1-Causes of Cell InjuryThe causes of cell injury range from the external gross physical violence of an automobile accident to internal endogenous causes, such as a subtle genetic mutation causing Oxygen Deprivation. Hypoxia is a deficiency of oxygen, which causes cell injury by reducing aerobic oxidative respiration. Hypoxia is an extremely important and common cause of cell injury and cell death. Physical Agents. Physical agents capable of causing cell injury include mechanical trauma, extremes of temperature (burns and deep cold), sudden changes in atmospheric pressure, radiation, and electric shock.Chemical Agents and Drugs. The list of chemicals that may produce cell injury defies compilation. Simple chemicals such as glucose or salt in hypertonic concentrations may cause cell injury directly or by deranging electrolyte homeostasis of cells. Infectious Agents. These agents range from the submicroscopic viruses to the large tapeworms. In between are the rickettsiae, bacteria, fungi, and higher forms of parasites Immunologic Reactions. Although the immune system serves an essential function in defense against infectious pathogens, immune reactions may, in fact, cause cell injury Genetic DerangementsThe genetic injury may result in a defect as severe as the congenital malformations associated with Down syndrome, caused by a chromosomal abnormality, or as subtle as the decreased life of red blood cells caused by a single amino acid substitution in hemoglobin S in sickle cell anemia Nutritional Imbalances. Nutritional imbalances continue to be major causes of cell injury. Protein-calorie deficiencies cause an appalling number of deaths, chiefly among underprivileged populations.

Physical Agents e.g.. trauma, thermal injury Chemical Agents e.g. poisons, environmental pollutants and drugs Nutritional Infectious Diseases caused by protozoa, bacteria, viruses Immunological mechanisms Inherited diseases- inborn errors of metabolism

Mechanisms of Cell Injury

Two mechanisms serve as useful models: fatty change hypoxia fatty change is generally a reversible form of sublethal injury whereas the effects of hypoxia depend on the severity, duration and on the vulnerability of the cell Fatty Change Accumulation of fat in hepatocytes depends on rate of fat synthesis, catabolism and on the synthesis and export of lipoproteins. Alcohol increases triglycyeride synthesis and reduces fatty acid catabolism Malnutrition impairs protein synthesis and therefore reduces lipoprotein synthesis Hypoxia Interruption of oxidative phosphorylation within mitochondria- depletion of ATP Progressive loss of membrane functional integrity Increased cytosolic calcium 1

Cell injury results from functional and biochemical abnormalities in one or more of several essential cellular components

2-Pathophysiology of cell injury.Effects and responses.The normal cell is confined to a fairly narrow range of function and structure by its genetic programs of metabolism, differentiation, and specialization; by constraints of neighboring cells; and by the availability of metabolic substrates. It is nevertheless able to handle normal physiologic demands, maintaining a steady state called homeostasis. More severe physiologic stresses and some pathologic stimuli may bring about a number of physiologic and morphologic cellular adaptations, during which new but altered steady states are achieved, preserving the viability of the cell and modulating its function as it responds to such stimuli . The adaptive response may consist of an increase in the number of cells, called hyperplasia, or an increase in the sizes of individual cells, called hypertrophy. Conversely, atrophy is an adaptive response in which there is a decrease in the size and function of cells. If the limits of adaptive response to a stimulus are exceeded, or in certain instances when the cell is exposed to an injurious agent or stress, a sequence of events follows that is loosely termed cell injury. Cell injury is reversible up to a certain point, but if the stimulus persists or is severe enough from the beginning, the cell reaches a "point of no return" and suffers irreversible cell injury and ultimately cell death. Adaptation, reversible injury, and cell death can be considered stages of progressive impairment of the cell's normal function and structure. Cell death, the ultimate result of cell injury, is one of the most crucial events in the evolution of disease of any tissue or organ. It results from diverse causes, including ischemia(lack of blood flow), infection, toxins, and immune reactions. There are two principal patterns of cell death, necrosis and apoptosis. Necrosis is the type of cell death that occurs after such abnormal stresses as ischemia and chemical injury, and it is always pathologic. Apoptosis occurs when a cell dies through activation of an internally controlled suicide program. Cellular Adaptations of Growth and Differentiation Cells respond to increased demand and external stimulation by hyperplasia or hypertrophy, and they respond to reduced supply of nutrients and growth factors by atrophy. In some situations, cells change from one type to another, a process called metaplasia. There are numerous molecular mechanisms for cellular adaptations. Some adaptations are induced by direct stimulation of cells by factors produced by the responding cells themselves or by other cells in the environment. Others are due to activation of various cell surface receptors and downstream signaling pathways. Adaptations may be associated with the induction of new protein synthesis by the target cells, as in the response of muscle cells to increased physical demand, and the induction of cellular proliferation, as in responses of the endometrium to estrogens. Adaptations can also involve a switch by cells from producing one type of proteins to another or markedly overproducing one protein; such is the case in cells producing various types of collagens and extracellular matrix proteins in chronic inflammation and fibrosis. HYPERPLASIA Hyperplasia is an increase in the number of cells in an organ or tissue, usually resulting in increased volume of the organ or tissue. HYPERTROPHY 2

Hypertrophy refers to an increase in the size of cells, resulting in an increase in the size of the organ. Thus, the hypertrophied organ has no new cells, just larger cells.

3) ApoptosisDeath of cells occurs in two ways: 1. Necrosis--(irreversible injury) changes produced by enzymatic digestion of dead cellular elements 2. Apoptosis--vital process that helps eliminate unwanted cells--an internally programmed series of events effected by dedicated gene products Mechanisms of Cell Death Mechanisms of cell death caused by different agents may vary. However, certain biochemical events are seen in the process of cell necrosis:

ATP depletion Loss of calcium homeostasis and free cytosolic calcium Free radicals: superoxide anions, Hydroxyl radicals, hydrogen peroxide Defective membrane permeability Mitochondrial damage Cytoskeletal damage

Apoptosis This process helps to eliminate unwanted cells by an internally programmed series of events effected by dedicated gene products. It serves several vital functions and is seen under various settings.

During development for removal of excess cells during embryogenesis To maintain cell population in tissues with high turnover of cells, such as skin, bowels. To eliminate immune cells after cytokine depletion, and autoreactive T-cells in developing thymus. To remove damaged cells by virus To eliminate cells with DNA damage by radiation, cytotoxic agents etc. Hormone-dependent involution - Endometrium, ovary, breasts etc. Cell death in tumors.

Morphology of Apoptosis

Shrinkage of cells Condensation of nuclear chormatin peripherally under nuclear membrane Formation of apoptotic bodies by fragmentation of the cells and nuclei. The fragments remain membrane-bound and contain cell organelles with or without nuclear fragments. Phagocytosis of apoptotic bodies by adjacent healthy cells or phagocytes. Unlike necrosis, apoptosis is not accompanied by inflammatory reaction

Mechanisms of Apoptosis Apoptosis can be induced by various factors under both physiological and pathological conditions: It is an energy-dependent cascade of molecular events which include protein cleavage by a group of enzymes (caspases), protein cross-linking, DNA breakdown. Apoptosis is regulated by a large family of genes some of which are inhibitory (bcl-2) and some are stimulatory (bax).

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Apoptosis goes through several complex phases. To put it simply, abnormal mitochondrial membrane permeability is a crucial event which allows escape of cytochrome-c into the cystosol which, in turn, activates proteolytic enzymes (caspases) leading to the execution of the process. The final phase is the removal of dead cell fragments by phagocytosis without inflammatory reactions.

4- Free Radicals ACCUMULATION OF OXYGEN-DERIVED FREE RADICALS (OXIDATIVE STRESS)Cells generate energy by reducing molecular oxygen to water. During this process, small amounts of partially reduced reactive oxygen forms are produced as an unavoidable by product of mitochondrial respiration by phagocytes. Free radicals are chemical species that have a single unpaired electron in an outer orbit. Energy created by this unstable configuration is released through reactions with adjacent molecules, such as inorganic or organic chemicals proteins, lipids, carbohydrates particularly with key molecules in membranes and nucleic acids. Absorption of radiant energy Enzymatic metabolism of exogenous chemicals or drugs The reduction-oxidation reactions that occur during normal metabolic processes. Transition metals Nitric oxide Lipid peroxidation of membranes Oxidative modification of proteins Lesions in DNA. Reactions with thymine in nuclear and mitochondrial DNA produce single-stranded breaks in DNA. This DNA damage has been implicated in cell aging and in malignant transformation of cells Antioxidants either block the initiation of free radical formation or inactivate free radicals and terminate radical damage As we have seen, iron and copper can catalyze the formation of reactive oxygen species A series of enzymes acts as free radical-scavenging systems and break down hydrogen peroxide and superoxide anion

5- Mechanisms of cell deathAs stated at the beginning of the chapter, cell injury results when cells are stressed so severely that they are no longer able to adapt or when cells are exposed to inherently damaging agents. Injury may progress through a reversible stage and culminate in cell death (Fig. 1-7). An overview of the morphologic changes in cell injury is shown in .The biochemical alterations "Mechanisms of Cell Injury." These alterations may be divided into the following stages: -Reversible cell injury. Initially, injury is manifested as functional and morphologic changes that are reversible if the damaging stimulus is removed. The hallmarks of reversible injury are reduced oxidative phosphorylation, adenosine triphosphate (ATP) depletion, and cellular swelling caused by changes in ion concentrations and water influx. -Irreversible injury and cell death. With continuing damage, the injury becomes irreversible, at which time the cell cannot recover

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Cell injury occurs when an adverse stimulus reversibly disrupts the normal complex homeostatic balance of cellular metabolism. If the stimulus is persistent or of sufficient magnitude then irreversible injury may develop. The severity of the injury may also depend on the specific properties of the cell- selective vulnerability Cell death occurs when there is an irreversible loss of integrated cellular function.

