A.

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.

LOCAL

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.

Once the protective barrier is broken, the normal (physiologic) process of wound healing is immediately set in motion. The classic model of wound healing is divided into three or four sequential, yet overlapping phases: inflammatory phase proliferative phase

remodeling. phase

Upon injury to the skin, a set of complex biochemical events takes place in a closely orchestrated cascade to repair the damaged part. In the inflammatory phase, bacteria and debris are phagocytosed and removed, and factors are released that cause the migration and division of cells involved in the proliferative phase. The proliferative phase is characterized by angiogenesis, collagen deposition, granulation tissue formation, epithelialization, and wound contraction In angiogenesis, new blood vessels are formed by vascular endothelial cells In fibroplasia and granulation tissue formation, fibroblasts grow and form a new, provisional extracellular matrix (ECM) by excreting collagen and fibronectin. Concurrently, re-epithelialization of the epidermis occurs, in which epithelial cells proliferate and 'crawl' atop the wound bed, providing cover for the new tissue In contraction, the wound is made smaller by the action of myofibroblasts, which establish a grip on the wound edges and contract themselves using a mechanism similar to that in smooth muscle cells. When the cells' roles are close to complete, unneeded cells undergo apoptosis In the maturation and remodeling phase, collagen is remodeled and realigned along tension lines and cells that are no longer needed are removed by apoptosis. However, this process is not only complex but fragile, and susceptible to interruption or failure leading to the formation of chronic non-healing wounds. Factors which may contribute to this include diabetes, venous or arterial disease, old age, and infection. Wound healing is classically divided into hemostasis, inflammation, proliferation, and remodeling. Although a useful construct, this model employs considerable overlapping among individual phases. In this construct, the process of wound healing is divided into major two phases: early phase and cellular phase The early phase, which begins immediately following skin injury, involves cascading molecular and cellular events leading to hemostasis and formation of an early, makeshift extracellular matrixproviding structural support for cellular attachment and subsequent cellular proliferation. The cellular phase follows the early phase, and involves several types of cells working together to mount an inflammatory response, synthesize granulation tissue, and restore the epithelial layer. INFLAMMATION

Inflammation is the body's reaction to invasion by an infectious agent, antigen challenge or even just physical, chemical or traumatic damage. This is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process. Inflammation is not a synonym for infection. Even in cases where inflammation is caused by infection, the two are not synonymous: infection is caused by an exogenous pathogen, while inflammation is one of the responses of the organism to the pathogen.Without inflammation, wounds and infections would never heal. Similarly, progressive destruction of the tissue would compromise the survival of the organism. However, chronic inflammation can also lead to a host of diseases, such as hay fever, atherosclerosis, and rheumatoid arthritis. It is for that reason that inflammation is normally closely regulated by the body. Inflammation can be classified as either acute or chronic. 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. A cascade of biochemical events propagates and matures the inflammatory response, involving the local vascular system, the immune system, and various cells within the injured tissue. Prolonged inflammation, known as chronic inflammation, 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.There are fivecardinal signs of inflammation, namely; rubor, dolor, calor, tumor, and functiona laesa.

D. FLUID AND ELECTROLYTE BALANCE 1.BODY AND WATER COMPARTMENTS The Intracellular Fluid is composed of at least 1014 separate tiny cellular packages. The concept of a single united "compartment" called intracellular fluid is clearly artificial. The ICF compartment is really a "virtual compartment" considered as the sum of this huge number of discontinuous small collections. 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, the collections have extremely important unifying similarities which make the ICF concept of practical usefulness in physiology. In particular, similarities of location, composition and behavior:

* 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, it is convenient to talk of an idealized ICF as though it were a single real entity. The use of this convention allows predictions to be made about what will happen with various interventions and within limits these are physiologically meaningful. A similar argument applies to the Extracellular Fluid. The ECF is divided into several smaller compartments (e.g. plasma, interstitial fluid, fluid of bone and dense connective tissue and transcellular fluid). These compartments are distinguished by different locations and different kinetic characteristics. The ECF compositional similarity is in some ways, the opposite of that for the ICF (i.e. low in potassium & magnesium and high in sodium and chloride). Interstitial fluid (ISF) consists of all the bits of fluid which lie in the interstices of all body tissues. This is also a virtual fluid (i.e. 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). The ISF bathes all the cells in the body and is the link between the ICF and the intravascular compartment. Oxygen, nutrients, wastes and chemical messengers all pass through the ISF. 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). Lymph is considered as a part of the ISF. The lymphatic system returns protein and excess ISF to the circulation. Lymph is more easily obtained for analysis than other parts of the ISF. Plasma is the only major fluid compartment that exists as a real fluid collection all in one location. It differs from ISF in its much higher protein content and its high bulk flow (transport function). Blood contains suspended red and white cells so plasma has been called the interstitial fluid of the blood. 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. This fluid is mobilized only very slowly and this lessens its importance when considering the effects of acute fluid interventions.

Transcellular fluid is a small compartment that represents all those body fluids which are formed from the transport activities of cells. It is contained within epithelial lined spaces. It includes CSF, GIT fluids, bladder urine, aqueous humor and joint fluid. It is important because of the specialized functions involved. The fluid fluxes involved with GIT fluids can be quite significant. 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. 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. 2. MAINTAINANCE OF WATER COMPARTMENTS BALANCE HYDROSTATIC AND ONCOTIC PRESSURE

-H2O is one of the most essential molecules for cellular life. Cell volume, osmolality and hydrostatic pressure are tightly controlled by multiple signaling cascades and they drive crucial cellular functions ranging from exocytosis and growth to apoptosis. Ion fluxes and cell shape restructuring induce asymmetries in osmotic potential across the plasma membrane and lead to localized hydrodynamic flow. Cells have evolved fascinating strategies to harness the potential of hydrodynamic flow to perform crucial functions. Plants exploit hydrodynamics to drive processes including gas exchange, leaf positioning, nutrient acquisition and growth. This paradigm is extended by recent work that reveals an important role for hydrodynamics in pollen tube growth. Osmotic pressure is the primary determinant of the distribution of water between the three major compartments. The concentrations of the major solutes in these fluids differ, 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), Na + salts in the interstitial fluid, and proteins in the plasma. 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. A characteristic of an osmotically active solute is that it cannot freely leave its compartment. The capillary wall, for example, is relatively impermeable to plasma proteins, 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, Na + freely crosses the capillary wall and achieves similar concentrations in the

interstitium and plasma; as a result, it does not contribute to fluid distribution between these compartments. Similarly, urea crosses both the capillary wall and the cell membrane and is osmotically inactive. Thus, the retention of urea in renal failure does not alter the distribution of the total body water.

