CELL INJURY AND DEATH Cell Injury: There are many ways of injuring cells in the body: • Ischemia: deficit of oxygen in the cells that interferes with cellular metabolism. Hypoxia- reduced oxygen in the tissue. Physical agents, excessive heat / cold or radiation exposure; Mechanical damage such as pressure of tearing of tissue. Chemical toxins / foreign substances - Exogenous – chemicals from the environment - Endogenous- chemicals “ inside the body Microorganisms (bacteria, viruses, and parasites) Abnormal metabolites accumulating in cells Nutritional deficits
• • •
• • •
• Imbalance of fluids and electrolytes Cell Death • Apoptosis: Programmed cell death which may occur when cell development is abnormal. Cell numbers are excessive or cells are injured / aged. Necrosis: when a group of cells die - Liquefaction Necrosis- process by which dead cells liquefy under the influence of certain cell enzymes - Coagulative Necrosis- when the cell proteins are altered or denatured and retain some form for a time after death - Fat Necrosis- fatty tissue is broken down into fatty acids in the presence of infection or certain enzymes - Caseous Necrosis- form of coagulation necrosis in which a thick, yellowish, “cheesy” substance forms - Infarction- an area of dead cells resulting from lack of oxygen Gangrene- an area of necrotic tissue that has been invaded by bacteria
B. CELLULAR ABERRATION Terms Common Cause Atrophy- decrease in Reduced use of the the size of cells, tissue, insufficient resulting in reduce nutrition, decrease tissue mass neurological or hormonal stimulation and aging Hypertrophy- increase Additional work by the in the size of individual tissue, excessive cells, resulting in an hormonal stimulation enlarge tissue mass Hyperplasia- increased number of cells resulting in an enlarge tissue mass May be compensatory mechanism to meet increased demands, or it may be pathologic when there is abnormal imbalance May result from deficit of vitamin A, may be an adaptive mechanism that provides a more resistant tissue occurs when differentiated body cells return to an undifferentiated state, often forming a tumor, cells show an increased ability to multiply and also fails to differentiate properly Genetic, Lymphoid neoplasm, Hematogenic, Idiopathic, UV rays , X rays , Diet rich in red meat, Smoking, Alcohol ,Hormone
Example/s Shrinkage of skeletal muscles that occurs when a limb is immobilized in a cast for several weeks Enlarge heart muscle resulting from increased demands, effect of consistent exercise on skeletal muscle Uterine enlargement that occurs during pregnancy
Metaplasia- one mature cell type is replace by a different matured cell type
Anaplasia- cells that are undifferentiated and have variable nuclei and cell structure and numerous mitotic figures
When stratified squamous epithelium replaces ciliated columnar epithelium in the respiratory tracts of cigarette smokers Associated with malignancy or cancer and is basis for grading a tumor
Neoplasm- means “new growth” and commonly called tumor
Benign neoplasms include uterine fibroids and melanocytic nevi (skin moles), Potentially malignant neoplasms , Malignant neoplasms are commonly called
replacement therapy if used for more than 5 years, Obesity, Immunogenic, Chemical exposure, Mutation, Radiation exposure
cancer. They invade and destroy the surrounding tissue, may form metastases and eventually kill the host.
C. RESPONSES OF BODY TO INJURY The mechanism for triggering the response the body to injury is extremely sensitive. Responses are to tissue damage that might not normally be thought of as injury, for example when the skin is stroked quite firmly or if some pressure is applied to a tissue. In addition, the body has the capacity to respond to both minor injuries such as bruising, scratching, cuts, and abrasions, as well as to major injuries such as severe burns and amputation of limbs. • SYSTEMIC
Four major organ systems are involved in wound healing: the sympathetic nervous system, the endocrine organs, the cardiovascular system, and an acute phase reaction involving the liver. During the immediate systemic response, the wounded person becomes alert, opiumlike substances are released to decrease pain, the heart and respiratory rates quicken, blood glucose levels rise, and the basal metabolic rate speeds up. This is a stress reaction, with organ systems functioning at supraphysiological levels. A sustained level of stress takes a toll on the body's physiology unless supported by appropriate nutritional therapy. The systemic response is produced as local chemical mediators spill into blood vessels from the wound. They activate circulating monocytes (a kind of immune cell) to release chemical messengers called cytokines. These cytokines cause the various metabolic changes seen after trauma. In cases of major trauma, there may be generalized fever; increased oxygen consumption; and increased metabolism of fats, glucose, and proteins. As the reaction is prolonged over days or weeks, local lymph nodes and the spleen enlarge to supply immune cells. More serious injury is also accompanied by systemic response in which the cardiovascular, endocrine and indeed the whole body metabolism are involved. NEUROENDOCRINE
The neuroendocrine response to multiple trauma is a coordinated, complex, changing response which has as its objective maintenance of life by preserving oxygen delivery and the mobilization and utilization of the synthetic and energetic substrates required by the body. The afferent system is composed of neural input from the various chemoceptors, nociceptors, and baroceptors which monitor normal bodily function, in addition to the effects of plasma factors directly on the brain (e.g., glucose and amino acids). The efferent system is composed of the autonomic nervous system and the output of the anterior and posterior pituitary and other hormones. The efferent response is shown by measurements of ACTH, arginine vasopressin, growth hormone, prolactin, norepinephrineepinephrine, and opiate peptides. This efferent output then modulates the response of the pancreatic islets with the observed changes in glucagon and insulin and of the adrenal glands with additional changes in the catechol-amines and cortisol. The renin-angiotensin-aldosterone system involving the kidney and adrenal gland is another responding system.
IMMUNOLOGIC Immunologic response is a bodily defense reaction that recognizes an invading substance such as a virus or fungus or bacteria or transplanted organ and produces antibodies specific against that antigen. The immune system protects organisms from infection with layered defenses of increasing specificity. In simple terms, physical barriers prevent pathogens such as bacteria and viruses from entering the organism. If a pathogen breaches these barriers, the innate immune system provides an immediate, but non-specific response. Innate immune systems are found in all plants and animals. If pathogens successfully evade the innate response, vertebrates possess a third layer of protection, the adaptive immune system, which is activated by the innate response. Here, the immune system adapts its response during an infection to improve its recognition of the pathogen. This improved response is then retained after the pathogen has been eliminated, in the form of an immunological memory, and allows the adaptive immune system to mount faster and stronger attacks each time this pathogen is encountered.
WOUND HEALING Wound healing, or wound repair, is an intricate process in which the the organ or skin repairs itself after injury In normal skin, the epidermis (outermost layer) and dermis (inner or deeper layer) exists in a steady-state equilibrium, forming a protective barrier against the external environment.
Factors which may contribute to this include diabetes. synthesize granulation tissue. phase
Upon injury to the skin. and remodeling. The cellular phase follows the early phase.Once the protective barrier is broken. Concurrently. granulation tissue formation. fibroblasts grow and form a new. involves cascading molecular and cellular events leading to hemostasis and formation of an early. the wound is made smaller by the action of myofibroblasts. and infection. When the cells' roles are close to complete. epithelialization. collagen deposition. unneeded cells undergo apoptosis In the maturation and remodeling phase. re-epithelialization of the epidermis occurs. venous or arterial disease. a set of complex biochemical events takes place in a closely orchestrated cascade to repair the damaged part. this process is not only complex but fragile. providing cover for the new tissue In contraction. and susceptible to interruption or failure leading to the formation of chronic non-healing wounds. and involves several types of cells working together to mount an inflammatory response. In this construct. which begins immediately following skin injury. the process of wound healing is divided into major two phases: early phase and cellular phase The early phase. collagen is remodeled and realigned along tension lines and cells that are no longer needed are removed by apoptosis. Wound healing is classically divided into hemostasis. provisional extracellular matrix (ECM) by excreting collagen and fibronectin. proliferation. bacteria and debris are phagocytosed and removed. The classic model of wound healing is divided into three or four sequential. and wound contraction In angiogenesis. old age. and factors are released that cause the migration and division of cells involved in the proliferative phase. in which epithelial cells proliferate and 'crawl' atop the wound bed. However. new blood vessels are formed by vascular endothelial cells In fibroplasia and granulation tissue formation. The proliferative phase is characterized by angiogenesis. yet overlapping phases: inflammatory phase • proliferative phase
remodeling. which establish a grip on the wound edges and contract themselves using a mechanism similar to that in smooth muscle cells. this model employs considerable overlapping among individual phases. inflammation. the normal (physiologic) process of wound healing is immediately set in motion. and restore the epithelial layer. INFLAMMATION
. Although a useful construct. makeshift extracellular matrix—providing structural support for cellular attachment and subsequent cellular proliferation. In the inflammatory phase.