Types of Cell Death: Necrosis

Cell death is very often a passive process, an inevitable consequence of severe perturbations of the external environment beyond the limits of homeostatic mechanisms. This type of cell death is known as necrosis. Necrosis is invariably pathological. Caused by infarction, infectious diseases, poisoning etc. Affects contiguous groups of cells Cell swelling and cell lysis accompanied by loss of cell membrane integrity and lysosomal leakage Necrosis usually precipitates an inflammatory response

Types of Cell Death: Apoptosis

In contrast to the passive pathological process of necrosis, a second type of cell death is now recognised which is an active process and which may occur as a physiological regulatory mechanism. This process is known as apoptosis. May be induced by physiological influences e.g. glucocorticoids or pathological influences e.g. ionising radiation or viral infections Active process characterised by specific biochemical mechanisms- DNA fragmentation, vitronectin expression Causes deletion of individual cells in the midst of others Cell shrinkage, preservation of membrane integrity, nuclear fragmentation with dense chromatin No inflammatory response but rapid phagocytosis Apoptosis important in inflammation, neoplasia, AIDS and neurodegenerative disorders

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8-Traumatic ShockShock is the systemic disease that results from any process that impairs the systemic delivery of oxygen to the cells of the body, or that prevents its normal uptake and utilization. Hemorrhage with decreased cardiac output is the most common cause of shock in trauma patients (Table 1), although it is not unusual for shock to result from a combination of events. Hemorrhage, tension pneumothorax, and cardiac contusion can all coexist in the patient with chest trauma, for example, with each contributing to systemic hypoperfusion. Iatrogenic contributors to shock may include anemia following vigorous crystalloid infusion, the use of tourniquets, and the use of systemic pressor agents. Underlying medical conditions can also play a part, with myocardial ischemia

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potentially contributing to decreased oxygen delivery, especially in older trauma patients. The effects of alcohol, medications, and illicit drugs may contribute to a state of hypoperfusion and may block normal compensatory mechanisms. It is important to recognize that the traumatic shock seen clinically in severely injured patients may be quite different from the induced shock seen in laboratory animals hemorrhaged under controlled conditions. Stages of Shock Traumatic shock as occurring in four stages, based on arbitrary levels of blood loss and vital signs. Better approximation of the degree of shock, based on the patients symptoms, response to therapy, and prognosis. In compensated traumatic shock, an increase in heart rate and vasoconstriction of nonessential and ischemia-tolerant vascular beds will allow prolonged survival and easy recovery once hemostasis is achieved and resuscitation is completed. Decompensated traumatic shock, also known as progressive shock, is a transitory state in which lack of perfusion is creating cellular damage that will produce toxic effects. Shock is still reversible at this stage. In subacute irreversible shock, the patient is resuscitated to normal vital signs but succumbs at a later time to multiple organ system failure (MOSF) as the result of tissue ischemia and reperfusion. Finally, acute irreversible shock is the condition of ongoing hemorrhage, acidosis, and coagulopathy that spirals downward to early death from exsanguination. Progression from compensated to uncompensated shock (usually due to ongoing hemorrhage) is a surgical and metabolic emergency. Successful recovery requires rapid diagnosis and control of the inciting event (i.e., hemostasis) facilitated by resuscitative therapy directed toward minimizing the overall dose of shock. A patient who experiences substantial blood loss and massive transfusion will experience some degree of organ system failure thereafter (i.e., edema, pulmonary dysfunction). This is due to the systemic effects of tissue ischemia. Bleeding may be controlled and vital signs may be normal or even hypernormal, but the damage has been done on the cellular level. Ischemia can persist because of no reflow caused by cellular swelling and microcirculatory obstruction, while effects in nonischemic organ systems such as the lungs are actually a form of reperfusion injury. The Systemic Response to Shock The stages of traumatic shock are directly related to the physiologic response to hemorrhage. The initial response is on the macrocirculatory level and is mediated by the neuroendocrine system.Decreased blood pressure leads to vasoconstriction and catecholamine release. Heart and brain blood flow is preserved, while other regional beds are constricted. Pain, hemorrhage, and cortical perception of traumatic injuries lead to the release of a number of hormones as part of the fight or flight response, including reninangiotensin, vasopressin, antidiuretic hormone, growth hormone, glucagon, cortisol, epinephrine and norepinephrine.This rush of chemicals sets the stage for the microcirculatory responses that follow. On the cellular level the body responds to hemorrhage by takingup interstitial fluid, causing cells to swell.Edematous cells obstruct adjacent capillaries, resulting in the "no-reflow" phenomenon that can prevent the reversal of ischemia even in the presence of adequate macro flow. The Central Nervous System The central nervous system is exquisitely sensitive to hypoperfusion and is thus the prime trigger of the neuroendocrine response to shock, which maintains oxygen supply to the heart and brain at the expense of other tissues.Regional glucose uptake in the brain changes during shock. Cardiovascular

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The heart has little capacity to function anaerobically, and is relatively preserved from ischemia during hemorrhage because of maintenance or even increase of nutrient blood flow driven by the fight or flight response. Kidney and Adrenal Glands The kidney and adrenal glands are prime responders to the neuroendocrine changes of shock, producing renin, angiotensin, aldosterone, cortisol, erythropoietin, and catecholamines.The kidney itself maintains glomerular filtration in the face of hypotension by selective vasoconstriction and concentration of blood flow in the medulla and deep cortical area. The Lung The lung is almost never the trigger of the shock syndrome because it cannot itself become ischemic. The lung is nonetheless the downstream filter for the inflammatory byproducts of the ischemic body, and is itself an active immune organ.downstream filter for the inflammatory byproducts of the ischemic body, and is itself an active immune organ. The Gut Splanchnic perfusion is very strongly controlled by the autonomic nervous system, and the gut becomes vasoconstricted early in the course of hemorrhagic shock. The intestine is one of the earliest organs affected by hypoperfusion and may be a primary trigger of MOSF(Multi-Organ System Failure) The Liver The liver has a complex microcirculation and has been demonstrated to suffer both no reflow and reperfusion injury during recovery from shock. Hepatic cells are also metabolically active and contribute to the inflammatory response to decompensated shock. Skeletal Muscle, Bone, and Skin Vasoconstrictive mechanisms in peripheral tissue are important to spontaneous hemostasis and tissues of the musculoskeletal system are ischemia-tolerant as long as motor function is not required. Conclusion Traumatic shock is a disease of tissue ischemia, and is characterized by a trigger that produces tissue ischemia (usually hemorrhage) and the inflammatory disease that follows. Surgical hemostasis and precision resuscitation can restore normal blood volume quickly after major trauma, but the patient can still die as a result of the systemic effects of shock. The future management of this disease will depend on a clear understanding of the effects of shock in different organ systems, the ways in which inflammatory mediators can exacerbate ongoing ischemic distress, and our ability to support multiple failing organ systems simultaneously.

9-SORU YOK 10-Pathogenic Effect Of Electric CurrentThe passage of an electric current through the body may be without effect; may cause sudden death by disruption of neural regulatory impulses, producing, for example, cardiac arrest; or may cause thermal injury to organs interposed in the pathway of the current. Many variables are involved, but most important are the resistance of the tissues to the conductance of the electric current and the intensity of the current. The greater the resistance of tissues, the greater the heat generated. Although all tissues of the body are conductors of electricity, their resistance to flow varies inversely with their water content. Dry skin is particularly resistant, but when skin is wet or immersed in water, its resistance is greatly decreased. Thus, an electric current may cause only a surface burn of dry skin 7

but may cause death by disruption of regulatory pathways when it is transmitted through wet skin, producing, for example, ventricular fibrillation or respiratory paralysis without injury to the skin. The thermal effects of the passage of the electric current depend on its intensity. High-intensity current, such as lightning coursing along the skin, produces linear arborizing burns known as lightning marks. Sometimes intense current is conducted around the victim (so-called flashover), blasting and disrupting the clothing but doing little injury. When lightning is transmitted internally, it may produce sufficient heat and steam to explode solid organs, fracture bones, or char areas of organs. Focal hemorrhages from rupture of small vessels may be seen in the brain. Sometimes, death is preceded by violent convulsions related to brain damage. Less intense voltage may heat, coagulate, or rupture vessels and cause hemorrhages or, in solid organs such as the spleen and kidneys, cause infarctions or ruptures.