3. 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. 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. Infants lose more fluid through the kidneys because immature kidneys are less able to conserve water than adult kidneys. In addition, infants respirations are more rapid and the body surface area is proportionately greater than that of adults. Increasing insensible fluid losses. 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, the normal aging process may affect fluid balance. The thirst response often is blunted. Antidiuretic hormone levels remain normal

or may even be elevated, but the nephrons become less able to conserve water in response to ADH. Increased levels of atrial natriuretic factor seen in older adults may also contribute to this impaired ability to conserve water. These normal changes of aging increase the risk of dehydration. When combined with the increased likelihood of heart diseases, impaired renal function, and multiple drug regimens, the older adults risk for fluid and electrolyte imbalance is significant. Additionally, it is important to consider that the older adult has thinner, more fragile skin and veins, which can make an intravenous insertion more difficult.

GENDER AND BODY SIZE Total body water also is affected by gender and body size. Because fat cells contain little or no water and lean tissue has a high water content, people with a higher percentage of body fat have less body fluid. Women have proportionately more body fat and less body water than men. Water accounts for approximately 60% of an adult mans weight, but only 52% for an adult woman. In an obese individual this may be even less, with water responsible for only 30% to 40% of the persons weight.

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. Fluid losses through sweating are increased in hot environments as the body attempts to dissipate heat. These losses are even greater in people who have not been acclimatized to the environment. Both salt and water are lost through sweating. When only water is replaced, salt depletion is a risk. The person who is salt depleted may experience fatigue, weakness, headache and gastrointestinal symptoms such as anorexia and nausea. The risk of adverse effects is even greater if lost water is not replaced. Body temperature rises, and the person is at risk for heat exhaustion or heatstroke. Heatstroke may occur in older adults or ill people during prolonged periods of heat; it can also affect athletes and laborers when their heat production exceeds the bodys ability to dissipate heat. Consuming adequate amounts of cool liquids, particularly during strenuous activity, reduces the risk of adverse effects from heat. Balanced electrolyte solutions and carbohydrate-electrolyte solutions such as sports drinks are

recommended because they replace both water and electrolyte lost through sweat.

LIFESTYLE Other factors such as diet, exercise, and stress affect fluid, electrolyte and acid-base balance. The intake of fluids and electrolytes is affected by diet. People with anorexia nervosa or bulimia are at risk for severe fluid and electrolyte imbalance because of inadequate intake or purging regimens (e.g. induced vomiting, use of diuretics and laxatives). Seriously malnourished people have decreased serum albumin levels, and may develop edema because the osmotic draw of fluid into the vascular compartment is reduced. When calorie intake is not adequate to meet the bodys needs, fat stores are broken down and fatty acids are released, increasing the risk of acidosis. Regular weight-bearing physical exercise such as walking, running, or bicycling has a beneficial effect on calcium balance. The rate of bone loss that occurs in postmenopausal women and older men is slowed with regular exercise, reducing the risk of osteoporosis. Stress can increase cellular metabolism, blood glucose concentration and catecholamine levels. In addition, stress can increase production of ADH, which in turn decreases urine production. The overall response of the body to stress is to increase the blood volume. Other lifestyle factors can also affect fluid, electrolyte, and acid-base balance. Heavy alcohol consumption affects electrolyte balance, increasing the risk of low calcium, magnesium, and phosphate levels. The risk of acidosis associated with breakdown of fat tissue also is greater in the person who drinks large amounts of alcohol. 5. ACID BASE BALANCE An acid is a substance that acts as a proton donor. In contrast, a base, also known as an alkali, is frequently defined as a substance that combines with a proton to form a chemical bond. Acid solutions have a sour taste and produce a burning sensation with skin contact. A base is any chemical compound that produces hydroxide ions when dissolved in water. Base solutions have a bitter taste and a slippery feel. Despite variations in metabolism, diet, and environmental factors, the body's acid-base balance,

fluid volume, and electrolyte concentration are maintained within a narrow range. Function Many naturally occurring acids are necessary for life. For example, hydrochloric acid is secreted by the stomach to assist with digestion. The chemical composition of food in the diet can have an effect on the body's acid-base production. Components that affect acid-base balance include protein, chloride, phosphorus, sodium, potassium, calcium, and magnesium. In addition, the rate at which nutrients are absorbed in the intestine will alter acid-base balance. Cells and body fluids contain acid-base buffers, which help prevent rapid changes in body fluid pH over short periods of time, until the kidneys pulmonary systems can make appropriate adjustments. The kidneys and pulmonary system then work to maintain acid-base balance through excretion in the urine or respiration. 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. PCO2 can then be used as an indicator of the concentration of acid in the body. The concentration of base in the body can be determined by measuring plasma bicarbonate (HCO3-) concentration. When the acid-base balance is disturbed, the respiratory system can alter PCO2 quickly, thus changing the blood pH and correcting imbalances. Excess acid or base is then excreted in the urine by the renal system to control plasma bicarbonate concentration. Changes in respiration occur primarily in minutes to hours, while renal function works to alter blood pH within several days. Role in human health Production of CO2 is a result of normal body metabolism. Exercise or serious infections will increase the production of CO2 through increased respiration in the lungs. When oxygen (O2) is inhaled and CO2 is exhaled, the blood transports these gases to the lungs and body tissues. 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. Disruptions in CO2 levels and HCO3create acid-base imbalances. When acid-base imbalances occur, the disturbances can be broadly divided into either acidosis (excess acid) or alkalosis (excess base/alkali). Common diseases and disorders Acid-base metabolism imbalances are often characterized in terms of the HCO3-/CO2 buffer system. Acid-base imbalances result primarily from metabolic or respiratory failures. An increase in HCO3-is called metabolic alkalosis, while a decrease in the same substance is called metabolic acidosis. An increase in PCO2, on the other hand, is known as respiratory

