxonic.

Synapses
- Synapses (Gr. synapsis, union) are sites where nerve impulses are transmitted from
one • neuron to another, or from neurons and other effector cells.

- The structure ensures that transmission is unidirectional.

- Synapses convert an electrical signal (nerve impulse) from the presynaptic cell into
a chemical signal that affects the postsynaptic cell.

- Most synapses act by releasing neurotransmitters, which are usually small

molecules that bind specific receptor proteins to either open or close ion channels or
initiate second- messenger cascades, the synapse consist of:

- The presynaptic axon terminal (terminal bouton) contains mitochondria and

numerous synaptic vesicles from which neurotransmitter is released by exocytosis.

- The postsynaptic cell membrane contains receptors for the neurotransmitter, and
ion channels or other mechanisms to initiate a new impulse.

- Intercellular space called the synaptic cleft separates these presynaptic and •
postsynaptic membranes.

- At the presynaptic region the nerve impulse briefly opens calcium channels,
promoting a Ca2+ influx that triggers neurotransmitter release by exocytosis or
similar mechanisms.

- Immediately the released neurotransmitter molecules diffuse across the synaptic

cleft and bind receptors at the postsynaptic region. This produces either an
excitatory or an inhibitory effect at the postsynaptic membrane

Glial cells

- Glial cells support neuronal survival and activities, and are ten times more abundant
than neurons in the mammalian brain.

- Like neurons most glial cells develop from progenitor cells of the embryonic neural
plate.

- In the CNS glial cells surround both the neuronal cell bodies, which are often larger
than the glial cells, and the processes of axons and dendrites occupying the spaces
between neurons. Glial cells replace for the connective tissues in the CNS .
Nerve Organization
- In the PNS nerve fibers are grouped into bundles to form nerves. Except for very
thin • nerves containing only unmyelinated fibers, nerves have a whitish, glistening
appearance because of their myelin and collagen content.

- Axons and Schwann cells are enclosed within layers of connective tissue).
Immediately around the external lamina of the Schwann cells is a thin layer called the
endoneurium, consisting of reticular fibers, scattered fibroblasts, and capillaries.

- Groups of axons with Schwann cells and endoneurium are bundled together as
fascicles by a sleeve of perineurium, containing flat fibrocytes with their edges sealed
together by tight junctions.

- From two to six layers of these unique connective tissue cells regulate diffusion into
the fascicle and make up the blood-nerve barrier that helps maintain the fibers’
microenvironment.

- Externally, peripheral nerves have a dense, irregular fibrous coat called the
epineurium, which extends deeply to fill the space between fascicles.

- Very small nerves consist of one fascicle . Small nerves can be found in sections of
many organs and often show a winding disposition in connective tissue.

- Peripheral nerves establish communication between centers in the CNS and the •
sense organs and effectors (muscles, glands).

- They generally contain both afferent and efferent fibers. Afferent fibers carry
information from internal body regions and the environment to the CNS.

- Efferent fibers carry impulses from the CNS to effector organs commanded by these
centers. Nerves possessing only sensory fibers are called sensory nerves; those
composed only of fibers carrying impulses to the effectors are called motor nerves.
- Most nerves have both sensory and motor fibers and are called mixed nerves,
usually also with both myelinated and unmyelinated axons.

Ganglia
- Ganglia are typically ovoid structures containing neuronal cell bodies and their
surrounding glial satellite cells supported by delicate connective tissue and
surrounded by a denser capsule.

- Because they serve as relay stations to transmit nerve impulses, at least one nerve
enters and another exits from each ganglion. The direction of the nerve impulse
determines whether the ganglion will be a sensory or an autonomic ganglion.

Sensory Ganglia

Sensory ganglia receive afferent impulses that go to the CNS. Sensory ganglia are
associated with both cranial nerves (cranial ganglia) and the dorsal roots of the
spinal nerves (spinal ganglia).

- The large neuronal cell bodies of ganglia are associated with thin, sheet-like
extensions of small glial satellite cells .

- Sensory ganglia are supported by a distinct connective tissue capsule and an

internal framework continuous with the connective tissue layers of the nerves.

- The neurons of these ganglia are pseudounipolar and relay information from the
ganglion’s nerve endings to the gray matter of the spinal cord via synapses with local
neurons.
Autonomic Ganglia
- Autonomic ganglia are small bulbous dilations in autonomic nerves, usually with
multipolar neurons.

- Some are located within certain organs, especially in the walls of the digestive tract,
where they constitute the intramural ganglia.