11-Pathogenic effect of radiationINJURY PRODUCED BY IONIZING RADIATION Radiation is energy that travels in the form of waves or high-speed particles. Radiation has a wide range of energies that span the electromagnetic spectrum; it can be divided into non-ionizing and ionizing radiation. The energy of non-ionizing radiation such as UV and infrared light, microwave, and sound waves, can move atoms in a molecule or cause them to vibrate, but is not sufficient to displace bound electrons from atoms. By contrast, ionizing radiation has sufficient energy to remove tightly bound electrons. Collision of electrons with other molecules releases electrons in a reaction cascade, referred to as ionization. The main sources of ionizing radiation are x-rays and gamma rays (electromagnetic waves of very high frequencies), high-energy neutrons, alpha particles (composed of two protons and two neutrons), and beta particles, which are essentially electrons. At equivalent amounts of energy, alpha particles induce heavy damage in a restricted area, whereas x-rays and gamma rays dissipate energy over a longer, deeper course, and produce considerably less damage per unit of tissue. About 25% of the total dose of ionizing radiation received by the US population is human-made, mostly originated in medical devices and radioisotopes.

Effects.Cells surviving radiant energy damage show a wide range of structural changes in chromosomes, including deletions, breaks, translocations, and fragmentation. The mitotic spindle often becomes disorderly, and polyploidy and aneuploidy may be encountered. Nuclear swelling and condensation and clumping of chromatin may appear; sometimes the nuclear membrane breaks down. Apoptosis may occur. All forms of abnormal nuclear morphology may be seen. Giant cells with pleomorphic nuclei or more than one nucleus may appear and persist for years after exposure. At extremely high doses of radiant energy, markers of cell death, such as nuclear pyknosis, and lysis appear quickly. In addition to affecting DNA and nuclei, radiant energy may induce a variety of cytoplasmic changes, including cytoplasmic swelling, mitochondrial distortion, and degeneration of the endoplasmic reticulum. Plasma membrane breaks and focal defects may be seen. The histologic constellation of cellular pleomorphism, giant-cell formation, conformational changes in nuclei, and abnormal mitotic figures creates a more than passing similarity between radiation-injured cells and cancer cells, a problem that plagues the pathologist when evaluating post-irradiation tissues for the possible persistence of tumor cells.

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At the light microscopic level, vascular changes and interstitial fibrosis are prominent in irradiated tissues .During the immediate post-irradiation period, vessels may show only dilation. With time, or with higher doses, a variety of degenerative changes appear, including endothelial cell swelling and vacuolation, or even dissolution with total necrosis of the walls of small vessels such as capillaries and venules. Affected vessels may rupture or thrombose. Still later, endothelial cell proliferation and collagenous hyalinization with thickening of the media are seen in irradiated vessels, resulting in marked narrowing or even obliteration of the vascular lumens. At this time, an increase in interstitial collagen in the irradiated field usually becomes evident, leading to scarring and contractions.

12- SORU YOK 13- SORU YOK 14- SORU YOK 15- SORU YOK 16 -SORU YOK 17. Allergy. Essence and classification. Humorally mediated allergy.Mechanism Exposure to an antigen results in the formation of IgE. The antigen reacts with CD4+ cells, which differentiate to TH2 cells. TH2 cells release interleukin-3 (IL-3), IL-4, and IL-5. IL-5 stimulates eosinophils, and IL-4 activates IgE-producing B cells. The IgE binds to mast cells. Subsequent exposure to the same antigen results in binding of the antigen to IgE bound to mast cells, with the consequence of degranulation of the mast cells and release of mediators (e.g., histamine). The release of mediators causes increased vascular permeability, leading to edema and increased smooth muscle contraction and eventuallyto bronchoconstriction. Sequence of events in type I hypersensitivity reaction; 1. Early phase (occurs within 530 minutes of exposure to antigen): Characterized by vasodilation, increased vascular permeability, and increased smooth muscle contraction. The early phase is due to binding of antigen to IgE bound to mast cells, with subsequent degranulation of the mast cells and release of mediators. 2. Late phase (occurs after 224 hours and lasts for days): Characterized by infiltration by neutrophils, eosinophils, basophils, and monocytes, and results in mucosal damage due to release of mediators by these recruited inflammatory cells. Immediate Response Vasodilation Vascular Leakage Smooth Muscle Spasm Forms of type I hypersensitivity reactions Systemic anaphylaxis: Due to parenteral administration of antigen; for example, a bee sting or a reaction to penicillin. Local reaction: Urticaria (hives). Causes: Penicillin, angiotensin-converting enzyme (ACE) inhibitors, intravenous (IV) contrast and other drugs, proteins (e.g., insect venoms), and food. Clinical and Pathologic Manifestations An immediate hypersensitivity reaction may occur as a systemic disorder or as a local reaction. The nature of the reaction is often determined by the route of antigen exposure. Systemic (parenteral) 9

administration of protein antigens (e.g., in bee venom) or drugs (e.g., penicillin) may result in systemic anaphylaxis. Within minutes of an exposure in a sensitized host, itching, urticaria (hives), and skin erythema appear, followed in short order by profound respiratory difficulty caused by pulmonary bronchoconstriction and accentuated by hypersecretion of mucus. Laryngeal edema may exacerbate matters by causing upper airway obstruction. In addition, the musculature of the entire gastrointestinal tract may be affected, with resultant vomiting, abdominal cramps, and diarrhea. Without immediate intervention, there may be systemic vasodilation with fall in blood pressure (anaphylactic shock), and the patient may progress to circulatory collapse and death within minutes. Local reactions generally occur when the antigen is confined to a particular site, such as skin (contact, causing urticaria), gastrointestinal tract (ingestion, causing diarrhea), or lung (inhalation, causing bronchoconstriction). The common forms of skin and food allergies, hay fever, and certain forms of asthma are examples of localized allergic reactions. Susceptibility to localized type I reactions is genetically controlled, and the term atopy is used to imply familial predisposition to such localized reactions. Patients who suffer from nasobronchial allergy (including hay fever and some forms of asthma) often have a family history of similar conditions. Linkage studies have identified several chromosomal regions that are associated with susceptibility to asthma and other allergic diseases. Among the candidate genes that are present close to these chromosomal loci are genes that encode HLA molecules (which may confer immune responsiveness to particular allergens), cytokines (which may control TH2 responses), a component of the FcRI, and ADAM33, a metalloproteinase that may be involved in tissue remodeling in the airways. Type I Clinical allergy represents IgE-mediated hypersensitivity response arising from deleterious inflammation in response to the presence of normally harmless environmental antigens. Anaphylactic or immediate hypersensitivity reactions occur after binding of antigen to IgE antibodies attached to the surface of the mast cell or basophil and result in the release of preformed and newly generated inflammatory mediators that produce the clinical manifestations. Examples of type I mediated reactions include anaphylactic shock, allergic rhinitis, allergic asthma, and allergic drug reactions. Type II Cytotoxic reactions involve the binding of either IgG or IgM antibody to antigens covalently bound to cell membrane structures. Antigen-antibody binding activates the complement cascade and results in destruction of the cell to which the antigen is bound. Examples of tissue injury by this mechanism include immune hemolytic anemia and Rh hemolytic disease in the newborn. Another example of the type IImediated disease process without cell death is autoimmune hyperthyroidism, a disorder in which thyroid-stimulating antibodies stimulate thyroid tissue. Type III Immune complexmediated reactions occur when immune complexes are formed by the binding of antigens to antibodies with fixation of complement. Complement-bound immune complexes facilitate opsonization by phagocytes and ADCC. Complexes are usually cleared from the circulation in the reticuloendothelial system. However, deposition of these complexes in tissues or in vascular endothelium can produce immune complexmediated tissue injury by leading to complement activation, anaphylatoxin generation, chemotaxis of polymorphonuclear leukocytes, mediator release and tissue injury. Cutaneous Arthus reaction, systemic serum sickness, some aspects of clinical autoimmunity, and certain features of infective endocarditis are clinical examples of type III mediated diseases. Type IV Cell-mediated immunity is responsible for host defenses against intracellular pathogenic organisms, although abnormal regulation of this system may result in delayed-type hypersensitivity. Type IV

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hypersensitivity reactions are mediated not by antibody but by antigen-specific T lymphocytes. Classic examples are tuberculin skin test reactions and contact dermatitis.