acidosis, and a decrease in the same substance is called respiratory alkalosis. Acidosis Acidosis is a condition resulting from higher than normal acid levels in the body fluids. It is not a disease, but may be an indicator of disease. Metabolic acidosis is related to processes that transform food into energy and body tissues. Conditions such as diabetes, kidney failure, severe diarrhea, and poisoning can result in metabolic acidosis. Mild acidosis is often compensated by the body in a number of ways. However, prolonged acidosis can result in heavy or rapid breathing, weakness, and headache. Acidemia (arterial pH < 7.35) is an accumulation of acids in the bloodstream that may occur with severe acidosis when the acid load exceeds respiratory capacity. This condition can sometimes result in coma and, if the pH falls below 6.80, it will lead to death. Diabetic ketoacidosis is a condition where excessive glucagon and a lack of insulin contribute to the production of ketoacids in the liver. This condition can be caused by chronic alcoholism and poor carbohydrate utilization. Respiratory acidosis is caused by the lungs failure to remove excess carbon dioxide from the body, reducing the pH in the body. Several conditions, including chest injury, blockage of the upper air passages, and severe lung disease, may lead to respiratory acidosis. Blockage of the air passages may be caused by bronchitis, asthma, or airway obstruction, resulting in mild or severe acidosis. Regular, consistent retention of carbon dioxide in the lungs is referred to as chronic respiratory acidosis. This disorder results in only mild acidosis because it is balanced by increased bicarbonate production. 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, nausea, and vomiting. Most often, severe metabolic acidosis (pH < 7.20) is associated with increased respiration to compensate for a shortage of HCO3-. This is followed by a secondary decrease in PCO2 that occurs as part of respiratory compensation process. Treatment options for acidosis typically require correction of the underlying condition by venous administration of sodium bicarbonate or another alkaline substance. Alkalosis Alkalosis is a condition resulting from a higher than normal level of base/alkali in the body fluids. An excessive loss of HCO3-in the blood causes metabolic alkalosis. The body can compensate for mild alkalinity, but prolonged alkalosis can result in convulsions, muscular weakness, and even death if the pH rises above 7.80. Alkalosis can be caused by drugs or

disorders that upset the normal acid-base balance. Prolonged vomiting and hyperventilation (abnormally fast, deep breathing) can result in alkalosis. The predominant symptoms of alkalosis are neuromuscular hyperexcitability and irritability. Alkalemia (abnormal blood alkalinity) increases protein binding of ionized calcium even though plasma total calcium does not change. Severe cases may induce hypocalcemia (a low level of plasma calcium). Low plasma potassium leads to a condition called hypokalemic alkalosis. It is frequently accompanied by metabolic alkalosis, resulting in cramping, muscle weakness, polyuria, and ileus (obstruction of the intestines). Diuretic medications may cause hypokalemic alkalosis. Prolonged vomiting may induce hypochloremic alkalosis (a large loss of chloride). The kidneys may conserve bicarbonate in order to compensate for the chloride reduction. Compensated alkalosis results when the body has partially compensated for alkalosis, and has restored normal acid-base balances. However, in compensated alkalosis, abnormal bicarbonate and carbon dioxide levels persist. Alkalosis requires correction of the underlying condition and may involve venous administration of a weak acid to restore normal balance. If the source of alkalosis is excessive drug intake, it may be appropriate to reduce intake to restore the normal acid-base balance. Respiratory alkalosis results from decreased CO2 levels caused by conditions such as hyperventilation (a faster breathing rate), anxiety, and fever. The pH is elevated in the body. 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. Symptoms of respiratory alkalosis may include dizziness, lightheadedness, and numbing of the hands and feet. Treatments include breathing into a paper bag or a mask that induces rebreathing of carbon dioxide. E. 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. Normal fluid homeostasis Includes maintenance of vessel wall integrity (intact circulation) as well as intravascular pressure, blood volume, and protein content (osmolarity) within certain physiologic ranges. Therefore any change in one of these factors will affect the tissue homeostasis and may result in edema or congestion. Also means maintaining blood as a liquid until such time as injury

necessitates clot formation. Clotting at inappropriate sites (thrombosis) or migration of clots (embolism) obstructs blood flow to tissues & leads to cell death (infarction). Conversely inability to clot after injury results in hemorrhage. Extensive hemorrhage can result in shock. 1. Etiology 2. Morphology 3. Effects A. EDEMA Edema is defined as in increase in interstitial fluid and is manifested clinically as swelling of tissues.It may be localized to a single organ or limb or generalized. The distribution of water between the compartments depends upon: 1. Capillary pressure forcing fluid outward through the capillary membrane. 2. The interstitial fluid (IF) pressure. Usually this is negative, and tends to force fluid out of the capillaries, as a consequence of pumping by the lymphatic system. 3. Plasma colloid osmotic pressure which tends to draw fluid into the blood stream by osmosis. Average protein concentration in plasma is 7g per dl. Approximately 75% of the total colloid osmotic pressure is due to albumin, 25% from the globulins and negligible amounts from fibrinogen. 4. The interstitial fluid osmotic pressure. 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. 5. 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. This can overwhelm the edema safety factor and result in edema. The interstitial fluid fills the spaces between body cells. 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. Normally almost all the IF is in this form and a small amount is present in free fluid vesicles and channels. When edema develops large quantities of free fluid accumulate in the tissues. Fluid in the tissue gel is highly permeable to nutrients but is relatively immobile and does not shift easily. Free fluid in the tissues moves easily and

"pits" on pressure as well as shifting to dependent regions due to the effect of gravity. Factors Controlling Distribution of Extracellular Body Water 1. Factors which cause fluid to leave the vascular compartment. (a) Increase in hydrostatic pressure in the vascular compartment. An example is mitral stenosis which can cause a rise in pulmonary venous pressure and therefore in pulmonary capillary pressure. 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. (b) Increase in colloid osmotic pressure in the interstitial fluid. This may occur in lymphatic obstruction. (c) Increase in capillary permeability. 2. Factors which tend to retain fluid within the vascular compartment (a) Osmotic pressure of the plasma proteins. This depends predominantly on the concentration of albumin in the plasma. Hypoalbuminemia may be due to reduced synthesis, as in liver disease, increased loss as in nephrotic syndrome or nutritional deficiency. (b) The selective permeability function of the endothelium. 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. 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. (c) The tissue tension in the interstitial fluid will also tend to limit egress of fluid from the microvasculature. ` The Role of Sodium Retention in Edema The presence of generalized edema invariably reflects an increase in total body sodium.