- The capsules of these ganglia may be poorly defined among the sacral portion of
the spinal cord.

- Sympathetic second neurons are located in small ganglia along the vertebral
column, while second neurons of the parasympathetic series are found in very small
ganglia always located near or within the effector organs, for example in the walls of
the stomach and intestines.

- Parasympathetic ganglia may lack distinct capsules altogether, neurons and

associated satellite cells simply forming a loosely organized plexus within the
surrounding connective tissue.

CENTRAL NERVOUS SYSTEM

- The major structures comprising the CNS are the cerebrum, cerebellum, and spinal
cord .

- The CNS is completely covered by connective tissue layers, the meninges, but CNS
tissue contains very little collagen , making it relatively soft and easily damaged by
injuries affecting the protective skull or vertebral bones.

- It consist of areas of white matter and gray matter, differences caused by the
differential distribution of lipid-rich myelin.

- The main components of white matter are myelinated axons , often grouped
together as tracts, and the myelin- producing oligodendrocytes.

- Astrocytes and microglia are also present, but very few neuronal cell bodies. Gray
matter contains abundant neuronal cell bodies, dendrites, astrocytes, and microglial
cells, and is where most synapses occur.

- Gray matter makes up the thick cortex or surface layer of both the cerebrum and the
cerebellum; most white matter is found in deeper regions.

- Deep within the brain are localized, variously shaped darker areas called the
cerebral nuclei, each containing large numbers of aggregated neuronal cell bodies.
- Neurons of the cerebral cortex function in the integration of sensory information
and the initiation of voluntary motor responses.

- The sharply folded cerebellar cortex coordinates muscular activity throughout the
body and is organized with three layers:

- A thick outer molecular layer

- A thin middle layer consists only of very large neurons called Purkinje cells

- A thick inner granular layer contains various very small, densely packed neurons

- In spinal cord the white matter is peripheral and the gray matter forms a deeper, H-
shaped mass.

- The two anterior projections of this gray matter, the anterior horns, contain cell
bodies of very large motor neurons whose axons make up the ventral roots of spinal
nerves.

- The two posterior horns contain interneurons which receive sensory fibers from
neurons in the spinal (dorsal root) ganglia.

- Near the middle of the cord the gray matter surrounds a small central canal, which
develops from the lumen of the neural tube, is continuous with the ventricles of the
brain, is lined by ependymal cells, and contains CSF.

Meninges
- The skull and the vertebral column protect the CNS, meninges are the connective
tissues • between the bone and the nervous tissues.

- We have three meningeal layers: the dura, arachnoid, and pia maters:

Dura Mater
- The thick external dura mater consists of two layers ,dense irregular connective
tissue organized as an outer periosteal layer continuous with the periosteum of the
skull, and an inner meningeal layer.

- The two layers are usually fused, but along the superior sagittal surface and other
specific areas around the brain they separate to form the blood-filled dural venous
sinuses .

- In the spinal cord the dura mater is separated from the periosteum of the vertebrae
by the epidural space, which contains a plexus of thin- walled veins and loose
connective tissue .
- The dura mater may be separated from the arachnoid by formation of a thin
subdural space.

Arachnoid
It has two components:
(1) a sheet of connective tissue(which is a vascular, but large • vessels run through it)
in contact with the dura mater.

(2) a system of loosely arranged trabeculae composed of collagen and fibroblasts,

continuous with the underlying pia mater layer.

Surrounding these trabeculae is a large, sponge-like cavity, the subarachnoid space,

filled with CSF. This fluid-filled space helps cushion and protect the CNS from minor
trauma. The subarachnoid space communicates with the ventricles of the brain where
the CSF is produced.

- The arachnoid and the pia mater are intimately associated and are often considered
a single membrane called the pia-arachnoid.

- In some areas, the arachnoid penetrates the dura mater and protrudes into blood-
filled dural venous sinuses located there.

- These CSF-filled protrusions, which are covered by the vascular endothelial cells
lining the sinuses, are called arachnoid villi and function as sites for absorption of
CSF into the blood of the venous sinuses.

Pia Mater
- The innermost pia mater consists of flattened, mesenchymally derived cells closely
applied to the entire surface of the CNS tissue.

- The pia does being separated from the neural elements by the very thin superficial
layer of astrocytic processes (the glial limiting membrane, or glia limitans), which
adheres firmly to the pia mater. Together, form a physical barrier separating CNS
tissue from CSF in the subarachnoid space.