18) Cell-mediated allergy AllergiesImmunologists, as well as the general public, use the term allergy in several different ways. An allergy is a harmful immune response elicited by an antigen that is not itself intrinsically harmful. Examples:

The windblown pollen released by orchard grass has no effect on me but produces a violent attack of hay fever (known to physicians as allergic rhinitis) in my wife. She, on the other hand, can safely handle the leaves of poison ivy while if I do so, I break out in a massive skin rash a day or two later.

Antigens that trigger allergies are often called allergens. Four different immune mechanisms can result in allergic responses. 1. Immediate Hypersensitivities. These occur quickly after exposure to the allergen. They are usually mediated by antibodies of the IgE class. Examples:

hay fever hives asthma

2. Antibody-Mediated Cytotoxicity Cell damage caused by antibodies directed against cell surface antigens. Hence a form of autoimmunity. Examples:

Hemolytic disease of the newborn (Rh disease). Myasthenia gravis (MG)

3. Immune Complex Disorders Damage caused by the deposit in the tissues of complexes of antigen and their antibodies. Examples:

Serum sickness Systemic lupus erythematosus (SLE)

4. Cell-Mediated Hypersensitivities These reactions are mediated by CD4+ T cells. Examples:

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The rash produced following exposure to poison ivy. Because it takes a day or two for the T cells to mobilize following exposure to the antigen, these responses are called delayed-type hypersensitivities (DTH). Those, like poison ivy, that are caused by skin contact with the antigen are also known as contact sensitivities or contact dermatitis. certain autoimmune diseases, including o Type 1 diabetes mellitus o Multiple sclerosis (MS) o Rheumatoid arthritis (RA)

Immediate Hypersensitivities Local Anaphylaxis The constant region of IgE antibodies (shown in blue) has a binding site for a receptor present on the surface of basophils and their tissue-equivalent the mast cell. These cell-bound antibodies have no effect until and unless they encounter allergens (shown in red) with epitopes that can bind to their antigen-binding sites. When this occurs, the mast cells to which they are attached

explosively discharge their granules by exocytosis. The granules contain a variety of active agents including histamine; synthesize and secrete other mediators including leukotrienes and prostaglandins.

Release of these substances into the surrounding tissue causes local anaphylaxis: swelling, redness, and itching. In effect, each IgE-sensitized mast cell is a tiny bomb that can be exploded by a particular antigen. The most common types of local anaphylaxis are:

allergic rhinitis (hay fever) in which airborne allergens react with IgE-sensitized mast cells in the nasal mucosa and the tissues around the eyes; bronchial asthma in which the allergen reaches the lungs either by inhalation or in the blood [Further discussion of asthma]; hives (physicians call it urticaria) where the allergen usually enters the body in food.

ome people respond to environmental antigens (e.g., pollen grains, mold spores) with an unusually vigorous production of IgE antibodies. Why this is so is unclear; heredity certainly plays a role. In any case, the immune system of these people is tilted toward the production of T helper cells of the Th2 subtype. These release interleukin 4 (IL-4) and interleukin 13 (IL-13) on the B cells that they "help". These lymphokines promote class switching in the B cell causing it to synthesize IgE antibodies. An inherited predisposition to making IgE antibodies is called atopy. Atopic people are apt to have higher levels of circulating IgE (up to 12 g/ml) than is found usually (about 0.3 g/ml). Whereas only 2050% of the receptors on mast cells are normally occupied by IgE, all the receptors may be occupied in atopic individuals.

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Systemic Anaphylaxis Some allergens can precipitate such a massive IgE-mediated response that a life-threatening collapse of the circulatory and respiratory systems may occur. Frequent causes:

insect (e.g., bee) stings many drugs (e.g., penicillin) a wide variety of foods. Egg white, cow's milk, and nuts are common offenders in children; in fact, some school systems in the U. S. now ban peanuts and peanut-butter sandwiches when they have a student at risk of systemic anaphylaxis from exposure to peanuts. Fish and shellfish are frequent causes of anaphylaxis in adults.

Treatment of systemic anaphylaxis centers on the quick administration of adrenaline, antihistamines, and if shock has occurred intravenous fluid replacement. Anti-IgE Antibodies IgE molecules bind to mast cells and basophils through their constant region. If you could block this region, you could interfere with binding hence sensitization of these cells. Humanized monoclonal antibodies specific for the constant region of IgE are in clinical trials. They have shown some promise against asthma and peanut allergy, but such treatment will probably have to be continued indefinitely (and will be very expensive).

19. Autoimmune response essence and mechanism of generation.The evidence is compelling that an immune reaction to self-antigens (i.e., autoimmunity) is the cause of certain human diseases; a growing number of entities have been attributed to this process. However, in many of these disorders the proof is not definitive, and an important caveat is that the simple presence of autoreactive antibodies or T cells does not equate to autoimmune disease. For example, low-affinity antibodies and T cells reactive with self-antigens can be readily demonstrated in most otherwise healthy individuals; presumably, these antibodies and T cells are not pathogenic and are of little consequence. Moreover, similar innocuous autoantibodies to selfantigens are frequently generated following other forms of injury (e.g., ischemia) and may even serve a physiologic role in the removal of products of tissue breakdown. Thus, the presence of a multiplicity of autoantibodies accounts for many of the clinical and pathologic manifestations of SLE. Moreover, these autoantibodies can be identified within lesions by immunofluorescence and electron-microscopic techniques. In many other disorders, an autoimmune etiology is suspected but is unproven. Indeed, in some cases of apparent autoimmunity the response may be directed against an exogenous antigen, such as a microbial protein; such is the probable pathogenesis of the vasculitis in many cases of polyarteritis nodosa. Presumed autoimmune diseases range from those in which specific immune responses are directed against one particular organ or cell type and result in localized tissue damage, to multisystem diseases characterized by lesions in many organs and associated with multiple autoantibodies or cellmediated reactions against numerous self-antigens. In the systemic diseases, the lesions affect principally the connective tissue and blood vessels of the various organs involved. Thus, even though the systemic reactions are not specifically directed against constituents of connective tissue or blood vessels, the diseases are often referred to as "collagen vascular" or "connective tissue" disorders. It is obvious that autoimmunity implies loss of self-tolerance, and the question arises as to how this happens. To understand the pathogenesis of autoimmunity, it is important to first familiarize ourselves with the mechanisms of normal immunologic tolerance.

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Immunological tolerance is unresponsiveness to an antigen that is induced by exposure of specific lymphocytes to that antigen. Self-tolerance refers to a lack of immune responsiveness to one's own tissue antigens. During the generation of billions of antigen receptors in developing T and B lymphocytes, it is not surprising that receptors are produced that can recognize self-antigens. Since these antigens cannot all be concealed from the immune system, there must be means of eliminating or controlling self-reactive lymphocytes. Several mechanisms work in concert to select against selfreactivity and to thus prevent immune reactions against one's own antigens. These mechanisms are broadly divided into two groups: central tolerance and peripheral tolerance.Central tolerance. This refers to deletion of self-reactive T and B lymphocytes during their maturation in central lymphoid organs (i.e., in the thymus for T cells and in the bone marrow for B cells). Many autologous (self) protein antigens are processed and presented by thymic APCs in association with self-MHC. Any developing T cell that expresses a receptor for such a self-antigen is negatively selected (deleted by apoptosis), and the resulting peripheral T-cell pool is thereby depleted of self-reactive cells. An exciting recent advance has been the identification of putative transcription factors that induce the expression of apparently peripheral tissue antigens in the thymus. One such factor is called the autoimmune regulator (AIRE); mutations in the AIRE gene are responsible for an autoimmune polyendocrine syndrome in which T cells specific for multiple self-antigens escape deletion, presumably because these self-antigens are not expressed in the thymus. Some T cells that encounter self-antigens in the thymus are not killed but differentiate into regulatory T cells. Immature B cells that recognize, with high affinity, self-antigens in the bone marrow may also die by apoptosis. Some self-reactive B cells may not be deleted but may undergo a second round of rearrangement of antigen receptor genes and express new receptors that are no longer self-reactive (a process called "receptor editing").Unfortunately, the process of deletion of self-reactive lymphocytes is far from perfect. Many self-antigens may not be present in the thymus, and hence T cells bearing receptors for such autoantigens escape into the periphery. There is similar "slippage" in the B-cell system as well, and B cells that bear receptors for a variety of self-antigens, including thyroglobulin, collagen, and DNA, can be found in healthy individuals.Peripheral tolerance. Selfreactive T cells that escape negative selection in the thymus can potentially wreak havoc unless they are deleted or effectively muzzled. Several mechanisms in the peripheral tissues that silence such potentially autoreactive T cells have been identified: Anergy: This refers to functional inactivation (rather than death) of lymphocytes induced by encounter with antigens under certain conditions. Recall that activation of T cells requires two signals: recognition of peptide antigen in association with self-MHC molecules on APCs, and a set of second costimulatory signals (e.g., via B7 molecules) provided by the APCs. If the second costimulatory signals are not delivered, or if an inhibitory receptor on the T cell (rather than the costimulatory receptor) is engaged when the cell encounters self-antigen, the T cell becomes anergic and cannot respond to the antigen. Because costimulatory molecules are not strongly expressed on most normal tissues, the encounter between autoreactive T cells and self-antigens in tissues may result in anergy. B cells can also become anergic if they encounter antigen in the absence of specific helper T cells.Suppression by regulatory T cells: The responses of T lymphocytes to self-antigens may be actively suppressed by regulatory T cells. The best-defined populations of regulatory T cells express CD25, one of the chains of the receptor for IL-2, and require IL-2 for their generation and survival. These cells also express a unique transcription factor called FoxP3, and this one protein seems to be both necessary and sufficient for the development of regulatory cells. Mutations in the FOXP3 gene are responsible for a systemic autoimmune disease called IPEX (immune dysregulation, 14