Factors that promote sodium retention are: (a) Arterial Underfilling. The predominant determinant of renal sodium and water exertion is the integrity of the arterial circulation. This may be altered by changes in cardiac output and peripheral vascular resistance or compliance. Baro-receptors in the left ventricle, carotid sinus, aortic arch and renal afferent arterioles can sense arterial underfilling and cause an increase in sympathetic flow

from the CNS with resulting activation of the renin-angiotensinaldosterone system, nonosmotic release of arginine vasopressin and stimulation of thirst. (b) The role of natriuretic peptide. This hormone is synthesized in the atria and to a lesser extent in the ventricles and is released into the circulation in heart failure. 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. (c) Reduction in renal flood flow with reduced glomerular filtration rate and activation of therenin-angiotensin-aldosterone system. (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. Sodium retention is a major component of the pathogenesis of edema. The relief of edema requires medication to promote excretion of sodium in addition to management of theprimary cause of the edema. The various causes of edema are classified below. Note that multiple mechanisms may occur in some diseases. 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 - or hypoproteinemic.

CLASSIFICATION OF EDEMA I. Increased Capillary Pressure A. Local 1) Venous obstruction - phlebothrombosis, cirrhosis (ascites), SVC syndrome 2) Arteriolar dilation (inflammation) 3) Congestive heart failure (i.e., LVF with pulmonary edema) B. Generalized 1) Congestive heart failure 2) Constrictive pericarditis 3) Fluid overload (renal failure, iatrogenic) II. Increased Capillary Permeability A. Local 1) Inflammation 2) Thermal injury (burns, frost bite) 3) Chemical injury 4) Mechanical injury (trauma) B. Generalized 1) Anaphylaxis

2) Shock 3) Idiopathic cyclic edema III. Decreased Plasma Protein Concentration (generalized only) 1) Protein loss (nephrotic syndrome, protein losing gastroenteropathy) 2) Decreased synthesis (cirrhosis, malnutrition) 3) Protein sequestration (burns) IV. Lymphatic obstruction (local only) 1) Iatrogenic (surgical resection, radiation) 2) Tumor 3) Cirrhosis 4) Filariasis (elephantiasis) V. Renal Salt and Water Retention (generalized only) 1) Acute glomerulonephritis 2) Acute renal failure 3) Chronic renal failure VI. Defective pre-capillary vasoconstrictor mechanism (localized only). This is seen in paralyzed limbs due to polio-myelitis, spinal injuries and other causes of denervation. Types of Edema a. LOCALIZED EDEMA Mechanisms: Local Increase in hydrostatic pressure Lymphatic obstruction Inflammation PULMONARY EDEMA is common and produces symptoms by interfering with gas exchange.Capillary pressures are normally low and lymphatics are abundant, 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. This occurs particularly when edema develops rapidly and there is no time to compensate. Initially edema fluid accumulates in the interstitial spaces, chiefly in the loosely structured peribronchial connective tissue where anionic glycoproteins soak up water like a sponge. When the "sponge" is saturated fluid begins to spreads to the alveolar walls and interferes with gaseous exchanges. Finally fluid seeps into the alveolar spaces eventually flooding individual alveoli. Lymphatic flow can compensate for fluid accumulation by increasing up to 10 fold but eventually this protection fails when the pressures are too great. These changes lead to dyspnoea, cyanosis and hypoxia. Chest x-ray may distinguish alveolar (fluffy infiltrate with "bronchial" markings) and interstitial edema ("Kerley B" or "septal) lines). Pulmonary edema is most commonly due to increases in capillary

pressure from heart disease or increase in capillary permeability from toxic or inflammatory insults; it is very rarely due to hypoproteinemia. 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. This leads to headache, vomiting, drowsiness, convulsions, loss of consciousness and ultimately death. The final "coup" is usually due to brain stem compression following tentorial or tonsillar herniation. Causes of increased fluid volume and cerebral edema include areas of infection, inflammation ortumor, abscesses, hemorrhage, obstruction to the flow of cerebro- spinal fluid and cerebral tumors. Fluid collections in the VIRTUAL SPACES (PLEURA, PERITONEUM, PERICARDIUM, JOINTSPACES) can be thought of as edema fluid escaping from the adjacent tissues where it is formed by the usual mechanism. The pressure within virtual spaces is normally negative. a. GENERALIZED EDEMA Mechanism: 1. Increased hydrostatic pressure of blood 2. Decreased colloid osmotic pressure of plasma proteins 3. Sodium retention CARDIAC EDEMA Two hypotheses have been proposed to explain the edema of cardiac failure. 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. The effect of the low plasma volume on the kidney is to stimulate sodium retention and further increase the ECF volume. However, 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. These "facts" undermine this hypothesis although in some circumstance elevated venous pressure may contribute to the precipitation of cardiac edema. 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. In patients with heart failure there is a striking and consistent reduction in renal plasma flow. Minimal exercises in these patients result in a further sharp reduction in renal plasma flow and GFR. The effect on the kidney is similar to that of an

actual reduction in blood and plasma volume and therefore sodium is retained and the ECF volume increases. 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. 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. Characteristically the edema involves the face and eyelids, alike in some cases the ankle and genitalia may also be involved. HEPATIC EDEMA Edema can occur in patients with liver disease. This is frequently associated with fluid in the peritoneal space, known as Ascites. The protein content of the ascitic fluid is low and has the characteristics of a transudate. Ascites is not detectable clinically until at least 500ml is present. PREGNANCY EDEMA Generalized edema is quite common in pregnancy but the mechanism is poorly understood. 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 large pregnant uterus may exaggerate the normal reduction in sodium excretion by the kidney on standing upright. 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. This results in edema. Reduced osmotic pressure within the vessels will not pull fluid from the tissue spaces into the vessel. The fluid accumulates within the tissue space and results in edema. Fluid retention (water retention) where there is excessive fluid within the blood vessel and tissue spaces. If the body is not able to pass out this excess fluid, it will be retained within the tissue spaces thereby resulting in edema.