- Blood vessels penetrate CNS tissue through long peri- vascular spaces covered by
pia mater, although the pia disappears when the blood vessels branch to form the
small capillaries. However, these capillaries remain completely covered by the
perivascular layer of astrocytic processes.
Blood-Brain Barrier
- The blood-brain barrier (BBB) is a functional barrier that allows much tighter •
control than that in most tissues over the passage of substances moving from blood
into the CNS tissue.

- The main structural component of the BBB is the capillary endothelium, in which the
cells are tightly sealed together with well- developed occluding junctions, with little or
no transcytosis activity, and surrounded by the basement membrane.

- The limiting layer of perivascular astrocytic feet that envelops the basement
membrane of capillaries in most CNS regions contributes to the BBB and further
regulates passage of molecules and ions from blood to brain.

- The BBB protects neurons and glia from bacterial toxins, infectious agents, and
other exogenous substances, and helps maintain the stable composition and
constant balance of ions in the interstitial fluid required for normal neuronal function.

- The BBB is not present in regions of the hypothalamus where plasma components
are monitored, in the posterior pituitary which releases hormones, or in the choroid
plexus where CSF is produced.

Choroid Plexus
The choroid plexus consists of highly vascular tissue, folded and projecting into the
large ventricles of the brain . It is found in the roofs of the third and fourth ventricles
and in parts of the two lateral ventricular walls, all regions in which the ependymal
lining directly contacts the pia mater.

- Each villus of the choroid plexus contains a thin layer of well- vascularized pia
mater • covered by cuboidal ependymal cells.

- The function of the choroid plexus is to remove water from blood and release it as
the CSF. CSF is clear, contains Na+, K+, and Cl– ions but very little protein, and its
only cells are normally very sparse lymphocytes.

- It is produced continuously and it completely fills the ventricles, the central canal of
the spinal cord, the subarachnoid and perivascular spaces.

- It provides the ions required for CNS neuronal activity and in the arachnoid serves
to help absorb mechanical shocks.

- Arachnoid villi provide the main pathway for absorption of CSF back into the venous
circulation. There are very few lymphatic vessels in CNS tissue.
 Peripheral Nervous System

- The main components of the peripheral nervous system (PNS) are the nerves,
ganglia, and nerve endings. Nerves are bundles of nerve fibers (axons) surrounded
by Schwann cells and layers of connective tissue .

- In peripheral nerve fibers, axons are sheathed by Schwann cells, or

neurolemmocytes .The sheath may or may not form myelin around the axons,
depending on their diameter. The PNS divided into somatic (voluntary) and autonomic
(involuntary) .

Myelinated Fibers

- Axons of large diameter grow in the PNS, they are engulfed along their length by a
series of differentiating neurolemmocytes and become myelinated nerve fibers.

- The plasma membrane of each covering Schwann cell fuses with itself at an area
termed the mesaxon and a wide, flattened process of the cell continues to extend
itself, moving circumferentially around the axon many times .

- The multiple layers of Schwann cell membrane unite as a thick myelin sheath.
Composed mainly of lipid bilayers and membrane proteins, myelin is a large
lipoprotein complex , represent the fused, protein-rich cytoplasmic surfaces of the
Schwann cell membrane.

- Membranes of Schwann cells have a higher proportion of lipids than do other cell
membranes, and the myelin sheath serves to insulate axons and maintain a constant
ionic microenvironment most suitable for action potentials.

- Between adjacent Schwann cells on an axon the myelin sheath shows small nodes
of Ranvier (or nodal gaps), where the axon is only partially covered by interdigitating
Schwann cell processes.

- At these nodes the axolemma is exposed to ions in the interstitial fluid and has a
much higher concentration of voltage-gated Na+ channels, which renew the action
potential and produce saltatory conduction of nerve impulses, their rapid movement
from node to node.

- The length of axon ensheathed by one Schwann cell, the internodal segment, varies
directly with axonal diameter and ranges from 300 to 1500 μm.

Unmyelinated Fibers

- Unlike the CNS where many short axons are not myelinated at all but run free among
the other neuronal and glial processes, the smallest-diameter axons of peripheral
nerves are still enveloped within simple folds of Schwann cells .
- In these unmyelinated fibers the glial cell does not form the multiple wrapping of a
myelin sheath , here, each Schwann cell can enclose portions of many axons with
small diameters.