There are fivecardinal signs of inflammation. The ICF compartment is really a "virtual compartment" considered as the sum of this huge number of discontinuous small collections. the immune system. known as chronic inflammation. involving the local vascular system.
D. However. In particular. Similarly. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process. and rheumatoid arthritis. How can the term ‘intracellular fluid’ be used as though it was a single body of fluid? The reason is that though not united physically. composition and behavior:
. and various cells within the injured tissue. such as pathogens. Even in cases where inflammation is caused by infection. antigen challenge or even just physical. It is for that reason that inflammation is normally closely regulated by the body. A cascade of biochemical events propagates and matures the inflammatory response. The concept of a single united "compartment" called intracellular fluid is clearly artificial. calor. tumor.Inflammation is the body's reaction to invasion by an infectious agent. chemical or traumatic damage. similarities of location. while inflammation is one of the responses of the organism to the pathogen. atherosclerosis. dolor.Without inflammation. progressive destruction of the tissue would compromise the survival of the organism. Inflammation can be classified as either acute or chronic. leads to a progressive shift in the type of cells present at the site of inflammation and is characterized by simultaneous destruction and healing of the tissue from the inflammatory process. Prolonged inflammation. such as hay fever. FLUID AND ELECTROLYTE BALANCE 1. and functiona laesa. chronic inflammation can also lead to a host of diseases. Acute inflammation is the initial response of the body to harmful stimuli and is achieved by the increased movement of plasma and leukocytes especially granulocytes from the blood into the injured tissues. the two are not synonymous: infection is caused by an exogenous pathogen. rubor. Inflammation is not a synonym for infection. wounds and infections would never heal. This is part of the complex biological response of vascular tissues to harmful stimuli. damaged cells. the collections have extremely important unifying similarities which make the ICF concept of practical usefulness in physiology. or irritants. namely.BODY AND WATER COMPARTMENTS The Intracellular Fluid is composed of at least 1014 separate tiny cellular packages.
The fluid compartment called the blood volume is interesting in that it is a composite compartment containing ECF (plasma) and ICF (red cell water). The fluid of bone & dense connective tissue is significant because it contains about 15% of the total body water. plasma. wastes and chemical messengers all pass through the ISF. This fluid is mobilized only very slowly and this lessens its importance when considering the effects of acute fluid interventions.e. Lymph is more easily obtained for analysis than other parts of the ISF. The ISF bathes all the cells in the body and is the link between the ICF and the intravascular compartment. interstitial fluid. the opposite of that for the ICF (i.* Location: The distinction between ICF and ECF is clear and is easy to understand: they are separated by the cell membranes * Composition: Intracellular fluids are high in potassium and magnesium and low in sodium and chloride ions * Behavior: Intracellular fluids behave similarly to tonicity changes in the ECF Because of this physiological usefulness.g. This is also a ‘virtual’ fluid (i. fluid of bone and dense connective tissue and transcellular fluid). The use of this convention allows predictions to be made about what will happen with various interventions and within limits these are physiologically meaningful. it exists in many separate small bits but is spoken about as though it was a pool of fluid of uniform composition in the one location). it is convenient to talk of an idealized ICF as though it were a single real entity. Plasma is the only major fluid compartment that exists as a real fluid collection all in one location. Interstitial fluid (ISF) consists of all the bits of fluid which lie in the interstices of all body tissues. The ECF compositional similarity is in some ways. nutrients. Lymph is considered as a part of the ISF.
. A similar argument applies to the Extracellular Fluid. These compartments are distinguished by different locations and different kinetic characteristics. ISF has the compositional characteristics of ECF (as mentioned above) but in addition it is distinguished by its usually low protein concentration (in comparison to plasma). The ECF is divided into several smaller compartments (e. low in potassium & magnesium and high in sodium and chloride).e. Blood contains suspended red and white cells so plasma has been called the ‘interstitial fluid of the blood’. Oxygen. It differs from ISF in its much higher protein content and its high bulk flow (transport function). The lymphatic system returns protein and excess ISF to the circulation.
2. for example. is relatively impermeable to plasma proteins. leaf positioning. It includes CSF. Regulation of the plasma volume is somewhat more complicated because of the tendency of the plasma proteins to hold water in the vascular space by an oncotic effect which is in part counterbalanced by the hydrostatic pressure in the capillary that is generated by cardiac contraction. osmolality and hydrostatic pressure are tightly controlled by multiple signaling cascades and they drive crucial cellular functions ranging from exocytosis and growth to apoptosis. It is contained within epithelial lined spaces. The concentrations of the major solutes in these fluids differ. and proteins in the plasma. Na + salts in the interstitial fluid. This paradigm is extended by recent work that reveals an important role for hydrodynamics in pollen tube growth. The fluid fluxes involved with GIT fluids can be quite significant. and the cell membrane is 'impermeable' to Na + and K + because the Na + -K + -ATPase pump largely restricts Na + to the extracellular fluid and K + to the intracellular fluid. By contrast. nutrient acquisition and growth. Osmotic pressure is the primary determinant of the distribution of water between the three major compartments. Cell volume. Cells have evolved fascinating strategies to harness the potential of hydrodynamic flow to perform crucial functions. It is important because of the specialized functions involved. and each compartment has one solute that is primarily limited to that compartment and therefore determines its osmotic pressure: K + salts in the intracellular fluid (most of the cell Mg 2+ is bound and osmotically inactive). GIT fluids. Plants exploit hydrodynamics to drive processes including gas exchange. A characteristic of an osmotically active solute is that it cannot freely leave its compartment. The electrolyte compositions of the various transcellular fluids are quite dissimilar and typical values or ranges for some of these fluids are listed in the Table. aqueous humor and joint fluid.Transcellular fluid is a small compartment that represents all those body fluids which are formed from the transport activities of cells. bladder urine. The total body water is divided into compartments and useful physiological insight and some measure of clinical predictability can be gained from this approach even though most of these fluid compartments do not exist as discrete real fluid collections. MAINTAINANCE OF WATER COMPARTMENTS BALANCE • HYDROSTATIC AND ONCOTIC PRESSURE
-H2O is one of the most essential molecules for cellular life. The capillary wall. Ion fluxes and cell shape restructuring induce asymmetries in osmotic potential across the plasma membrane and lead to localized hydrodynamic flow. Na + freely crosses the capillary wall and achieves similar concentrations in the
Similarly. Antidiuretic hormone levels remain normal
. Thus. Infants lose more fluid through the kidneys because immature kidneys are less able to conserve water than adult kidneys. VARIABLES AFFECTING FLUID AND ELECTROLYTE BALANCE AGE Infants and growing children have much greater fluid turnover than adults because their higher metabolic rate increases fluid loss. In addition. infants respirations are more rapid and the body surface area is proportionately greater than that of adults. The more rapid turnover of fluid plus the losses produced by disease can create critical fluid imbalances in children much more rapidly than in adults. In elderly people. ELECTROLYTE IMBALANCES Common Electrolyte Electrolyt Ionic e formula Sodium Na+ Potassiu K+ m Calcium Ca2+ Magnesiu Mg2+ m Chloride ClPhosphat PO43e Bicarbon HCO3ate Imbalances Elevation disorder hypernatremia hyperkalemia Depletion disorder hyponatremia hypokalemia
hypercalcemia hypocalcemia hypermagnesem hypomagnesemi ia a hyperchloremia hypochloremia hyperphosphate hypophosphate mia mia hyperbicarbonat hypobicarbonat emia emia
4. Increasing insensible fluid losses. the normal aging process may affect fluid balance.
3. The thirst response often is blunted. as a result. urea crosses both the capillary wall and the cell membrane and is osmotically inactive. it does not contribute to fluid distribution between these compartments. the retention of urea in renal failure does not alter the distribution of the total body water.interstitium and plasma.
headache and gastrointestinal symptoms such as anorexia and nausea.or may even be elevated. Additionally. Water accounts for approximately 60% of an adult man’s weight. These normal changes of aging increase the risk of dehydration. These losses are even greater in people who have not been acclimatized to the environment. but only 52% for an adult woman. Women have proportionately more body fat and less body water than men. The person who is salt depleted may experience fatigue. particularly during strenuous activity. Body temperature rises. Balanced electrolyte solutions and carbohydrate-electrolyte solutions such as sports drinks are
. but the nephrons become less able to conserve water in response to ADH. Both salt and water are lost through sweating. which can make an intravenous insertion more difficult. with water responsible for only 30% to 40% of the person’s weight. Because fat cells contain little or no water and lean tissue has a high water content. The risk of adverse effects is even greater if lost water is not replaced. reduces the risk of adverse effects from heat.