polyendocrinopathy, enteropathy, X-linked syndrome), which is associated with deficiency of regulatory T cells. The probable mechanism by which regulatory T cells control immune responses is by secreting immunosuppressive cytokines (e.g., IL-10 and TGF-), which can dampen a variety of Tcell responses.Activation-induced cell death: Another mechanism of peripheral tolerance involves apoptosis of mature lymphocytes as a result of self-antigen recognition. T cells that are repeatedly stimulated by antigens in vitro undergo apoptosis. One mechanism of apoptosis is the death receptor Fas (a member of the TNF receptor family) being engaged by its ligand coexpressed on the same cells. The same pathway is important for the deletion of self-reactive B cells by Fas ligand expressed on helper T cells. The importance of this pathway of self-tolerance is illustrated by the discovery that mutations in the FAS gene are responsible for an autoimmune disease called the autoimmune lymphoproliferative syndrome, characterized by lymphadenopathy and multiple autoantibodies including anti-DNA. Defects in Fas and Fas ligand are also the cause of similar autoimmune diseases in mice. Mechanisms of Autoimmunity Now that we have summarized the principal mechanisms of self-tolerance, we can ask how these mechanisms might break down to give rise to pathologic autoimmunity. Unfortunately, there are no simple answers to this question, and we still do not understand the underlying causes of most human autoimmune diseases. We referred above to mutations that compromise one or another pathway of self-tolerance and cause pathologic autoimmunity. These single-gene mutations are extremely informative, and they help to establish the biologic significance of the various pathways of selftolerance. The diseases caused by such mutations are rare, however, and most autoimmune diseases cannot be explained by defects in single genes. The breakdown of self-tolerance and the development of autoimmunity are probably related to the inheritance of various susceptibility genes and changes in tissues, often induced by infections or injury, that alter the display and recognition of self-antigens. Genetic Factors in Autoimmunity There is abundant evidence that susceptibility genes play an important role in the development of autoimmune diseases. Autoimmune diseases have a tendency to run in families, and there is a greater incidence of the same disease in monozygotic than in dizygotic twins.Several autoimmune diseases are linked with the HLA locus, especially class II alleles. Two genetic polymorphisms have recently been shown to be quite strongly associated with certain autoimmune diseases. One, called PTPN22, encodes a phosphatase, and particular variants are associated with rheumatoid arthritis and several other autoimmune diseases. Another, called NOD2, encodes an intracellular receptor for microbial peptides, and certain variants or mutants of this gene are present in as many as 25% of patients with Crohn's disease in some populations. How these genes contribute to autoimmunity is not established.

20)IMMUNODEFCENCY STATES.PRIMARY IMMUNODEFICIENCY DISEASEImmunodeficiency is a state in which the immune system's ability to fight infectious disease is compromised or entirely absent. Immunodeficiency may also decrease cancer immunosurveillance. Most cases of immunodeficiency are acquired ("secondary") but some people are born with defects in their immune system, or primary immunodeficiency. Transplant patients take medications to suppress their immune system as an anti-rejection measure, as do some patients suffering from an over-active immune system. A person who has an immunodeficiency of any kind is said to be immunocompromised. An immunocompromised 15

person may be particularly vulnerable to opportunistic infections, in addition to normal infections that could affect everyone. Primary immunodeficiencies are disorders in which part of the body's immune system is missing or does not function properly. To be considered a primary immunodeficiency, the cause of the immune deficiency must not be secondary in nature (i.e., caused by other disease, drug treatment, or environmental exposure to toxins). Most primary immunodeficiencies are genetic disorders; the majority are diagnosed in children under the age of one, although milder forms may not be recognized until adulthood. About 1 in 500 people is born with a primary immunodeficiency. Types of immunodeficiencies:

a primary immunodeficiency results from a genetic or developmental defect in the immune system. a secondary or acquired immunodeficiency is a loss of immune function due to exposure to an external agent.

Primary immunodeficiences:

may affect either adaptive or innate immune functions. categorized by the type of cells involved or the developmental stage at which the defect occurs . defects generally affect either the lymphoid or myeloid cell lineages and involve specific genes Depending on the affected component of the immune system, there will be increased susceptibility to infection by different pathogens.

Lymphoid immunodeficiencies:

may involve B cells, T cells or both B and T cells. B cell defects range from a complete absence of B cells, plasma cells, and immunoglobulin to a selective loss of certain immunoglobulin classes. Serious B cell defects cause frequent bacterial infections due to the absence of humoral immunity. T cell defects cause frequent viral and fungal infections due to the absence of cell-mediated immunity. Humoral immunity to T-dependent antigens is also affected.

T cell immunodeficiencies:

can affect humoral, as well as cell-mediated immunity since many antigens are T-dependent, leading to a form of SCID. Although there is some decrease in antibody levels, the main result is increased susceptibility to viral, fungal and protozoal infections. DiGeorge Syndrome (congenital thymic aplasia) is the result of a developmental defect in which children are born without a thymus or parathyroids (in some cases the thymus is not completely absent). Because few functional T cells are present, cell-mediated immunity is undetectable, although a diminished humoral response is able to deal with most common bacterial infections. However, viral, fungal and protozoal infections are often fatal. A fetal thymus transplant can provide a source of thymic hormones and an environment for T cell maturation.

B cell immunodeficiencies:

may range from a complete absence of mature B cells, plasma cells and immunoglobulin to a selective deficiency in one class of immunoglobulin. 16

patients suffer from recurrent bacterial infections (especially by encapsulated bacteria because antibodies are critical for the opsonization and clearance of these microbes), although immunity to most viral and fungal infections is normal. X-linked agammaglobulinemia occurs in 1 in 103 to 106 males (X chromosome-linked). Pre-B cells in the bone marrow fail to differentiate into mature B cells because of a defect in a tyrosine kinase (Brutons tyrosine kinase) that is required to couple the pre-B cell receptor to nuclear events that lead to light chain gene rearrangement and B cell maturation. These individuals have little or no circulating antibody because of arrested B cell development at the pre-B cell stage. The condition can be treated with injections of purified pooled human IgG, although sinopulmonary infections persist due to lack of secretory IgA. X-linked hyper-IgM syndrome results from a defect in the gene coding for CD40 ligand. Since CD40 on B cells must interact with CD40 ligand on T cells for B cell activation to occur, these individuals fail to respond to T-dependent antigens. The response to T-independent antigens is normal, leading to heightened IgM production. selective immunoglobulin deficiencies result when one class or subclass of antibody is missing. The most common is an IgA deficiency due to a failure of IgA-committed B cells to differentiate into plasma cells. These patients suffer frequent bacterial and viral sinopulmonary infections, and increased allergies due to excessive IgE production. Treatment is with broad-spectrum antibiotics.

Myeloid immunodeficiencies:

congenital agranulocytosis results from decreased production of G-CSF and a failure of myeloid stem cells to differentiate into neutrophils and other granulocytes. Frequent bacterial infections are common. chronic granulomatous disease is caused by a defect in the oxidative pathway that phagocytes use to generate hydrogen peroxide. As a result phagocytes are unable to kill many types of phagocytosed bacteria, leading to excessive inflammatory responses and susceptibility to bacterial and fungal infections. Antigen processing and presentation by macrophages is also impaired. leukocyte adhesion deficiency (LAD) is caused by a failure to express the subunit of the adhesion molecules LFA-1, MAC-1 (CR3), and p150,90 (CR4). These adhesion molecules, which are required for cellular interactions (Table 19-2), are nearly absent from the cell membrane. Individuals with this defect exhibit impaired extravasation of neutrophils, monocytes and lymphocytes; impaired ability of CTL and NK cells to adhere to target cells; and failure of T helper cells and B cells to form conjugates. Frequent bacterial infections and impaired wound healing are major problems.