- Without the thick myelin sheath, nodes of Ranvier are not seen along unmyelinated
nerve fibers. Moreover, these small-diameter axons have evenly distributed voltage-
gated ion channels; their impulse conduction is not saltatory and is much slower
than that of myelinated axons.

Somatic Nervous System

- The somatic nervous system includes everything under voluntary control as well as
one involuntary function, the somatic reflex arc (tests for when tapping the tendon
under knee with rubber hammer).

- The SNS includes both afferent (sensory) nerves that transmit various types of
information (e.g., smells, pressure and pain) to the the brain for processing and
efferent (motor) nerves that direct the muscles under control, such as those in legs
and arms, to execute certain movements, such as throwing or running.

- The nerves of the SNS are classified on the basis of location. For example, there are
12 pairs of cranial nerves, which originate in the head and supply the muscles of the
eyes, throat and other areas within the head with both motor and sensory fibers; and
31 pairs of spinal nerves, all of which service the voluntary muscles of the trunk,
pelvis, arms and legs. The neurotransmitter chemical acetylcholine is an excitatory
neurotransmitter in the SNS, meaning that it tends to stimulate movements.

Autonomic Nervous System

- The autonomic nervous system is the part of the nervous system that supplies the
internal organs, including the blood vessels, stomach, intestine, liver, kidneys,
bladder, genitals, lungs, pupils, heart, and sweat, salivary, and digestive glands.

- Autonomic nerves use two-neuron circuits. The first neuron of the chain, with the
preganglionic fiber, is located in the CNS. Its axon forms a synapse with
postganglionic fibers of the second multipolar neuron in the chain located in a
peripheral ganglion system.

- The chemical mediator present in the synaptic vesicles of all preganglionic axons is
acetylcholine.
- The autonomic nervous system has two main divisions:

1- Sympathetic 2- Parasympathetic

- After the autonomic nervous system receives information about the body and
external environment, it responds by stimulating body processes, usually through the
sympathetic division, or inhibiting them, usually through the parasympathetic
division.

- An autonomic nerve pathway involves two nerve cells. One cell is located in the
brain stem or spinal cord.

- It is connected by nerve fibers to the other cell, which is located in a cluster of nerve
cells (called an autonomic ganglion).

- Nerve fibers from these ganglia connect with internal organs. Most of the ganglia for
the sympathetic division are located just outside the spinal cord on both sides of it.

- The ganglia for the parasympathetic division are located near or in the organs they
connect with.

The autonomic nervous system controls internal body processes such as the
following:

1- Blood pressure

2- Heart and breathing rates

3- Body temperature

4- Digestion

5- Metabolism (thus affecting body weight)

6- The balance of water and electrolytes (such as sodium and calcium)

7- The production of body fluids (saliva, sweat, and tears)

8- Urination

9- Defecation

10- Sexual response

- Many organs are controlled primarily by either the sympathetic or the
parasympathetic division.

- Sometimes the two divisions have opposite effects on the same organ. For example,
the sympathetic division increases blood pressure, and the parasympathetic division
decreases it.

- Overall, the two divisions work together to ensure that the body responds
appropriately to different situations.

- Generally, the sympathetic division does the following:

- Prepares the body for stressful or emergency situations—fight or flight

- Thus, the sympathetic division increases heart rate and the force of heart
contractions and widens (dilates) the airways to make breathing easier.

- It causes the body to release stored energy. Muscular strength is increased. This
division also causes palms to sweat, pupils to dilate, and hair to stand on end.

- It slows body processes that are less important in emergencies, such as digestion
and urination.

The parasympathetic division does the following:

- Controls body process during ordinary situations.

- Generally, the parasympathetic division conserves and restores. It slows the heart
rate and decreases blood pressure.

- It stimulates the digestive tract to process food and eliminate wastes. Energy from
the processed food is used to restore and build tissues.

- Both the sympathetic and parasympathetic divisions are involved in sexual activity,
as are the parts of the nervous system that control voluntary actions and transmit
sensation from the skin (somatic nervous system).

- Two chemical messengers (neurotransmitters) are used to communicate within the

autonomic nervous system:

- Acetylcholine

- Norepinephrine

- Nerve fibers that secrete acetylcholine are called cholinergic fibers.

- Fibers that secrete norepinephrine are called adrenergic fibers.

- Generally, acetylcholine has parasympathetic (inhibiting) effects and norepinephrine

has sympathetic (stimulating) effects. However, acetylcholine has some sympathetic
effects. For example, it sometimes stimulates sweating or makes the hair stand on
end.