GENDER AND BODY SIZE Total body water also is affected by gender and body size. In an obese individual this may be even less. weakness. Fluid losses through sweating are increased in hot environments as the body attempts to dissipate heat. Increased levels of atrial natriuretic factor seen in older adults may also contribute to this impaired ability to conserve water. Heatstroke may occur in older adults or ill people during prolonged periods of heat.
ENVIRONMENTAL TEMPERATURE People with an illness and those participating in strenuous activity are at risk for fluid and electrolyte imbalances when the environmental temperature is high. salt depletion is a risk. impaired renal function. and multiple drug regimens. people with a higher percentage of body fat have less body fluid. it can also affect athletes and laborers when their heat production exceeds the body’s ability to dissipate heat. When combined with the increased likelihood of heart diseases. it is important to consider that the older adult has thinner. Consuming adequate amounts of cool liquids. and the person is at risk for heat exhaustion or heatstroke. the older adult’s risk for fluid and electrolyte imbalance is significant. When only water is replaced. more fragile skin and veins.
exercise. diet. and stress affect fluid. electrolyte and acid-base balance. and phosphate levels. A base is any chemical compound that produces hydroxide ions when dissolved in water. or bicycling has a beneficial effect on calcium balance. 5. is frequently defined as a substance that combines with a proton to form a chemical bond. reducing the risk of osteoporosis. The intake of fluids and electrolytes is affected by diet. In contrast. use of diuretics and laxatives). running. and environmental factors.
LIFESTYLE Other factors such as diet. People with anorexia nervosa or bulimia are at risk for severe fluid and electrolyte imbalance because of inadequate intake or purging regimens (e. Regular weight-bearing physical exercise such as walking. which in turn decreases urine production. and acid-base balance. induced vomiting.
. increasing the risk of acidosis. a base. magnesium. Acid solutions have a sour taste and produce a burning sensation with skin contact. increasing the risk of low calcium. and may develop edema because the osmotic draw of fluid into the vascular compartment is reduced. Stress can increase cellular metabolism. Other lifestyle factors can also affect fluid. The rate of bone loss that occurs in postmenopausal women and older men is slowed with regular exercise. Base solutions have a bitter taste and a slippery feel. Despite variations in metabolism. ACID – BASE BALANCE An acid is a substance that acts as a proton donor. stress can increase production of ADH. Heavy alcohol consumption affects electrolyte balance.g. The overall response of the body to stress is to increase the blood volume. also known as an alkali. fat stores are broken down and fatty acids are released. the body's acid-base balance.recommended because they replace both water and electrolyte lost through sweat. The risk of acidosis associated with breakdown of fat tissue also is greater in the person who drinks large amounts of alcohol. In addition. blood glucose concentration and catecholamine levels. When calorie intake is not adequate to meet the body’s needs. electrolyte. Seriously malnourished people have decreased serum albumin levels.
while a decrease in the same substance is called metabolic acidosis. The kidneys and pulmonary system then work to maintain acid-base balance through excretion in the urine or respiration. Disruptions in CO2 levels and HCO3create acid-base imbalances. the disturbances can be broadly divided into either acidosis (excess acid) or alkalosis (excess base/alkali). Excess acid or base is then excreted in the urine by the renal system to control plasma bicarbonate concentration. Exercise or serious infections will increase the production of CO2 through increased respiration in the lungs. sodium. phosphorus. Role in human health Production of CO2 is a result of normal body metabolism. the blood transports these gases to the lungs and body tissues. The partial pressure of carbon dioxide gas (PCO2) in the pulmonary system can be measured with a blood sample and correlates with blood carbon dioxide (CO2) levels. Changes in respiration occur primarily in minutes to hours. An increase in PCO2. and magnesium. For example. which help prevent rapid changes in body fluid pH over short periods of time. When acid-base imbalances occur. until the kidneys pulmonary systems can make appropriate adjustments. When oxygen (O2) is inhaled and CO2 is exhaled. In addition. Components that affect acid-base balance include protein. The concentration of base in the body can be determined by measuring plasma bicarbonate (HCO3-) concentration. The body's metabolism produces acids that are buffered and then excreted by the lungs and kidneys to maintain body fluids at a neutral pH. calcium. Acid-base imbalances result primarily from metabolic or respiratory failures. An increase in HCO3-is called metabolic alkalosis. PCO2 can then be used as an indicator of the concentration of acid in the body. thus changing the blood pH and correcting imbalances. Cells and body fluids contain acid-base buffers. the respiratory system can alter PCO2 quickly. on the other hand. the rate at which nutrients are absorbed in the intestine will alter acid-base balance. is known as respiratory
. Common diseases and disorders Acid-base metabolism imbalances are often characterized in terms of the HCO3-/CO2 buffer system. while renal function works to alter blood pH within several days. and electrolyte concentration are maintained within a narrow range. The chemical composition of food in the diet can have an effect on the body's acid-base production. potassium.fluid volume. When the acid-base balance is disturbed. Function Many naturally occurring acids are necessary for life. hydrochloric acid is secreted by the stomach to assist with digestion. chloride.
weakness. prolonged acidosis can result in heavy or rapid breathing. but prolonged alkalosis can result in convulsions. kidney failure. It is not a disease. and headache. or airway obstruction. Respiratory acidosis is caused by the lung’s failure to remove excess carbon dioxide from the body. Blockage of the air passages may be caused by bronchitis. and severe lung disease. Acidosis Acidosis is a condition resulting from higher than normal acid levels in the body fluids. may lead to respiratory acidosis. Treatment options for acidosis typically require correction of the underlying condition by venous administration of sodium bicarbonate or another alkaline substance. nausea. Most often. and vomiting. blockage of the upper air passages. severe metabolic acidosis (pH < 7. Mild acidosis is often compensated by the body in a number of ways. However. This is followed by a secondary decrease in PCO2 that occurs as part of respiratory compensation process. including chest injury. This condition can sometimes result in coma and. Conditions such as diabetes. Acidemia (arterial pH < 7. An excessive loss of HCO3-in the blood causes metabolic alkalosis. if the pH falls below 6. and even death if the pH rises above 7. resulting in mild or severe acidosis. The predominant symptoms of acidosis are sometimes difficult to distinguish from symptoms of an underlying disease or disorder. Mild conditions of acidosis may be asymptomatic or may be accompanied by weakness or listlessness. muscular weakness. and a decrease in the same substance is called respiratory alkalosis. reducing the pH in the body.80. consistent retention of carbon dioxide in the lungs is referred to as chronic respiratory acidosis. Regular. Alkalosis Alkalosis is a condition resulting from a higher than normal level of base/alkali in the body fluids. This condition can be caused by chronic alcoholism and poor carbohydrate utilization. Metabolic acidosis is related to processes that transform food into energy and body tissues. it will lead to death. This disorder results in only mild acidosis because it is balanced by increased bicarbonate production. severe diarrhea. Alkalosis can be caused by drugs or
.35) is an accumulation of acids in the bloodstream that may occur with severe acidosis when the acid load exceeds respiratory capacity. Diabetic ketoacidosis is a condition where excessive glucagon and a lack of insulin contribute to the production of ketoacids in the liver. The body can compensate for mild alkalinity.acidosis. and poisoning can result in metabolic acidosis.20) is associated with increased respiration to compensate for a shortage of HCO3-. but may be an indicator of disease. asthma. Several conditions.80.
and ileus (obstruction of the intestines). muscle weakness. lightheadedness. Compensated alkalosis results when the body has partially compensated for alkalosis. and protein content (osmolarity) within certain physiologic ranges. and numbing of the hands and feet. Low plasma potassium leads to a condition called hypokalemic alkalosis. Severe cases may induce hypocalcemia (a low level of plasma calcium). in compensated alkalosis. E. Prolonged vomiting may induce hypochloremic alkalosis (a large loss of chloride). Respiratory alkalosis results from decreased CO2 levels caused by conditions such as hyperventilation (a faster breathing rate). blood volume. The pH is elevated in the body. The kidneys may conserve bicarbonate in order to compensate for the chloride reduction. Diuretic medications may cause hypokalemic alkalosis. Prolonged vomiting and hyperventilation (abnormally fast. Alkalemia (abnormal blood alkalinity) increases protein binding of ionized calcium even though plasma total calcium does not change. Also means maintaining blood as a liquid until such time as injury
. it may be appropriate to reduce intake to restore the normal acid-base balance. abnormal bicarbonate and carbon dioxide levels persist. and fever. and has restored normal acid-base balances. deep breathing) can result in alkalosis. The predominant symptoms of alkalosis are neuromuscular hyperexcitability and irritability. Therefore any change in one of these factors will affect the tissue homeostasis and may result in edema or congestion. anxiety. It is frequently accompanied by metabolic alkalosis.disorders that upset the normal acid-base balance. Treatments include breathing into a paper bag or a mask that induces rebreathing of carbon dioxide. Alkalosis requires correction of the underlying condition and may involve venous administration of a weak acid to restore normal balance. Normal fluid homeostasis Includes maintenance of vessel wall integrity (intact circulation) as well as intravascular pressure. resulting in cramping. polyuria. However. Symptoms of respiratory alkalosis may include dizziness. If the source of alkalosis is excessive drug intake. Hyperventilation causes the body to lose excess carbon dioxide in expired air and can be triggered by altitude or a disease that reduces the amount of oxygen in the blood. CIRCULATORY DISTURBANCE The health of cells and tissues depends not only on an intact circulation to deliver oxygen and remove wastes but also on normal fluid balance.