21. Immunodeficient states. Acquired immunodeficiency syndrome (AIDS).Clinical Presentation AIDS is the most common immunodeficiency disorder worldwide, and HIV infection is one of the greatest epidemics in human history. AIDS is the consequence of a chronic retroviral infection that produces severe, life-threatening CD4 helper T lymphocyte dysfunction, opportunistic infections, and malignancy. Retroviruses contain viral RNA that is transcribed by viral reverse transcriptase into double-stranded DNA, which is integrated into the host genome. Cellular activation leads to transcription of HIV gene products and viral replication. AIDS is defined by serologic evidence of HIV infection with the presence of a variety of indicator diseases associated with clinical immunodeficiency. Table 3-7 lists criteria for defining and 17

diagnosing AIDS. HIV is transmitted by exposure to infected body fluids or sexual or perinatal contact. Transmissibility of the HIV virus is related to subtype virulence, viral load, and immunologic host factors. Acute HIV infection may present as an acute, self-limited, febrile viral syndrome characterized by fatigue, pharyngitis, myalgias, rash, lymphadenopathy, and significant viremia without detectable anti-HIV antibodies. Over time, there is a progressive decline in CD4 T lymphocytes, a reversal of the normal CD4:CD8 T lymphocyte ratio, and numerous other immunologic derangements. The clinical manifestations are directly related to HIV tissue tropism and defective immune function. Development of neurologic complications, opportunistic infections, or malignancy signal marked immune deficiency. The time course for progression of the disease varies; the majority of individuals remain asymptomatic for as long as 5-10 years. Typically, up to 70% of individuals will develop AIDS after a decade of subclinical HIV infection. Pathology & Pathogenesis Chemokines (chemoattractant cytokines) regulate leukocyte trafficking to sites of inflammation and have been discovered to play a significant role in the pathogenesis of HIV disease. During the initial stages of infection and viral proliferation, virion entry and cellular infection requires binding to two coreceptors on target T lymphocytes and monocyte/macrophages. All HIV strains express the envelope protein gp120 that binds to CD4 molecules, but different viral strains display tissue tropism or specificity based on the coreceptor they recognize. These coreceptors belong to the chemokine receptor family. Changes in viral phenotype during the course of HIV infection may lead to changes in tropism and cytopathology at different stages of disease. Viral strains isolated in early stages of infection (eg, R5 viruses) demonstrate tropism toward macrophages. X4 strains of HIV are more commonly seen in later stages of disease. X4 viruses bind to chemokine receptor CXCR4, more broadly expressed on T cells, and are associated with syncytium formation. A small percentage of individuals possessing nonfunctional alleles for the polymorphic chemokine receptor CCR5 appear to be highly resistant to HIV infection or display delayed progression of disease. Mathematical models estimate that during HIV infection billions of virions are produced and cleared each day. The reverse transcription step of HIV replication is error prone; mutations are frequent, and even within an individual patient HIV heterogeneity develops rapidly. The development of antigenically and phenotypically distinct strains contributes to progression of disease, clinical drug resistance, and lack of efficacy of early vaccines. Cellular activation is critical for viral infectivity and reactivation of integrated proviral DNA. Although only 2% of mononuclear cells are found peripherally, lymph nodes from HIV-infected individuals can contain large amounts of virus sequestered among infected follicular dendritic cells in the germinal centers. With HIV infection there is an absolute reduction of CD4 T lymphocytes, an accompanying deficit in CD4 T lymphocyte function, and an associated increase in CD8 cytotoxic T lymphocytes (CTLs). CTL activity is initially brisk and effective at controlling viremia through elimination of virus and virus-infected cells. Ultimately, viral proliferation outpaces host responses, and HIV-induced immunosuppression leads to disease progression. Loss of viral containment occurs with diminution of CD8+ T-cell dependent cytotoxic responses, lack of adequate helper T function, accumulation of viral escape mutations, and general cytokine dysregulation detrimental to effective immune responses. In addition to the cell-mediated immune defects, B-lymphocyte function is altered such that many infected individuals have marked hypergammaglobulinemia but impaired specific antibody responses. Both anamnestic responses and those to neoantigens can be impaired. However, the role of humoral immunity in controlling viremia or slowing disease progression is unclear. The development of assays to measure viral burden (plasma HIV-RNA quantification) has led to a better understanding of HIV dynamics and has provided a tool for assessing response to therapy. It is now well recognized that viral replication continues throughout the disease, and immune deterioration occurs despite clinical latency. The risk of progression to AIDS appears correlated with 18

an individual's viral load after seroconversion. The marked decline in CD4 T lymphocyte counts characterizing HIV infectionis due to several mechanisms, including (1) direct HIV-mediated destruction of CD4 T lymphocytes, (2) autoimmune destruction of virus-infected T cells, (3) depletion by fusion and formation of multinucleated giant cells (syncytium formation), (4) toxicity of viral proteins to CD4 T lymphocytes and hematopoietic precursors, and (5) induction of apoptosis (programmed cell death). Data from several large clinical cohorts have shown that there is a direct correlation between the CD4 T-lymphocyte count number and the risk of AIDS-defining opportunistic infections. Thus, the viral load and the degree of CD4 T-lymphocyte depletion serve as important clinical indicators of immune status in HIV-infected individuals. Prophylaxis for opportunistic infections such as pneumocystis pneumonia is started when CD4 T lymphocyte counts reach the 200-250 cells/L range. Similarly, patients with HIV infection with fewer than 50 CD4 T lymphocytes/L are at significantly increased risk for cytomegalovirus (CMV) retinitis and Mycobacterium avium complex (MAC) infection. Cells other than CD4 T lymphocytes contribute to the pathogenesis of HIV infection. Monocytes, macrophages, and dendritic cells can be infected with HIV and facilitate transfer of virus to lymphoid tissues and immunoprivileged sites, such as the CNS. HIV-infected monocytes will also release large quantities of the acute-phase reactant cytokines, including IL-1, IL-6, and TNF, contributing to constitutional symptomatology. TNF, in particular, has been implicated in the severe wasting syndrome seen in patients with advanced disease. Clinical Manifestations The clinical manifestations of AIDS are the direct consequence of the progressive and severe immunologic deficiency induced by HIV. Patients are susceptible to a wide range of atypical or opportunistic infections with bacterial, viral, protozoal, and fungal pathogens. Common nonspecific symptoms include fever, night sweats, and weight loss. Weight loss and cachexia can be due to nausea, vomiting, anorexia, or diarrhea. They often portend a poor prognosis. The incidence of infection increases as the CD4 T lymphocyte number declines. Lung infection with Pneumocystis jiroveci is the most common opportunistic infection, affecting 75% of patients. Patients present clinically with fevers, cough, shortness of breath, and hypoxemia ranging in severity from mild to life threatening. A diagnosis of pneumocystis pneumonia can be made by substantiation of the clinical and radiographic findings with Wright-Giemsa or silver methenamine staining of induced sputum samples. A negative sputum stain does not rule out disease in patients in whom there is a strong clinical suspicion of disease, and further diagnostic maneuvers such as bronchoalveolar lavage or fiberoptic transbronchial biopsy may be required to establish the diagnosis. Complications of pneumocystis pneumonia include pneumothoraces, progressive parenchymal disease with severe respiratory insufficiency, and, most commonly, adverse reactions to the medications used for treatment and prophylaxis. For reasons that are not clear, HIV-infected patients have an unusually high rate of adverse reactions to a wide variety of antibiotics and frequently develop severe debilitating cutaneous reactions. As a consequence of chronic immune dysfunction, HIV-infected individuals are also at high risk for other pulmonary infections, including bacterial infections with S pneumoniae and H influenzae; mycobacterial infections with M tuberculosis or M avium-intracellulare (MAC); and fungal infections with C neoformans, H capsulatum, or C immitis. Clinical suspicion followed by early diagnosis of these infections should lead to aggressive treatment. The development of active tuberculosis is significantly accelerated in HIV infection as a result of compromised cellular immunity. The risk of reactivation is estimated to be 5-10% per year in HIVinfected patients compared with a lifetime risk of 10% in those without HIV. Furthermore, diagnosis may be delayed because of anergic skin responses. Extrapulmonary manifestations occur in up to 70% of HIV-infected patients with tuberculosis, and the emergence of multidrug resistance may 19