Increased vascular permeability is when blood vessel wall allows fluid to pass out of the blood vessel unabated. 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. Lymphatic obstruction is where the lymph vessels are blocked at some point and the interstitial fluid cannot be drained from the tissue spaces. Fluid accumulates in the tissue space and the result is edema.

Pathophysiology of Edema Fluid in the body exists within cells (intracellular fluid), within the tissue space between cells (interstitial fluid), within the blood vessels (blood) or lymphatic vessels (lymph or lymphatic fluid). This fluid is not just water but there are also cells, nutrients, electrolytes and waste products existing with water in these areas. Two forces are responsible for maintaining the fluid in specific areas or pulling and pushing fluid into other areas. These forces are known as hydrostatic pressure and osmotic pressure. Hydrostatic pressure is the force that pushes fluid from an area of high pressure to low pressure. Osmotic pressure is the force that draws fluid from an area of low electrolyte concentration to one of a higher electrolyte concentration. Fluid within our blood vessels are at a higher pressure than the fluid in the tissue spaces. This is due to the pumping heart that pushes the blood with force within the vessels. Blood does not just ooze out of the vessels unless the vessel wall becomes permeable and allows it to exit. 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. Usually fluid from the tissue spaces enters the blood vessel due to a difference in osmotic pressure. Fluid is pushed away from an area of high hydrostatic pressure but is pulled into an area of high osmotic pressure. 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. This allows for the exchange of nutrients, gases and wastes. 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. Five Pathophysiologic Mechanisms that underlie the development of edema 1. Decrease plasma (intravascular) colloidal-osmotic pressure

2. 3. 4. 5.

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.

Anasarca is the term for severe generalized edema. Ascites is the term for excessive fluid accumulation within the peritoneal cavity. This is the area between the lining of the abdomen and organs within the abdominal cavity. Pleural effusion is the term for edema in the pleural space between the outer layers of the lung. It is also known as a hydrothorax. Pericardial effusion is the term for edema within the pericardial space between the outer layers of the heart. It is also known as a hydropericardium. Pulmonary edema is the term for edema within the lungs. Cerebral edema is the term for edema within the brain. Lymphedema is the excessive fluid accumulation within tissues because the tissue fluid cannot be drained by the lymphatic vessels in that area. Hepatic edema is the term for excessive fluid accumulation in tissues due to a liver dysfunction. Cardiac edema is the term for excessive fluid accumulation in tissues due to heart failure. Renal edema is the excessive fluid accumulation in they bodys tissues due to kidney disease or failure.

Types of Edema There are two types of edema that can be identified upon examination.
1. Pitting edema is the swelling of a body part where an indentation

will persist after pressure is applied to the area. This indentation will slowly disappear over time.

2. Non-pitting edema is where there is swelling of a body part with no indentation upon applying pressure. B. CONGESTION HYPEREMIA: An excessive amount of blood in an organ (refers to both volume and flow) implication - active, arteriolar-mediated engorgement of vascular bed CONGESTION: An excessive amount of blood (refers to volume) implication - passive, venous engorgement NOTES: -Both indicate a local increase in blood volume in a particular tissue. -Congestion within capillaries beds is closely related to edema formation. Therefore, congestion and edema frequently are observed together. HEMORRHAGE VS HYPEREMIA: Hemorrhage - blood outside vessel wall ie: extravascular Hyperemia - blood inside of vessel wall ie: intravascular ETIOLOGY of HYPEREMIA: 1. Too much blood via the arterioles - Active Hyperemia red 2. Too little blood is being removed by the venules - Passive Hyperemia blue TYPES of Hyperemia: 1. 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. 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. Duration 2. Extent 3. Mechanisms 1. DURATION: acute/chronic Acute: implies abrupt onset with rapid development Chronic: slowly developing and/or present for a long time 2. EXTENT: localized/generalized Local: change confined to a discrete area (localized or limited) Generalized: indicates a systemic change or generalized within an

organ 3. 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. Excessively bloody - blood oozes on cut section. Wet - Due to edematous tissue. Red colour associated with acute local active hyperemia. Dark brown colour is associated with congestion (passive hyperemia). HISTO: acute - associated with capillaries engorged with blood usually some edema chronic - engorgement by poorly oxygenated venous blood Degree of chronic local hypoxia Degeneration, Atrophy or even Necrosis of parenchymal cells Congestion or hyperemia generally reflects increased capillary pressures. Capillary pressures are normally regulated by arteriolar opening or closing, an active process. Active hyperemia, then reflects arteriolar dilation occurring normally with exercise, blushing or the need to dissipate heat and pathologically in inflammation, fever, infections, hormonal alterations, etc. Capillary pressure increases may also be transmitted from venous pressure increases, a passive process. Passive congestion occurs locally due to venous obstruction, for example by thrombi, tumors, or extrinsic compression. It may also occur "up stream" of the liver as in cirrhosis with varices, caput medusa and hemorrhoids or in the lungs as in chronic lung disease with cor pulmonale and right heart failure. And it may occur systemically in heart failure when both left and right ventricles are decompensated. 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. Congestion of capillary beds also leads to edema and the two process commonly occur together. 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. ` Morphology: Cut surfaces of congested organs are excessively bloody and wet.

LUNG Acute congestion and edema is seen after left ventricular failure, commonly due to a myocardial infarct. The congestion leads to edema and the lungs are red and "wet". Chronic congestion in the most extreme form is seen with long standing mitral stenosis or any condition causing reduced left ventricular output. The alveolar capillaries are engorged, tortuous and dilated. This results in minute intra-alveolar hemorrhages, phagocytosis of red cells and many hemosiderinladen macrophages known as heart failure cells in the alveolar spaces.The alveolar septa become widened, edematous and later fibrotic producing so-called "brown induration". Eventually even the walls of the pulmonary arteries and arterioles become thickened. 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. The cut surface oozes blood. Microscopically the central veins are prominent and the centri-lobular zones become reddish blue surround by a pale peripheral zone. This is the typical "Nut Meg" liver. The central hepatocytes become atrophic and the peripheral cells develop fatty changes due to a lesser degree of hypoxia. With severe prolonged chronic congestion central hemorrhagic necrosis may occur possibly due to reduced hepatic blood flow consequent upon reduced circulating blood volume. Centrilobular necrosis is also seen in shock without chronic passive congestion. Long standing congestive changes can lead to fibrosis of central veins, spreading to the surrounding lobule and the characteristic pattern called cardiac cirrhosis (centrizonal). SPLEEN This organ becomes enlarged, tense and oozes blood when cut. Microscopically the sinuses are distended, there are microscopic haemorrhages and many hemosiderm laden macrophages. n severe cases the spleen weight can reach 500-700g (normal = less than 150g) with marked fibrous thickening, congested sinusoid, edema and sometimes sidero-fibrotic nodules of scar tissue following focal hemorrhages. THROMBOSIS PATHOGENESIS: - 3 primary influences - Virchows triad 1. Endothelial injury Dominant influence = can lead to thrombosis by itself eg: inflammation of heart valves