The interstitial fluid (IF) pressure. Capillary pressure forcing fluid outward through the capillary membrane. as a consequence of pumping by the lymphatic system.It may be localized to a single organ or limb or generalized. Morphology 3. This can overwhelm the edema safety factor and result in edema. Approximately 75% of the total colloid osmotic pressure is due to albumin. Usually this is negative. Average protein concentration in plasma is 7g per dl. and tends to force fluid out of the capillaries. Etiology 2. EDEMA Edema is defined as in increase in interstitial fluid and is manifested clinically as swelling of tissues. Extensive hemorrhage can result in shock. 2. When edema develops large quantities of free fluid accumulate in the tissues. 1. The interstitial fluid fills the spaces between body cells. The distribution of water between the compartments depends upon: 1. 25% from the globulins and negligible amounts from fibrinogen.necessitates clot formation. The interstitial fluid osmotic pressure. Conversely inability to clot after injury results in hemorrhage. Plasma colloid osmotic pressure which tends to draw fluid into the blood stream by osmosis. Clotting at inappropriate sites (thrombosis) or migration of clots (embolism) obstructs blood flow to tissues & leads to cell death (infarction). 5. These spaces are known as the interstitium and contain two major types of solid structures: (1) Collagen fiber bundles which produce tensile strength and (2) Proteoglycan filaments which are composed of 98% hyaluronic acid and 2% protein arranged in extremely thin coiled molecules which entrap the IF and form a tissue gel. The average protein concentration of the IF is about 40% of that in plasma (3g per dl) but there is a wide variation of protein concentration in different organs and tissues. Effects A. If capillary permeability is increased by pathological process (See Table) then fluid will move out of the plasma at an increased rate and with a high protein concentration. 3. Free fluid in the tissues moves easily and
. 4. Normally almost all the IF is in this form and a small amount is present in free fluid vesicles and channels. Fluid in the tissue gel is highly permeable to nutrients but is relatively immobile and does not shift easily.
This will be aggravated by exercise and may lead to the escape of fluid from the capillaries into the alveolar walls and later into the air spaces. (c) Increase in capillary permeability. This may be altered by changes in cardiac output and peripheral vascular resistance or compliance. aortic arch and renal afferent arterioles can sense arterial underfilling and cause an increase in sympathetic flow
. An example is mitral stenosis which can cause a rise in pulmonary venous pressure and therefore in pulmonary capillary pressure. (c) The tissue tension in the interstitial fluid will also tend to limit egress of fluid from the microvasculature. Factors which tend to retain fluid within the vascular compartment (a) Osmotic pressure of the plasma proteins. 2. The resulting increase in the protein concentration in the interstitial fluid will diminish the osmotic gradient between the plasma and interstitial fluid and accentuate the loss of fluid from the plasma. Factors Controlling Distribution of Extracellular Body Water 1. Baro-receptors in the left ventricle. (a) Increase in hydrostatic pressure in the vascular compartment. ` The Role of Sodium Retention in Edema The presence of generalized edema invariably reflects an increase in total body sodium. (b) The selective permeability function of the endothelium. increased loss as in nephrotic syndrome or nutritional deficiency."pits" on pressure as well as shifting to dependent regions due to the effect of gravity. Factors which cause fluid to leave the vascular compartment. (b) Increase in colloid osmotic pressure in the interstitial fluid. as in liver disease. Damage to the endothelium and the capillary wall may permit the egress of large proteinmolecules and breakdown the normal barrier to fluid loss from the capillaries. Hypoalbuminemia may be due to reduced synthesis. This may occur in lymphatic obstruction. The predominant determinant of renal sodium and water exertion is the integrity of the arterial circulation.
Factors that promote sodium retention are: (a) Arterial Underfilling. This depends predominantly on the concentration of albumin in the plasma. carotid sinus.
This hormone is synthesized in the atria and to a lesser extent in the ventricles and is released into the circulation in heart failure. Local 1) Inflammation 2) Thermal injury (burns. cirrhosis (ascites). The various causes of edema are classified below. Generalized 1) Congestive heart failure 2) Constrictive pericarditis 3) Fluid overload (renal failure.e. (b) The role of natriuretic peptide. Local 1) Venous obstruction .or hypoproteinemic. nonosmotic release of arginine vasopressin and stimulation of thirst. LVF with pulmonary edema) B.from the CNS with resulting activation of the renin-angiotensinaldosterone system. Also the list of possible causes in a given patient can be limited by noting whether the edema is local or generalized and whether it is normo . iatrogenic) II. Increased Capillary Pressure A.. SVC syndrome 2) Arteriolar dilation (inflammation) 3) Congestive heart failure (i. frost bite) 3) Chemical injury 4) Mechanical injury (trauma) B. Increased Capillary Permeability A. Note that multiple mechanisms may occur in some diseases.phlebothrombosis. In patient with early heart failure it counters the factors causing sodium retention (see above) but with more severe failure the renal natriuretic receptors are down-regulated and become resistant to the action of the hormone. Generalized 1) Anaphylaxis
. The relief of edema requires medication to promote excretion of sodium in addition to management of theprimary cause of the edema. (d) Diminished blood flow to the liver may reduce the metabolism of aldosterone and cause an increase in the blood level with augmentation of sodium retention.
CLASSIFICATION OF EDEMA I. Sodium retention is a major component of the pathogenesis of edema. (c) Reduction in renal flood flow with reduced glomerular filtration rate and activation of therenin-angiotensin-aldosterone system.
When the "sponge" is saturated fluid begins to spreads to the alveolar walls and interferes with gaseous exchanges. These changes lead to dyspnoea.2) Shock 3) Idiopathic cyclic edema III. protein losing gastroenteropathy) 2) Decreased synthesis (cirrhosis. spinal injuries and other causes of denervation. LOCALIZED EDEMA Mechanisms: Local Increase in hydrostatic pressure Lymphatic obstruction Inflammation PULMONARY EDEMA is common and produces symptoms by interfering with gas exchange. Initially edema fluid accumulates in the interstitial spaces. Renal Salt and Water Retention (generalized only) 1) Acute glomerulonephritis 2) Acute renal failure 3) Chronic renal failure VI.Capillary pressures are normally low and lymphatics are abundant. Lymphatic obstruction (local only) 1) Iatrogenic (surgical resection. Decreased Plasma Protein Concentration (generalized only) 1) Protein loss (nephrotic syndrome. Chest x-ray may distinguish alveolar (fluffy infiltrate with "bronchial" markings) and interstitial edema ("Kerley B" or "septal) lines). This occurs particularly when edema develops rapidly and there is no time to compensate. chiefly in the loosely structured peribronchial connective tissue where anionic glycoproteins soak up water like a sponge. This is seen in paralyzed limbs due to polio-myelitis. Lymphatic flow can compensate for fluid accumulation by increasing up to 10 fold but eventually this protection fails when the pressures are too great. malnutrition) 3) Protein sequestration (burns) IV. Defective pre-capillary vasoconstrictor mechanism (localized only). radiation) 2) Tumor 3) Cirrhosis 4) Filariasis (elephantiasis) V. Pulmonary edema is most commonly due to increases in capillary
. cyanosis and hypoxia. Finally fluid seeps into the alveolar spaces eventually flooding individual alveoli. Types of Edema a. but the total interstitial volume is low so small amounts of pulmonary edema (>100 cc) may damage the delicate epithelium and spill over into the alveoli.