compound the problem. MAC is a less virulent pathogen than M tuberculosis, and disseminated infections usually occur only with severe clinical immunodeficiency. Symptoms are nonspecific and typically consist of fever, weight loss, anemia, and GI distress with diarrhea. The presence on physical examination of oral candidiasis (thrush) and hairy leukoplakia is highly correlated with HIV infection and portends rapid progression to AIDS. Abnormal outgrowth of Candida from normal mouth flora is the cause of persistent oral candidiasis, whereas Epstein-Barr virus is the cause of hairy leukoplakia. HIV-infected individuals with oral candidiasis are at much greater risk for esophageal candidiasis, which may present as substernal pain and dysphagia. This infection and its characteristic clinical presentation are so common that most practitioners treat with empiric oral antifungal therapy. Should the patient not respond rapidly, other explanations for the esophageal symptoms should be explored, including herpes simplex and CMV infections. Persistent diarrhea, especially when accompanied by high fevers and abdominal pain, may signal infectious enterocolitis. The list of potential pathogens in such cases is long and includes bacteria, MAC, protozoans (cryptosporidium, microsporidia, Isospora belli, Entamoeba histolytica, Giardia lamblia), and even HIV itself. HIV-associated gastropathy and malabsorption are commonly noted in these patients. Because of their reduced gastric acid concentrations, patients have an increased susceptibility to infection with Campylobacter, Salmonella, and Shigella. Skin lesions commonly associated with HIV infection are typically classified as infectious (viral, bacterial, fungal), neoplastic, or nonspecific. Herpes simplex virus (HSV) and herpes zoster virus (HZV) may cause chronic persistent or progressive lesions in patients with compromised cellular immunity. HSV commonly causes oral and perianal lesions but can be an AIDS-defining illness when involving the lung or esophagus. The risk of disseminated HSV or HZV infection and the presence of molluscum contagiosum appear to be correlated with the extent of immunoincompetence. Seborrheic dermatitis caused by Pityrosporum ovale and fungal skin infections (Candida albicans, dermatophyte species) are also commonly seen in HIV-infected patients. Staphylococcus can cause the folliculitis, furunculosis, and bullous impetigo commonly observed in HIV-infected patients, which require aggressive treatment to prevent dissemination and sepsis. Bacillary angiomatosis is a potentially fatal dermatologic disorder of tumor-like proliferating vascular endothelial cell lesions, the result of infection by Bartonella quintana or Bartonella henselae. The lesions may resemble those of Kaposi's sarcoma but respond to treatment with erythromycin or tetracycline. CNS manifestations in HIV-infected patients include infections and malignancies. Toxoplasmosis frequently presents with space-occupying lesions, causing headache, altered mental status, seizures, or focal neurologic deficits. Cryptococcal meningitis commonly manifests as headache and fever. Up to 90% of patients with cryptococcal meningitis exhibit a positive serum test for Cryptococcus neoformans antigen. HIV-associated cognitive-motor complex, or AIDS dementia complex, is the most frequently diagnosed cause of altered mental status in HIV-infected patients. Patients typically have difficulty with cognitive tasks, poor short-term memory, slowed motor function, personality changes, and waxing and waning dementia. Up to 50% of AIDS patients suffer from this disorder, perhaps caused by glial or macrophage infection by HIV resulting in destructive inflammatory changes within the CNS. The differential diagnosis can be broad, including metabolic disturbances and toxic encephalopathy resulting from drugs. Other causes of altered mental status include neurosyphilis, CMV or herpes simplex encephalitis, lymphoma, and progressive multifocal leukoencephalopathy, a progressive demyelinating disease caused by a JC papovavirus. Peripheral nervous system manifestations of HIV infection include sensory, motor, and inflammatory polyneuropathies. Almost 33% of patients with advanced HIV disease develop peripheral tingling, numbness, and pain in their extremities. These symptoms are likely to be due to loss of nerve axons from direct neuronal HIV infection. Alcoholism, thyroid disease, syphilis, vitamin B12 deficiency, drug toxicity (ddI, ddC), CMV-associated ascending polyradiculopathy, and transverse myelitis also cause peripheral neuropathies. Less commonly, HIV-infected patients can develop an inflammatory demyelinating polyneuropathy similar to Guillain-Barr syndrome; however, unlike 20

the sensory neuropathies, this inflammatory demyelinating polyneuropathy typically presents before the onset of clinically apparent immunodeficiency. The origin of this condition is not known, although an autoimmune reaction is suspected because the disease typically responds favorably to treatment with plasmapheresis. Retinitis resulting from CMV infection is the most common cause of rapidly progressive visual loss in HIV infection. The diagnosis can be difficult to make because Toxoplasma gondii infection, microinfarction, and retinal necrosis can all cause visual loss. HIV-related malignancies commonly seen in AIDS include Kaposi's sarcoma, non-Hodgkin's lymphoma, primary CNS lymphoma, invasive cervical carcinoma, and anal squamous cell carcinoma. Impairment of immune surveillance and defense and increased exposure to oncogenic viruses appear to contribute to the development of neoplasms. Kaposi's sarcoma is the most common HIV-associated cancer. In San Francisco, 15-20% of HIVinfected homosexual men develop this tumor during the progression of their disease. Kaposi's sarcoma is uncommon in women and children for reasons that are not clear. Unlike classic Kaposi's sarcoma, which affects elderly men in the Mediterranean, the disease in HIV-infected patients may present with either localized cutaneous lesions or disseminated visceral involvement. It is often a progressive disease, and pulmonary involvement can be fatal. Histologically, the lesions of Kaposi's sarcoma consist of a mixed cell population that includes vascular endothelial cells and spindle cells within a collagen network. Human herpesvirus 8 is associated with Kaposi's sarcoma in AIDS patients. HIV itself appears to induce cytokines and growth factors that stimulate tumor cell proliferation rather than causing malignant cellular transformation. Clinically, cutaneous Kaposi's sarcoma typically presents as a purplish nodular skin lesion or painless oral lesion. Sites of visceral involvement include the lung, lymph nodes, liver, and GI tract. In the GI tract, Kaposi's sarcoma can produce chronic blood loss or acute hemorrhage. In the lung it often presents as coarse nodular infiltrates bilaterally, frequently associated with pleural effusions. These infiltrates can be difficult to distinguish from opportunistic infections. Non-Hodgkin's lymphoma is particularly aggressive in HIV-infected patients and usually indicative of significant immune compromise. The majority of these tumors are high-grade B-cell lymphomas with a predilection for dissemination. The CNS is frequently involved either as a primary site or as an extranodal site of widespread disease. Anal dysplasia and squamous cell carcinoma are also more commonly found in HIV-infected homosexual men. These tumors appear to be associated with concomitant anal or rectal infection with human papillomavirus (HPV). In HIV-infected women, the incidence of HPV-related cervical dysplasia is as high as 40%, and dysplasia can progress rapidly to invasive cervical carcinoma. Other complications of HIV-infection include arthritides, myopathy, GI syndromes, dysfunction of the adrenal and thyroid glands, hematologic cytopenias, and nephropathy. Since the disease was first described in 1981, medical knowledge of the underlying pathogenesis of AIDS has increased at a rate unprecedented in medical history. This knowledge has led to the rapid development of therapies directed at controlling HIV infection as well as the multitude of complicating opportunistic infections and cancers.

22)DISTURBANCES OF PERIPHERAL CIRCULATION.ARTERIAL HYPEREMIABlood circulation in the area of peripheral vascular bed, but the movement of blood, ensuring the exchange water, electrolytes, gases, essential nutrients and metabolites in system of blood - tissue - blood. Peripheral arterial disease (P.A.D.) is a disease in which plaque (plak) builds up in the arteries that carry blood to your head, organs, and limbs. Plaque is made up of fat, cholesterol, calcium, fibrous tissue, and other substances in the blood.

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When plaque builds up in the body's arteries, the condition is called atherosclerosis . Over time, plaque can harden and narrow the arteries. This limits the flow of oxygen-rich blood to your organs and other parts of your body.P.A.D. usually affects the arteries in the legs, but it also can affect the arteries that carry blood from your heart to your head, arms, kidneys, and stomach. PVD, also known as arteriosclerosis obliterans, is primarily the result of atherosclerosis. The atheroma consists of a core of cholesterol joined to proteins with a fibrous intravascular covering. The atherosclerotic process may gradually progress to complete occlusion of medium and large arteries. The disease typically is segmental, with significant variation from patient to patient. Vascular disease may manifest acutely when thrombi, emboli, or acute trauma compromises perfusion. Thromboses are often of an atheromatous nature and occur in the lower extremities more frequently than in the upper extremities. Multiple factors predispose patients for thrombosis. These factors include sepsis, hypotension, low cardiac output, aneurysms, aortic dissection, bypass grafts, and underlying atherosclerotic narrowing of the arterial lumen. Arterial hyperemia is the enhanced blood filling of an organ because of the reinforced blood inflowing through arterial vessels.There are the physiological and pathological arterial hyperemia. The typical example of the physiological hyperemia is work hyperemia, which develops during the reinforced organ function. Pathological arterial hyperemia is observed when the part of body or all organism exposes to the influence of unusual factors of external or internal environment microbe toxins, chemical substances, biologically active substances etc. ngioneurotic hyperemia is displayed in two forms the neuroparalytic and neurotonic types. The first one arises due to paralysis of vasoconstrictor nerves, the other one at the stimulation of vasodilatator nerves. Collateral hyperemia arises in connection with the difficulty of blood flowing in the magistral artery, the lumen of which is closed by thrombus, mbol or is narrowed by tumor. Blood comes to the bloodless place through the collateral vessels, which reflexly expand. Hyperemia after anemia arises in the cases, when a factor, that pressed the artery, quickly liquidates. For such conditions the vessels of before bloodless organ sharply expand and become overflowed by blood what can bring about their break and bleeding. Also from the blood redistribution in the blood streem anemia of other organs appeares. The redistributory ischemia of the cerebrum can bring about the loss of consciousness. To avoid such complication, it is necessary to let the liquid out from abdominal cavity slowly.The vacate hyperemia develops in connection with the decreasing of the barometric pressure, for example into divers at their fast lifting from the depth.Arterial hyperemia is a permanent inflammation satellite.