Expose of subendothelial ECM platelet adherence release of tissue factor Depletion of prostacyclin primary and secondary hemostatic plug formation 2 Alterations in normal blood flow - turbulence or stasis Normal blood flow is laminar - cellular elements in the middle, surrounded by plasma. 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. Hypercoaguability Definition: any alteration of the coagulation pathways that predisposes to thombosis Coagulation factors Inhibitory factors

TERMINOLOGY AND MORPHOLOGY THROMBOSIS: Formation, development or presence of a solid mass within the blood vessels or heart. Adherent to the vascular endothelium and must be differentiated from a simple (post mortem) blood clot. THROMBUS: An aggregation of blood factors, primarily platelets and fibrin with entrapment of cellular elements, frequently causes vascular obstruction at the point of its formation or embolism. THROMBI: Pleural of thrombus ie: several aggregations within the blood vascular system. 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.

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, initial thrombus is composed of aggregated platelets and RBC's and is soft, friable and red. As arterial thrombi grow, flow patterns adjacent to the thrombi cause fibrin to be deposited and the platelet mass that persists is transformed into a fibrin mass. Fibrin strands polymerize between the separating and degenerating platelets. The alternating lines of yellow platelets and fibrin separating RBC's forms the lines of Zahn. VENOUS: A venous thrombi is composed of fibrin strands with entrapped RBC's, since the dominant mechanism of formation is coagulation. BLOOD CLOT: Clotted blood within a blood vessel (usually not associated with a pathological condition - usually post mortem clot). [NOTE: the distinction between a thrombus and a blood clot is difficult, since the two are clearly related]. 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. A chicken-fat clot is a gelatinous, post mortem clot with relatively few red cells. OUTCOME OF THROMBI:

1. Lysis of thrombus (due to potent thrombolytic/ fibrinolytic activity of blood) 2. Propagation of a thrombus (8 in size) - may eventually obstruct the vessel 3. Embolization - possible 4. Organization - The presence of a thrombus stimulates reaction which will result in inflammation and fibrosis. Smooth muscle cells and fibroblasts will proliferate and invade. The thrombus will become firm and grey-white. and Recanalization - New lumina, 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. The usual embolism is a thromboembolus. -or- Sudden blocking of an artery by a clot or foreign material which has been brought to its site of lodgement by the blood current. EMBOLUS: Detached intravascular solid, liquid, or gaseous mass that is carried by the blood to a site distant from its point of origin. EMBOLI: Pleural of embolus, ie: several emboli become dislodged and travel downstream of the blood current. THROMBOEMBOLUS: A thrombus formed in one location that detaches from the vessel wall and travels to a distant site. (99% of all emboli arise from a thrombus). THROMBOEMBOLISM: Obstruction of a blood vessel with thrombotic material carried by the blood stream from the site of origin to plug another vessel. EMBOLISM: Varies in composition - most are primarily fibrin (thrombi) Etiology: 1. Parasites A. Dirofilaria immitis B. Nematode larvae i) Ascarid larvae ii) Strongyle larvae

2. Fibrocartilaginous emboli A. Spinal cord infarcts B. Origin intervertebral disk material C. Necrotizing myelopathy 3. Fat A. Bone fractures B. Prolonged surgery C. Osteomyelitis D. 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. 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. Notes: -50% of all human deaths result from myocardial or cerebral infarction due to cardiovascular disease - Pulmonary infarction, intestinal infarction, renal infarction common in domestic animals - 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. The occluded -Margins may be irregular -Early - ill defined and hyperemic -48 hours most become paler

-Kidney infarcts are usually white (ischemic, pale) -Pulmonary infarcts are usually red PALE (WHITE) INFARCT: Lacks blood, also called anemic infarct. (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). Occurs with arterial occlusions in solid organs (heart, kidney).

Canine kidney white infarct RED INFARCT: Filled with blood. Characterized by coagulation necrosis and erythrocytes from adjacent arteries and veins. 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, liver) or extensive collateral circulation (brain, small intestine). The latter results because blood flows from the unobstructed vascular channels into the necrotic area. MICRO: -Ischemic coagulation necrosis of all parenchyma tissues -Infarcts arising from septic emboli may convert to an abscess REPAIR: Scar tissue - fibrous connective tissue Forms an indentation on the organ surface SEQUELLA: dependent upon 1. Degree/severity of injury to vascular supply 2. Size of artery affected 3. Degree of vascular occlusion 4. Collateral blood supply available 5. Vulnerability of cells to ischemia

6. 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) - Serious if anterior or posterior vena cava obstructed - 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, obstruction of the portal venous system, severe venous congestion, vascular stasis, 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, obstruction of the portal venous system, severe venous congestion, vascular stasis 6ischemia 6 loss of endothelial integrity, hemorrhages, shock Blockage of the pulmonary artery: Etiology: Pneumonia Congenital heart disease Bronchiectasis Parasite infestations Hyperadrenalcorticism Renal amyloidosis Result:- If sudden and large artery - death

- 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 - overwhelming infections Pathogenesis: 1. Acute, complete occlusion 6death 2. Collateral circulation could develop (azygous vein) ATHEROSCLEROSIS is the most common form of arteriosclerosis. It is characterized by soft deposits of intra- arterial fat and fibrin in the vessels walls that harden over time. 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. It is the leading cause of coronary artery and cerebrovascular disease.