Decreased colloid osmotic pressure of plasma proteins 3. The effect of the low plasma volume on the kidney is to stimulate sodium retention and further increase the ECF volume. in fact measurements of plasma volume in cardiac failure yield normal or high values and furthermore sodium retention usually precedes a rise in central venous pressure.pressure from heart disease or increase in capillary permeability from toxic or inflammatory insults. it is very rarely due to hypoproteinemia. Sodium retention CARDIAC EDEMA Two hypotheses have been proposed to explain the edema of cardiac failure. CEREBRAL EDEMA is less common but can have very severe clinical consequences. The brain is enclosed by a rigid skull and therefore small increases in fluid volume will lead to increased intra cranial pressure with consequent cerebral ischemia and anatomic lesions. Fluid collections in the VIRTUAL SPACES (PLEURA. vomiting. loss of consciousness and ultimately death. However.spinal fluid and cerebral tumors. drowsiness. The pressure within virtual spaces is normally negative. PERICARDIUM. These "facts" undermine this hypothesis although in some circumstance elevated venous pressure may contribute to the precipitation of cardiac edema. Causes of increased fluid volume and cerebral edema include areas of infection. In patients with heart failure there is a striking and consistent reduction in renal plasma flow. The final "coup" is usually due to brain stem compression following tentorial or tonsillar herniation. Minimal exercises in these patients result in a further sharp reduction in renal plasma flow and GFR. Increased hydrostatic pressure of blood 2. obstruction to the flow of cerebro. The backward failure hypothesis proposes that a reduced cardiac output leads to increased venous pressure which causes increased capillary filtration and therefore interstitial edema and a reduced plasma volume. JOINTSPACES) can be thought of as edema fluid escaping from the adjacent tissues where it is formed by the usual mechanism. The alternative forward failure hypothesis is based upon the concept that the impaired pumping action of the heart can lead to a subtle disturbance in the perfusion of the arterial tree such that receptors perceive this as equivalent to a reduction in blood volume. hemorrhage. convulsions. GENERALIZED EDEMA Mechanism: 1. PERITONEUM. abscesses. This leads to headache. The effect on the kidney is similar to that of an
. a. inflammation ortumor.
Ascites is not detectable clinically until at least 500ml is present. The utero-placental circulation may act as an A-V shunt and thereby distort the perception of plasma volume by the kidney leading to sodium retention. The protein content of the ascitic fluid is low and has the characteristics of a transudate. If the body is not able to pass out this excess fluid. Characteristically the edema involves the face and eyelids.
.actual reduction in blood and plasma volume and therefore sodium is retained and the ECF volume increases. known as Ascites. Fluid retention (water retention) where there is excessive fluid within the blood vessel and tissue spaces. The fluid accumulates within the tissue space and results in edema. The large pregnant uterus may exaggerate the normal reduction in sodium excretion by the kidney on standing upright. HEPATIC EDEMA Edema can occur in patients with liver disease. PREGNANCY EDEMA Generalized edema is quite common in pregnancy but the mechanism is poorly understood. alike in some cases the ankle and genitalia may also be involved. This results in edema. The mechanisms are complex but the sodium retention can often result in an increase in the ECF and plasma volume leading to hypertension with or without edema. Reduced osmotic pressure within the vessels will not pull fluid from the tissue spaces into the vessel. RENAL EDEMA Reduced glomerular filtration can lead to inadequate sodium excretion. This is seen in many cases of chronic renal failure and in acute renal failure due to both glomerular and tubular damage. This is frequently associated with fluid in the peritoneal space. In the presence of preeclampsia and hypertension abnormalities of tubular function and reduced GFR may add to the retention of sodium and therefore edema formation.
General Causes of Edema Edema will occur under these circumstances :
Increased hydrostatic pressure will push fluid out of the vessels into tissue spaces. it will be retained within the tissue spaces thereby resulting in edema.
The lymphatic system also plays an essential part here as the interstitial fluid is pulled from the tissue spaces into the lymphatic vessels which then empties into the blood vessels. within the blood vessels (blood) or lymphatic vessels (lymph or lymphatic fluid). These forces are known as hydrostatic pressure and osmotic pressure. Five Pathophysiologic Mechanisms that underlie the development of edema 1. Fluid within our blood vessels are at a higher pressure than the fluid in the tissue spaces. Lymphatic obstruction is where the lymph vessels are blocked at some point and the interstitial fluid cannot be drained from the tissue spaces. within the tissue space between cells (interstitial fluid). Decrease plasma (intravascular) colloidal-osmotic pressure
. gases and wastes. This fluid is not just water but there are also cells. This allows for the exchange of nutrients.
Pathophysiology of Edema Fluid in the body exists within cells (intracellular fluid). Therefore the blood vessels which have a higher hydrostatic and a higher osmotic pressure will push out some fluid into the tissue spaces and draw other fluids from the tissue spaces. Fluid is pushed away from an area of high hydrostatic pressure but is pulled into an area of high osmotic pressure.•
Increased vascular permeability is when blood vessel wall allows fluid to pass out of the blood vessel unabated. nutrients. Osmotic pressure is the force that draws fluid from an area of low electrolyte concentration to one of a higher electrolyte concentration. This is due to the pumping heart that pushes the blood with force within the vessels. Usually fluid from the tissue spaces enters the blood vessel due to a difference in osmotic pressure. Two forces are responsible for maintaining the fluid in specific areas or ‘pulling’ and ‘pushing’ fluid into other areas. Blood does not just ooze out of the vessels unless the vessel wall becomes permeable and allows it to exit. Hydrostatic pressure is the force that pushes fluid from an area of high pressure to low pressure. Fluid accumulates in the tissue space and the result is edema. electrolytes and waste products existing with water in these areas. Fluid within the tissue spaces also have a hydrostatic force but this is usually smaller than the pressure within the vessels so very little fluid flow from the tissues spaces into the vessel due to hydrostatic pressure. Fluid from the tissue spaces are not drawn into the blood vessel fast enough and fluid remains in the tissue space thereby resulting in edema.
This indentation will slowly disappear over time. Pleural effusion is the term for edema in the pleural space between the outer layers of the lung. Pitting edema is the swelling of a body part where an indentation
will persist after pressure is applied to the area. This is the area between the lining of the abdomen and organs within the abdominal cavity.
. Ascites is the term for excessive fluid accumulation within the peritoneal cavity.2. Cerebral edema is the term for edema within the brain. 5. Pulmonary edema is the term for edema within the lungs. It is also known as a hydropericardium. Cardiac edema is the term for excessive fluid accumulation in tissues due to heart failure. It is also known as a hydrothorax. 3.
1. Hepatic edema is the term for excessive fluid accumulation in tissues due to a liver dysfunction.
Anasarca is the term for severe generalized edema.
Increase intravascular hydrostatic pressure Lymphatic obstruction Increased microvascular permeability Sodium retention
Edema Terminology There are different medical terms for edema in specific areas or organs of the body. 4.
• • •
Types of Edema There are two types of edema that can be identified upon examination. Pericardial effusion is the term for edema within the pericardial space between the outer layers of the heart. Lymphedema is the excessive fluid accumulation within tissues because the tissue fluid cannot be drained by the lymphatic vessels in that area. Renal edema is the excessive fluid accumulation in they body’s tissues due to kidney disease or failure.
Therefore. Duration 2. Too little blood is being removed by the venules . B. EXTENT: localized/generalized Local: change confined to a discrete area (localized or limited) Generalized: indicates a systemic change or generalized within an
. Too much blood via the arterioles . DURATION: acute/chronic Acute: implies abrupt onset with rapid development Chronic: slowly developing and/or present for a long time 2. Physiologic Hyperemia: eg1: 8 blood flow to the stomach and intestines during digestion eg2: 8 blood flow in the muscles of athletes during exercise eg3: neurovascular Hyperemia 2. Extent 3.2.Passive Hyperemia – blue TYPES of Hyperemia: 1.active.passive. congestion and edema frequently are observed together. venous engorgement NOTES: -Both indicate a local increase in blood volume in a particular tissue. CONGESTION HYPEREMIA: An excessive amount of blood in an organ (refers to both volume and flow) implication .Active Hyperemia – red 2. Non-pitting edema is where there is swelling of a body part with no indentation upon applying pressure. Pathologic Hyperemia -manifestation of some alteration in blood flow (NOT THE CAUSE) -result of an underlying pathologic process 3 factors used in defining the types of pathological Hyperemia 1. arteriolar-mediated engorgement of vascular bed CONGESTION: An excessive amount of blood (refers to volume) implication . Mechanisms 1. -Congestion within capillaries beds is closely related to edema formation.blood outside vessel wall ie: extravascular Hyperemia . HEMORRHAGE VS HYPEREMIA: Hemorrhage .blood inside of vessel wall ie: intravascular ETIOLOGY of HYPEREMIA: 1.
organ 3. a passive process. etc. infections. Capillary pressure increases may also be transmitted from venous pressure increases. Congestion of capillary beds also leads to edema and the two process commonly occur together. fever. ` Morphology: Cut surfaces of congested organs are excessively bloody and wet. for example by thrombi. The pulmonary circuit only may be affected in left ventricular failure but in right ventricular failure the lungs may be spared while congestion spreads throughout the body.engorgement by poorly oxygenated venous blood ¸ Degree of chronic local hypoxia ¸ Degeneration. hormonal alterations. Wet . Capillary pressures are normally regulated by arteriolar opening or closing. It may also occur "up stream" of the liver as in cirrhosis with varices. blushing or the need to dissipate heat and pathologically in inflammation. caput medusa and hemorrhoids or in the lungs as in chronic lung disease with cor pulmonale and right heart failure. or extrinsic compression.Due to edematous tissue. Passive congestion occurs locally due to venous obstruction. Active hyperemia. tumors.blood oozes on cut section. Atrophy or even Necrosis of parenchymal cells Congestion or hyperemia generally reflects increased capillary pressures. Red colour associated with acute local active hyperemia. Dark brown colour is associated with congestion (passive hyperemia). an active process. MECHANISMS: active/passive Active: due to arteriolar flow Passive: due to impaired venous drainage APPEARANCE OF HYPEREMIA GROSS: Cut surfaces of hyperemic or congested tissues are hemorrhagic and wet.associated with capillaries engorged with blood usually some edema chronic . HISTO: acute . Excessively bloody . Note that in active hyperemia the affected parts show increased redness whereas passive congestion causes a blue-red coloration due to damming back of venous blood and cyanosis due to deoxygenation.
. And it may occur systemically in heart failure when both left and right ventricles are decompensated. then reflects arteriolar dilation occurring normally with exercise.
This results in minute intra-alveolar hemorrhages. LIVER Right ventricular failure or obstruction to the inferior vena cava or hepatic vein causes congestion of the liver which enlarges and shows a dusky red cyanosis. spreading to the surrounding lobule and the characteristic pattern called cardiac cirrhosis (centrizonal). Centrilobular necrosis is also seen in shock without chronic passive congestion. THROMBOSIS PATHOGENESIS: .The alveolar septa become widened. commonly due to a myocardial infarct.LUNG Acute congestion and edema is seen after left ventricular failure. edematous and later fibrotic producing so-called "brown induration".3 primary influences . The central hepatocytes become atrophic and the peripheral cells develop fatty changes due to a lesser degree of hypoxia. Endothelial injury Dominant influence = can lead to thrombosis by itself eg: inflammation of heart valves
. Chronic congestion in the most extreme form is seen with long standing mitral stenosis or any condition causing reduced left ventricular output. This is the typical "Nut Meg" liver. phagocytosis of red cells and many hemosiderinladen macrophages known as heart failure cells in the alveolar spaces. The cut surface oozes blood. tense and oozes blood when cut. tortuous and dilated. there are microscopic haemorrhages and many hemosiderm laden macrophages. Microscopically the central veins are prominent and the centri-lobular zones become reddish blue surround by a pale peripheral zone. The congestion leads to edema and the lungs are red and "wet". Microscopically the sinuses are distended. Eventually even the walls of the pulmonary arteries and arterioles become thickened. The alveolar capillaries are engorged. SPLEEN This organ becomes enlarged. edema and sometimes sidero-fibrotic nodules of scar tissue following focal hemorrhages.Virchow’s triad 1. Long standing congestive changes can lead to fibrosis of central veins. With severe prolonged chronic congestion central hemorrhagic necrosis may occur possibly due to reduced hepatic blood flow consequent upon reduced circulating blood volume. n severe cases the spleen weight can reach 500-700g (normal = less than 150g) with marked fibrous thickening. congested sinusoid.
frequently causes vascular obstruction at the point of its formation or embolism. primarily platelets and fibrin with entrapment of cellular elements. Thrombi may develop anywhere in cardiovascular system Cardiac chambers Valves Arteries (usually endothelial injury) Veins (often a result of stasis) Capillaries Arterial thrombi are attached and grow away from the heart. surrounded by plasma. Hypercoaguability Definition: any alteration of the coagulation pathways that predisposes to thombosis • • Coagulation factors Inhibitory factors
TERMINOLOGY AND MORPHOLOGY THROMBOSIS: Formation. Disrupt normal laminar flow • • • • allows platelets to contact endothelium Prevents dilution of activated clotting factors by fresh-flowing blood allows the build up of thrombi (slows the inflow of anticoagulants) promotes endothelial cell activation
3.turbulence or stasis Normal blood flow is laminar . THROMBI: Pleural of thrombus ie: several aggregations within the blood vascular system.ºExpose of subendothelial ECM º platelet adherence º release of tissue factor ºDepletion of prostacyclin º primary and secondary hemostatic plug formation 2 Alterations in normal blood flow . development or presence of a solid mass within the blood vessels or heart.
. THROMBUS: An aggregation of blood factors. Adherent to the vascular endothelium and must be differentiated from a simple (post mortem) blood clot.cellular elements in the middle.
since the dominant mechanism of formation is coagulation. BLOOD CLOT: Clotted blood within a blood vessel (usually not associated with a pathological condition . VENOUS: A venous thrombi is composed of fibrin strands with entrapped RBC's. friable and red. since the two are clearly related]. flow patterns adjacent to the thrombi cause fibrin to be deposited and the platelet mass that persists is transformed into a fibrin mass.Venous thrombi are attached and grow in the direction of blood flow (to heart). Arterial and venous thrombi differ!
Canine Venous Thrombus thrombus
Canine Pulmonary artery
ARTERIAL: Generally due to endothelial injury. OUTCOME OF THROMBI:
. post mortem clot with relatively few red cells. Fibrin strands polymerize between the separating and degenerating platelets. A chicken-fat clot is a gelatinous. [NOTE: the distinction between a thrombus and a blood clot is difficult. As arterial thrombi grow. The alternating lines of yellow platelets and fibrin separating RBC's forms the lines of Zahn.usually post mortem clot). CHICKEN-FAT CLOT: Common blood clot seen at necropsy in horses 6 plasma clot that develops because of spontaneous erythrocyte ROULEAUX formation and the rapid sedimentation rate of red cells in equine blood. initial thrombus is composed of aggregated platelets and RBC's and is soft.
Lysis of thrombus (due to potent thrombolytic/ fibrinolytic activity of blood) 2. lined by endothelial cells form to allow blood flow through the damaged vasculature EMBOLISM: Passage through the venous or arterial circulations of any material capable of lodging in a blood vessel and thereby obstructing the lumen.possible 4. ie: several emboli become dislodged and travel downstream of the blood current. or gaseous mass that is carried by the blood to a site distant from its point of origin.New lumina. Organization . THROMBOEMBOLISM: Obstruction of a blood vessel with thrombotic material carried by the blood stream from the site of origin to plug another vessel.Sudden blocking of an artery by a clot or foreign material which has been brought to its site of lodgement by the blood current.The presence of a thrombus stimulates reaction which will result in inflammation and fibrosis. Propagation of a thrombus (8 in size) . EMBOLI: Pleural of embolus. Dirofilaria immitis B. and Recanalization . EMBOLISM: Varies in composition . Smooth muscle cells and fibroblasts will proliferate and invade. liquid.most are primarily fibrin (thrombi) Etiology: 1.1. EMBOLUS: Detached intravascular solid.may eventually obstruct the vessel 3. -or. Nematode larvae i) Ascarid larvae ii) Strongyle larvae
. (99% of all emboli arise from a thrombus). The usual embolism is a thromboembolus. THROMBOEMBOLUS: A thrombus formed in one location that detaches from the vessel wall and travels to a distant site. Embolization . The thrombus will become firm and grey-white. Parasites A.