PATHOPHYSIOLOGY: Inflammation plays a fundamental role in mediating all of the steps in the initiation and progression of atherogenesis. Atherosclerosis begins with injury to the endothelial cells that line artery walls. Possible causes of endothelial injury include the common risk factors for atherosclerosis, such as smoking, hypertension, diabetes, increased level of low- density lipoprotein (LDL), decreased levels of high density lipoprotein (HDL), and hyperhomocystenemia. Other causes of endothelial injury are called the novel risk factors, such as elevated C- reactive protein, increased serum fibrinogen, insulin resistance, oxidative stress, infection, and periodontal disease. 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. Injured endothelial cells become inflamed and cannot make normal amounts of antithrombic and vasodilating cytokines. The next step in

atherogenesis occurs when inflamed endothelial cells express adhesion molecules that bind macrophages and other inflammatory and immune cells. Macrophages adhere to the injured endothelium and release numerous inflammatory cytokines (e.g., tumor necrosis factor alpha [TNF-], interferons, interleukins, and C- reactive protein) and enzymes that further injure the vessel wall. Toxic oxygen radicals generated by the inflammatory process cause oxidation (i.e. addition of oxygen) of LDL, which is the next important step in atherogenesis. Oxidated LDL is engulfted by macrophages, which then penetrate into the intima of the vessel. These lipid- laden macrophages are now called foam cells, and when they accumulate in significant amounts, they form a lesions called fatty steak. These lesions can be found in the walls of arteries of most people, even young children. Once formed, fatty steaks produce more toxic oxygen radicals and cause immunologic and inflammatory changes resulting in progressive damage to the vessel wall. Treatment that lowers LDL may reverse this process. Macrophages also release growth factors that stimulate smooth muscle cells proliferation. Smooth muscle cells in the region of endothelial injury proliferate, produce collagen, and migrate over the fatty steak forming a fibrous plaque. The fibrous plaque may calcify protrude into the vessel lumen, and obstruct blood flow distal tissues. (especially during exercise), which may cause symptoms (e.g., angina or intermittent claudication). CLINICAL MANIFESTATIONS Atherosclerosis presents with symptoms and signs that result from inadequate perfusion of tissues because of obstruction of the vessels that supply them. Partial vessel obstruction may lead to transient ischemic events, often associated with exercise or stress. As the lesion becomes complicated, increasing obstruction with superimposed thrombosis may result in tissue infarction. Obstruction of peripheral arteries can cause significant pain and disability. 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. Atherosclerotic obstruction of the vessels supplying the brain is the major cause of stroke. Similarly, any part of the body may become ischemic when its blood supply is compromised by atherosclerotic lesions. Often, 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 disease in one area may indicate that the individual is at risk for ischemic complications elsewhere.

EVALUATION AND TREATMENT In evaluating individuals for the presence of atherosclerosis, a complete health history (including risk factors), physical examination, and laboratory data, are considered . Judicious use of X-ray films, electrocardiography, ultrasonography, nuclear scanning, and angiography may be necessary to identify the affected vessels, particularly coronary vessels. The primary goal in the management of atherosclerosis is to restore adequate blood flow to the affected tissues. If an individual has presented with acute ischemia (e.g., myocardial ischemia, stroke), interventions are specific to the diseased area and are discussed further under those topics. In the situations where the disease process does not require immediate intervention, management focuses on removing the initial causes of vessel damage and preventing lesion progression. This includes exercise, smoking cessation, and control of hypertension and diabetes where appropriate while reducing LDL cholesterolby diet or medications or both. I. Oncogenesis Oncogenes - Are nonmutant genes are mutant genes that in their normal nonmutant state direct synthesis of proteins that positively regulate proliferation. A. Tumor suppressor genes Encode protein that in their normal state negatively regulate proliferation Also have been referred to as antioncogenes. MUTATIONS THAT CREATE ONCOGENES

Point Mutations - Small-scale change in DNA - Alteration of one or a few nucleotide base pairs - Can have profound effects on the activity of proteins. - In RAS converts it from a regulated proto-oncogene to an unregulated oncogene, an accelerator of cellular proliferation. It is found in many canceresp in pancreatic and in colorectal cancer. B. CHROMOSOME TRANSLOCATION

- Can activate oncogenes by either of two distinct mechanisms. - First, a translocation can cause excess and inappropriate production of a proliferation factor.

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 - The MYC PRONCOGENE found on chromosom 8 is normally turned on at low levels in proliferating lymphocytes and is turned off in mature lymphocytes. The MYC PROTEIN is part of the positive signal for cell proliferation.

- Chromosome translocations also can lead to production of novel proteins with growth promoting properties. - In a different type of leukemia, chronic myeloid leukemia, a specific translocation is found almost invariably A. t(9:22) - This tanslocation fuses two chromosomes right in the middle of two genes, BCR on chromosome 9 and the ABL on chromosome 22. - The result is production of a BCR-ABL fusion protein containing the first half of BCR and the second half of ABL. - BCR ABL is a misregulated protein tyrosine kinase thae promotes growth of myeloid cells. - 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. C. CHROMOSOME AMPLIFICATION

- Result of duplication of a small piece of a chromosome over and over again, so that instead of the normal two copies of gene, there are tens or even hundreds of copies - Gene amplification results in increased expression of an oncogene or in some cases drug-resistant genes. - The N-myc oncogene is amplified in 25% of childhood neuroblastomas and confers a poor prognosis, whereas the epidermal growth factor receptor erbB2 is amplifies in 20% of breast cancer II. Tumor suppressor genes

- Are genes whose major function is to negatively regulate cell growth - It slows the cell cycle , inhibit proliferation from growth signals and stop cell division when cells are damaged - RETINOBLASTOMA (Rb) GENE normally strongly inhibits the cell dividion cycle. When it is inactivated, the cell division cycle can proceed unchecked ; Rb is mutated in childhood retinoblastoma and in many lung, breast, and bone cancers.