Other Air bubbles Hair Tumour cell clusters Amnionic fluid INFARCTION DEFINITION: Area of ischemic necrosis caused by occlusion of either the arterial supply or the venous drainage in a particular tissue. Osteomyelitis D. Prolonged surgery C. intestinal infarction. Notes: -50% of all human deaths result from myocardial or cerebral infarction due to cardiovascular disease . Bone fractures B. Hyperlipidemia i) "Lipid glomerulopathy" 4. Systemic infections Any disease that causes widespread damage to endothelium i) Bacterial diseases ii) Viral diseases eg: hog cholera (swine fever) 5. Fat A. The occluded -Margins may be irregular -Early .Pulmonary infarction. Spinal cord infarcts B.2.Most infarcts are the results of thrombotic or embolic events or vascular occlusion due to twisting of a vessel GROSS: wedge-shaped: The base of the wedge is at the periphery. Origin intervertebral disk material C. renal infarction common in domestic animals . Necrotizing myelopathy 3. Fibrocartilaginous emboli A.ill defined and hyperemic -48 hours most become paler
Degree/severity of injury to vascular supply 2. (Usually has a red zone at periphery because of capillaries at the border of infarct undergo dissolution and blood seeps into the area of necrosis). liver) or extensive collateral circulation (brain. Vulnerability of cells to ischemia
. MICRO: -Ischemic coagulation necrosis of all parenchyma tissues -Infarcts arising from septic emboli may convert to an abscess REPAIR: Scar tissue . Size of artery affected 3. pale) -Pulmonary infarcts are usually red PALE (WHITE) INFARCT: Lacks blood. kidney).-Kidney infarcts are usually white (ischemic. Seen with venous occlusions or within loose tissue that allow blood to collect in the infarcted zone of in organs with dual blood supply (lung. also called anemic infarct. Collateral blood supply available 5. Degree of vascular occlusion 4.
Canine kidney – white infarct RED INFARCT: Filled with blood.fibrous connective tissue Forms an indentation on the organ surface SEQUELLA: dependent upon 1. Occurs with arterial occlusions in solid organs (heart. small intestine). The latter results because blood flows from the unobstructed vascular channels into the necrotic area. Characterized by coagulation necrosis and erythrocytes from adjacent arteries and veins.
Serious if anterior or posterior vena cava obstructed . ischemia. loss of endothelial integrity Acute Blockage of the Portal Vein: Result: Infarction of intestine Sequelae: shock and death w/o surgery Example: Gastric torsion in dogs. severe venous congestion. obstruction of the portal venous system.death
. hemorrhages. shock Blockage of the pulmonary artery: Etiology: Pneumonia Congenital heart disease Bronchiectasis Parasite infestations Hyperadrenalcorticism Renal amyloidosis Result:. severe venous congestion.If sudden and large artery . vascular stasis.6. obstruction of the portal venous system. O2 carrying capacity of RBC's at time of infarct SEPTIC INFARCT: When the necrotic tissue of an infarct is seeded by pyogenic bacteria the tissue becomes a good growth medium for these pathogenic organisms VENOUS OBSTRUCTION: Significance: -may cause slowly developing stasis with engorgement of the tributary venous system (chronic passive hyperemia) . vascular stasis 6ischemia 6 loss of endothelial integrity.common cause of shock Acute Blockage of the Portal Vein: Result: Infarction of intestine Sequelae: shock and death w/o surgery Example: Gastric torsion in dogs.
insulin resistance. Collateral circulation could develop (azygous vein) ATHEROSCLEROSIS is the most common form of arteriosclerosis. There is recent evidence that individuals with a defect in the production of precursor endothelial cells in the bone marrow are at greater risk for atherosclerotic disease because these precursor cells are not available to repair injured endothelium. and hyperhomocystenemia. infection. hypertension. Other causes of endothelial injury are called the “novel” risk factors. Atherosclerosis is not a single disease entity but rather a pathologic process that can affect vascular systems throughout the body resulting in ischemic syndromes that can vary widely in their severity and clinical manifestations. Injured endothelial cells become inflamed and cannot make normal amounts of antithrombic and vasodilating cytokines. increased serum fibrinogen. decreased levels of high density lipoprotein (HDL). such as smoking. Atherosclerosis begins with injury to the endothelial cells that line artery walls. oxidative stress. Possible causes of endothelial injury include the common risk factors for atherosclerosis. It is the leading cause of coronary artery and cerebrovascular disease. increased level of low.If incomplete and smaller arteries • Anastomoses develop between pulmonary arteries and bronchial arteries
Blockage of the posterior vena cava: Etiology: Hepatic abscesses in ruminants Dirofilariasis in dogs . complete occlusion 6death 2.overwhelming infections Pathogenesis: 1. Acute. The next step in
.reactive protein. such as elevated C.arterial fat and fibrin in the vessels walls that harden over time. It is characterized by soft deposits of intra.density lipoprotein (LDL). and periodontal disease.
PATHOPHYSIOLOGY: Inflammation plays a fundamental role in mediating all of the steps in the initiation and progression of atherogenesis.. diabetes.
reactive protein) and enzymes that further injure the vessel wall. they form a lesions called fatty steak. produce collagen. Treatment that lowers LDL may reverse this process. Oxidated LDL is engulfted by macrophages. Smooth muscle cells in the region of endothelial injury proliferate.atherogenesis occurs when inflamed endothelial cells express adhesion molecules that bind macrophages and other inflammatory and immune cells. fatty steaks produce more toxic oxygen radicals and cause immunologic and inflammatory changes resulting in progressive damage to the vessel wall. Often. and obstruct blood flow distal tissues. (especially during exercise). any part of the body may become ischemic when its blood supply is compromised by atherosclerotic lesions. which may cause symptoms (e. Obstruction of peripheral arteries can cause significant pain and disability.g. These lesions can be found in the walls of arteries of most people. Macrophages adhere to the injured endothelium and release numerous inflammatory cytokines (e. which then penetrate into the intima of the vessel. Atherosclerotic obstruction of the vessels supplying the brain is the major cause of stroke.. Once formed. which is the next important step in atherogenesis. interferons. CLINICAL MANIFESTATIONS Atherosclerosis presents with symptoms and signs that result from inadequate perfusion of tissues because of obstruction of the vessels that supply them. and C. angina or intermittent claudication). tumor necrosis factor alpha [TNF-α]. increasing obstruction with superimposed thrombosis may result in tissue infarction.. often associated with exercise or stress. interleukins.g. and when they accumulate in significant amounts.
.laden macrophages are now called foam cells. addition of oxygen) of LDL. Macrophages also release growth factors that stimulate smooth muscle cells proliferation. The fibrous plaque may calcify protrude into the vessel lumen. even young children. Coronary artery disease (CAD) caused by atherosclerosis is the major cause of myocardial ischemia and is one of the most important health issues in the United States. Partial vessel obstruction may lead to transient ischemic events. and disease in one area may indicate that the individual is at risk for ischemic complications elsewhere. As the lesion becomes complicated. Toxic oxygen radicals generated by the inflammatory process cause oxidation (i. Similarly. These lipid. more than one vessel will become involved with this disease process such that an individual may present with symptoms from several ischemic tissues at the same time. and migrate over the fatty steak forming a fibrous plaque.e.
. a complete health history (including risk factors). CHROMOSOME TRANSLOCATION
. If an individual has presented with acute ischemia (e.EVALUATION AND TREATMENT In evaluating individuals for the presence of atherosclerosis. nuclear scanning. an accelerator of cellular proliferation.First. stroke). and control of hypertension and diabetes where appropriate while reducing LDL cholesterolby diet or medications or both. electrocardiography. I.. This includes exercise.g. B. It is found in many canceresp in pancreatic and in colorectal cancer. The primary goal in the management of atherosclerosis is to restore adequate blood flow to the affected tissues.Small-scale change in DNA . Judicious use of X-ray films. . a translocation can cause excess and inappropriate production of a proliferation factor. particularly coronary vessels. ultrasonography. management focuses on removing the initial causes of vessel damage and preventing lesion progression.Are nonmutant genes are mutant genes that in their normal nonmutant state direct synthesis of proteins that positively regulate proliferation. and laboratory data. myocardial ischemia. Tumor –suppressor genes Encode protein that in their normal state negatively regulate proliferation Also have been referred to as antioncogenes.
. In the situations where the disease process does not require immediate intervention. and angiography may be necessary to identify the affected vessels.Can have profound effects on the activity of proteins. MUTATIONS THAT CREATE ONCOGENES
• Point Mutations .Alteration of one or a few nucleotide base pairs . smoking cessation.Can activate oncogenes by either of two distinct mechanisms. physical examination. interventions are specific to the diseased area and are discussed further under those topics. Oncogenesis • Oncogenes . • A.In RAS converts it from a regulated proto-oncogene to an unregulated oncogene. are considered .
.The MYC PRONCOGENE found on chromosom 8 is normally turned on at low levels in proliferating lymphocytes and is turned off in mature lymphocytes. C.Example: translocation found in many Burkitt lymphomas ( aggressive cancer of B lymphocytes means a chromosome with a piece of chromosome 8 fused to a piece of chromosome . and bone cancers.The N-myc oncogene is amplified in 25% of childhood neuroblastomas and confers a poor prognosis.Gene amplification results in increased expression of an oncogene or in some cases drug-resistant genes.This tanslocation fuses two chromosomes right in the middle of two genes.
.It slows the cell cycle . there are tens or even hundreds of copies .Chromosome translocations also can lead to production of novel proteins with growth promoting properties.Several other novel drugs that specifically inhibit this tyrosine kinase have shown great efficacy in the treatment of CML ands lack the side effects noted with nonspecific antileukemia drugs.In a different type of leukemia. so that instead of the normal two copies of gene. Rb is mutated in childhood retinoblastoma and in many lung. CHROMOSOME AMPLIFICATION
. When it is inactivated. whereas the epidermal growth factor receptor erbB2 is amplifies in 20% of breast cancer II.Are genes whose major function is to negatively regulate cell growth .BCR ABL is a misregulated protein tyrosine kinase thae promotes growth of myeloid cells.The result is production of a BCR-ABL fusion protein containing the first half of BCR and the second half of ABL. . inhibit proliferation from growth signals and stop cell division when cells are damaged . t(9:22) . The MYC PROTEIN is part of the positive signal for cell proliferation. breast. the cell division cycle can proceed unchecked . .Result of duplication of a small piece of a chromosome over and over again.
. .RETINOBLASTOMA (Rb) GENE – normally strongly inhibits the cell dividion cycle. chronic myeloid leukemia. . a specific translocation is found almost invariably A. BCR on chromosome 9 and the ABL on chromosome 22. Tumor suppressor genes
LOSS OF HETEROZYGOSITY .loss heterozygosis (unmasks mutations in recessive tumor suppressor genes IV.Can shut of critical tumor suppressors gene in the absence of its mutation.Characterization of cancer-causing genes and other genetic factors help identify individuals prone to developing cancer.Functional Rb can still be made and therefore the cell division cycle can still be made and therefore the cell division cyclecan be regulated appropriately.Shuts off whole regions of chromosomes.MUTAGENS-agent causing mutations.Because the other cop[y of the retinoblastoma gene. GUARDIANS OF THE GENOME
. GENE SILENCING
.For a tumor suppressor to be lost both chromosomal copes of the gene must be inactivated.The first allele is inactivatedby simple mutation.Inherited mutations can disrupt the caretaker genes that protect theintegrity of genome. IMMUNITY . INFLAMMATION. .Must be activated to allow cancer to occur . .SILENCING = regulates GENE EXPRESSION that does not require mutations or changes in DNA sequence . AND CANCER
. then all Rb function id lost and another step toward cancer occurs.Associated with methylation of DNA V.CANCER PRONE FAMILIES. VI. .Genetic events are the primary basis of carcinogenesis.\ ..CARETAKER GENES – responsible for the maintenance of genomic integrity.The integrity of genetic information can be compromised at several points. .demonstrate the inheritance of a mutated gene can cause cancer. . . .The first copy of a tumor suppressor is often inactivated by point mutation .If the remaining gene is mutated. III. GENETICS AND CANCER PRONE FAMILIES . INFECTION.Boundaries can be spread in cancer cells . .CHROMOSOME INSTABILITY – appears to be increased in malignant cells.TUMOR. . . but second allele is lost because entire region of the maternal chromosomes are lost .
Formation of DNA adducts c. These are the histology and the location. . Dysregulation of the gastric epithelial cycle b. lung and colon cancer. Alterations in growth factor secretion and cytokines e. respectively. the tissue presumed to be the origin of the tumor. tissue breakdown and angiogenesis.
BACTERIAL CAUSE OF CANCER
• HELICOBACTER PYLORI – a bacterium that infects more than half of the world’s population.Treatment with antibiotics result in regression of the lymphoma in most cases.Most common cause of gastric infection. or mesenchymal cells.COX-2 generates prostaglandins during inflammation protect against colon cancer colonies. Examples of general categories include:
Carcinoma: Malignant tumors derived from epithelial cells.Cancer cells and Macrophages secrete inflammatory mediators released by interleukin 8 that they stimulate immune and other cells to increase vascular permeability.Chronic Inflammation is a form of an immune response that has been recognized since 1860’s as an contributing factor to the development of cancer.Reacts to infection and tissue damage. MECHANISMS: a. .Recognizes nonself and new antigens .I. II. This group represents the most common cancers. Effects of decreased gastric secretions. ACTIVE IMMUNE RESPONSE IN CANCER
. Classifications: Cancers are classified by the type of cell that resembles the tumor and. . III.Plays a complex role in the development of and progression of cancer. Generation of free radicals d. prostate. Sarcoma: Malignant tumors derived from connective tissue. . . .Chronic inflammation as a result of HBV or HCV hepatitis markedly increases the risk of liver cancer.
.Patients receiving immunosuppression after an organ transplant have little or no increase in most prevalent cancers. including the common forms of breast. IMMUNITY AND CANCER . therefore. .
some cancers also use the -oma suffix.
Malignant tumors (cancers) are usually named using -carcinoma. (B) Phenologs can be identified based on significantly overlapping sets of orthologous genes (gene A is orthologous to A'. Number of unique gene-phenotype associations. (C) An example of a phenolog mapping high incidence of male C. the gene A' is a new candidate for phenotype 2. For common cancers. that is. identification of phenologs. Benign tumors (which are not cancers) are named using -oma as a suffix with the organ name as the root. and young children most often found on the body midline. Many of these tumors are most common in children. Unfortunately. resembling normal breast ducts. such that each gene in a given set (green box or cyan box) gives rise to the same phenotype in that organism. B to B'. 8–11. Thus. For instance. examples being melanoma and seminoma. (A) The rate of associating genes to organism-level phenotypes in model organisms greatly exceeds that in humans (data from refs. with the Latin or Greek word for the organ of origin as the root. particularly at the tip of the tailbone. the adjective ductal refers to the appearance of the cancer under the microscope. 14). in fetuses. As gene-phenotype associations are often incompletely mapped. For instance. Here. appropriate mapping of model organism phenotypes to human diseases could significantly accelerate discovery of human disease gene associations. a benign tumor of the smooth muscle of the uterus is called leiomyoma (the common name of this frequent tumor is fibroid). genes currently linked to only one of the orthologous phenotypes become candidate genes for the other phenotype. in horses most often found at the poll (base of the skull). In adults most often found in the testicle and ovary. Orthologous phenotypes (phenologs) offer one such approach.). the most common type of breast cancer is called ductal carcinoma of the breast or mammary ductal carcinoma.•
Lymphoma and leukemia: Malignancies derived from hematopoietic (blood-forming) cells Germ cell tumor: Tumors derived from totipotent cells. For instance. The phenotypes may differ in appearance between organisms because of differing organismal contexts. babies. elegans progeny to human breast/ovarian cancers
. the English organ name is used. etc. Blastic tumor or blastoma: A tumor (usually malignant) which resembles an immature or embryonic tissue. a cancer of the liver is called hepatocarcinoma. a cancer of the fat cells is called liposarcoma. -sarcoma or -blastoma as a suffix. and the example of a worm model of breast cancer.
Orthologous phenotypes (phenologs) offer one such approach. identification of phenologs. B to B'. The phenotypes may differ in appearance between organisms because of differing organismal contexts. appropriate mapping of model organism phenotypes to human diseases could significantly accelerate discovery of human disease gene associations. and the example of a worm model of breast cancer. the gene A' is a new candidate for phenotype 2. As gene-phenotype associations are often incompletely mapped.
. (C) An example of a phenolog mapping high incidence of male C. (B) Phenologs can be identified based on significantly overlapping sets of orthologous genes (gene A is orthologous to A'.). etc. genes currently linked to only one of the orthologous phenotypes become candidate genes for the other phenotype. (A) The rate of associating genes to organism-level phenotypes in model organisms greatly exceeds that in humans Thus. that is. such that each gene in a given set (green box or cyan box) gives rise to the same phenotype in that organism. elegans progeny to human breast/ovarian cancers.Number of unique genephenotype associations.
ENSALADA MA.Written Report In Pathophysiology
MECHANISM OF DISEASE
SUBMITTED BY: LEADER: ANNA ROSE CARONAN MEMBERS: DAN ATANIEL W.JOANNA OTILANO
.VERONICA SALAZA ANGEL BALMOCENA CATHRYN ORLANDA RODA SAMORTIN YVONNE LLACER SUBMITTED TO: PROF.