- Must be activated to allow cancer to occur - The first copy of a tumor suppressor is often inactivated by point mutation - Because the other cop[y of the retinoblastoma gene. - 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.\ - If the remaining gene is mutated, then all Rb function id lost and another step toward cancer occurs. III. LOSS OF HETEROZYGOSITY - For a tumor suppressor to be lost both chromosomal copes of the gene must be inactivated. - The first allele is inactivatedby simple mutation, but second allele is lost because entire region of the maternal chromosomes are lost - TUMOR- loss heterozygosis (unmasks mutations in recessive tumor suppressor genes IV. GENE SILENCING

- SILENCING = regulates GENE EXPRESSION that does not require mutations or changes in DNA sequence - Shuts off whole regions of chromosomes. - Boundaries can be spread in cancer cells - Can shut of critical tumor suppressors gene in the absence of its mutation. - Associated with methylation of DNA V. GUARDIANS OF THE GENOME

- The integrity of genetic information can be compromised at several points. - CARETAKER GENES responsible for the maintenance of genomic integrity. - Inherited mutations can disrupt the caretaker genes that protect theintegrity of genome. - CHROMOSOME INSTABILITY appears to be increased in malignant cells. VI. GENETICS AND CANCER PRONE FAMILIES - Genetic events are the primary basis of carcinogenesis. - MUTAGENS-agent causing mutations. - CANCER PRONE FAMILIES- demonstrate the inheritance of a mutated gene can cause cancer. - Characterization of cancer-causing genes and other genetic factors help identify individuals prone to developing cancer. INFECTION, IMMUNITY , INFLAMMATION, AND CANCER

I.

BACTERIAL CAUSE OF CANCER

HELICOBACTER PYLORI a bacterium that infects more than half of the worlds population. - Most common cause of gastric infection. - Treatment with antibiotics result in regression of the lymphoma in most cases. MECHANISMS: a. Dysregulation of the gastric epithelial cycle b. Formation of DNA adducts c. Generation of free radicals d. Alterations in growth factor secretion and cytokines e. Effects of decreased gastric secretions. II. IMMUNITY AND CANCER - Reacts to infection and tissue damage. - Recognizes nonself and new antigens - Plays a complex role in the development of and progression of cancer. - Patients receiving immunosuppression after an organ transplant have little or no increase in most prevalent cancers. III. ACTIVE IMMUNE RESPONSE IN CANCER

- Chronic Inflammation is a form of an immune response that has been recognized since 1860s as an contributing factor to the development of cancer. - Chronic inflammation as a result of HBV or HCV hepatitis markedly increases the risk of liver cancer. - COX-2 generates prostaglandins during inflammation protect against colon cancer colonies. - Cancer cells and Macrophages secrete inflammatory mediators released by interleukin 8 that they stimulate immune and other cells to increase vascular permeability, tissue breakdown and angiogenesis. Classifications: Cancers are classified by the type of cell that resembles the tumor and, therefore, the tissue presumed to be the origin of the tumor. These are the histology and the location, respectively. Examples of general categories include:

Carcinoma: Malignant tumors derived from epithelial cells. This group represents the most common cancers, including the common forms of breast, prostate, lung and colon cancer. Sarcoma: Malignant tumors derived from connective tissue, or mesenchymal cells.

Lymphoma and leukemia: Malignancies derived from hematopoietic (blood-forming) cells Germ cell tumor: Tumors derived from totipotent cells. In adults most often found in the testicle and ovary; in fetuses, babies, and young children most often found on the body midline, particularly at the tip of the tailbone; in horses most often found at the poll (base of the skull). Blastic tumor or blastoma: A tumor (usually malignant) which resembles an immature or embryonic tissue. Many of these tumors are most common in children.

Malignant tumors (cancers) are usually named using -carcinoma, -sarcoma or -blastoma as a suffix, with the Latin or Greek word for the organ of origin as the root. For instance, a cancer of the liver is called hepatocarcinoma; a cancer of the fat cells is called liposarcoma. For common cancers, the English organ name is used. For instance, the most common type of breast cancer is called ductal carcinoma of the breast or mammary ductal carcinoma. Here, the adjective ductal refers to the appearance of the cancer under the microscope, resembling normal breast ducts. Benign tumors (which are not cancers) are named using -oma as a suffix with the organ name as the root. For instance, a benign tumor of the smooth muscle of the uterus is called leiomyoma (the common name of this frequent tumor is fibroid). Unfortunately, some cancers also use the -oma suffix, examples being melanoma and seminoma. Number of unique gene-phenotype associations, identification of phenologs, and the example of a worm model of breast cancer. (A) The rate of associating genes to organism-level phenotypes in model organisms greatly exceeds that in humans (data from refs. 811, 14). Thus, appropriate mapping of model organism phenotypes to human diseases could significantly accelerate discovery of human disease gene associations. Orthologous phenotypes (phenologs) offer one such approach. (B) Phenologs can be identified based on significantly overlapping sets of orthologous genes (gene A is orthologous to A', B to B', etc.), such that each gene in a given set (green box or cyan box) gives rise to the same phenotype in that organism. The phenotypes may differ in appearance between organisms because of differing organismal contexts. As gene-phenotype associations are often incompletely mapped, genes currently linked to only one of the orthologous phenotypes become candidate genes for the other phenotype; that is, the gene A' is a new candidate for phenotype 2. (C) An example of a phenolog mapping high incidence of male C. elegans progeny to human breast/ovarian cancers

Number of unique genephenotype associations, identification of phenologs, and the example of a worm model of breast cancer. (A) The rate of associating genes to organism-level phenotypes in model organisms greatly exceeds that in humans Thus, appropriate mapping of model organism phenotypes to human diseases could significantly accelerate discovery of human disease gene associations. Orthologous phenotypes (phenologs) offer one such approach. (B) Phenologs can be identified based on significantly overlapping sets of orthologous genes (gene A is orthologous to A', B to B', etc.), such that each gene in a given set (green box or cyan box) gives rise to the same phenotype in that organism. The phenotypes may differ in appearance between organisms because of differing organismal contexts. As gene-phenotype associations are often incompletely mapped, genes currently linked to only one of the orthologous phenotypes become candidate genes for the other phenotype; that is, the gene A' is a new candidate for phenotype 2. (C) An example of a phenolog mapping high incidence of male C. elegans progeny to human breast/ovarian cancers.

Written Report In Pathophysiology

MECHANISM OF DISEASE
SUBMITTED BY: LEADER: ANNA ROSE CARONAN MEMBERS: DAN ATANIEL W. ENSALADA MA.VERONICA SALAZA ANGEL BALMOCENA CATHRYN ORLANDA RODA SAMORTIN YVONNE LLACER SUBMITTED TO: PROF.JOANNA OTILANO

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