23)VENOUS HYPEREMA.STASISPassive Hyperemia Passive Hyperemiais an excess of venous blood in a part. It is the result of a distention of a vein on account of some obstruction to the outflow of the blood. This can be caused by obstruction within the veins or capillaries, as by thickening of their walls, by thrombi, or by pressure from without, as from atumor. A common cause for general passivehyperemiais a lesion of the heart-valves. The circulation will continue slowly unless the venous pressure becomes as great as the arterial, when it will stop, a condition known as stasis.

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A part that is the seat of passive hyperemia becomes cyanotic, swollen, edematous, cooler than normal, and its function less. The rate of blood-flow is lessened. Theedemais due to the escape of fluid from the blood. If severe, red corpuscles may escape. Following long-continued passive hyperemia the tissues will undergo afatty degenerationon account of the decreased nutrition, or evennecrosisandgangrenemay result. There may also be some increase in the amount of connective tissue. Pigmentation from escapedhemoglobinis not uncommon -brown atrophy. When stasis occurs the blood-corpuscles slowly collect in the smaller vessels, the plasma is exuded, and the cells become packed closely together. Finally, the outline of the cells cannot be seen and the vessels appear to be filled with coagulated blood. Such is not the case, as when the circulation is reestablished the corpuscles separate and move along as usual. Localanemiaor ischemia is the condition in which the part contains less than its normal amount of blood. It is most commonly due to obstruction by pressure of the flow of arterial blood into a part. This may be due to tight bandaging, pressure from a tumor, or to thrombi or emboli, or to changes in the wall of the vessel. Disturbances of the vasomotor system may bring about marked lesions. If there is a good collateral circulation the area to which the obstructed vessel goes may show very slight change. If such is not the case,infarctionmay follow. An anemic area is pale in color,temperaturelower, and functional activity decreased.

24)ISCHEMIA. INFARCTIONIschemia, is a restriction in blood supply to tissues, causing a shortage of oxygenand glucose needed for cellular metabolism Ischemia is generally caused by problems with blood vessels, with resultant damage to or dysfunction of tissue. Since oxygen is carried to tissues in the blood, insufficient blood supply causes tissue to become starved of oxygen. In the highly aerobic tissues of the heart and brain, irreversible damage to tissues can occur in as little as 34 minutes at body temperature. Ischemia results in tissue damage in a process known as ischemic cascade. The damage is the result of the build-up of metabolic waste products, inability to maintain cell membranes, mitochondrial damage, and eventual leakage of autolyzing proteolytic enzymes into the cell and surrounding tissues. Restoration of blood supply to ischemic tissues can cause additional damage known as reperfusion injury that can be more damaging than the initial ischemia. Reintroduction of blood flow brings oxygen back to the tissues, causing a greater production of free radicals and reactive oxygen species that damage cells. It also brings more calcium ions to the tissues causing further calcium overloading and can result in potentially fatal cardiac arrhythmias and also accelerates cellular selfdestruction. The restored blood flow also exaggerates the inflammation response of damaged tissues, causing white blood cells to destroy damaged cells that may otherwise still be viable. Cardiac ischemia Cardiac ischemia may be asymptomatic or may cause chest pain, known as angina pectoris. It occurs when the heart muscle, or myocardium, receives insufficient blood flow. This most frequently results from atherosclerosis, which is the long-term accumulation of cholesterol-rich plaques in the coronary arteries. Classification By histopathology

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Infarctions are divided into 2 types according to the amount of blood present: White infarctions (anemic infarcts) affect solid organs such as the spleen and kidneys wherein the solidity of the tissue substantially limits the amount of nutrients that can flow into the area of ischemic necrosis Red infarctions (hemorrhagic infarcts), generally affect the lungs or other loose organs (testis, ovary, small intestines). The occlusionconsists more of red blood cells and fibrin strands. By localization Heart: Myocardial infarction (MI), commonly known as a heart attack, is an infarction of the heart, causing some heart cells to die. This is most commonly due to occlusion (blockage) of a coronary artery following the rupture of a vulnerable atherosclerotic plaque, which is an unstable collection of lipids and white blood cells in the wall of an artery. The resulting ischemia and oxygen shortage, if left untreated for a sufficient period of time, can cause damage or death of heart muscle tissue Causes. If the myocardial ischemia lasts for some time (even at rest [unstable angina]; tissue necrosis, i.e., myocardial infarction ,occurs within about an hour. In 85% of cases this is due to acute thrombus formation in the region of the atherosclerotic coronary stenosis. This development is promoted by turbulence, and atheroma rupture with collagen exposure. Both events activate thrombocytes. Thrombosis is also encouraged through abnormal functions of the endothelium, thus its vasodilators (NO, prostacyclin) and antithrombotic substances are not present Rare causes of MI are inflammatory vascular diseases, embolism ,severe coronary spasm, increased blood viscosity as well as a markedly raised O2 demand at rest Brain: Cerebral infarction is the ischemic kind of stroke due to a disturbance in the blood vessels supplying blood to the brain. It can be atherothrombotic or embolic.[6] Stroke caused by cerebral infarction should be distinguished from two other kinds of stroke: cerebral hemorrhage and subarachnoid hemorrhage. Cerebral infarctions vary in their severity with one third of the cases resulting in death.

Lung: Pulmonary infarction or lung infarction Spleen: Splenic infarction occurs when the splenic artery or one of its branches are occluded, for example by a blood clot. Although it can occur asymptomatically, the typical symptom is severe pain in the left upper quadrant of the abdomen, sometimes radiating to the left shoulder. Fever and chills develop in some cases.[7] It has to be differentiated from other causes of acute abdomen. Limb: Limb infarction is an infarction of an arm or leg. Causes include arterial embolisms and skeletal muscle infarction as a rare complication of long standing, poorly controlled diabetes mellitus.[8] A major presentation is painful thigh or leg swelling.[8] Bone: Infarction of bone results in avascular necrosis. Without blood, the bone tissue dies and the bone collapses.[9] If avascular necrosis involves the bones of a joint, it often leads to destruction of the joint articular surfaces Testicle: an infarction of a testicle may be caused by testicular torsion.

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Eye: an infarction can occur to the central retinal artery which supplies the retina causing sudden visual loss.

25. Thrombosis.Pathogenesis There are three primary influences on thrombus formation (called Virchow's triad): (1) endothelial injury, (2) stasis or turbulence of blood flow, and (3) blood hypercoagulability. Endothelial Injury This is a dominant influence, since endothelial loss by itself can lead to thrombosis. It is particularly important for thrombus formation occurring in the heart or in the arterial circulation, where the normally high flow rates might otherwise hamper clotting by preventing platelet adhesion or diluting coagulation factors. Thus, thrombus formation within the cardiac chambers (e.g., after endocardial injury due to myocardial infarction), over ulcerated plaques in atherosclerotic arteries, or at sites of traumatic or inflammatory vascular injury (vasculitis) is largely a function of endothelial injury. Clearly, physical loss of endothelium leads to exposure of subendothelial ECM, adhesion of platelets, release of tissue factor, and local depletion of PGI2 and plasminogen activators. However, it is important to note that endothelium need not be denuded or physically disrupted to contribute to the development of thrombosis; any perturbation in the dynamic balance of the prothrombotic and antithrombotic activities of endothelium can influence local clotting events. Thus, dysfunctional endothelium may elaborate greater amounts of procoagulant factors (e.g., platelet adhesion molecules, tissue factor, plasminogen activator inhibitors) or may synthesize fewer anticoagulant effectors (e.g., thrombomodulin, PGI2, t-PA). Significant endothelial dysfunction (in the absence of endothelial cell loss) may occur with hypertension, turbulent flow over scarred valves, or by the action of bacterial endotoxins. Even relatively subtle influences, such as homocystinuria, hypercholesterolemia, radiation, or products absorbed from cigarette smoke, may be sources of endothelial dysfunction. Alterations in Normal Blood Flow Turbulence contributes to arterial and cardiac thrombosis by causing endothelial injury or dysfunction, as well as by forming countercurrents and local pockets of stasis; stasis is a major contributor to the development of venous thrombi. Normal blood flow is laminar, such that platelets flow centrally in the vessel lumen, separated from the endothelium by a slower moving clear zone of plasma. Stasis and turbulence therefore: Disrupt laminar flow and bring platelets into contact with the endothelium. Prevent dilution of activated clotting factors by fresh-flowing bloodRetard the inflow of clotting factor inhibitors and permit the buildup of thrombiPromote endothelial cell activation, resulting in local thrombosis, leukocyte adhesion, etc. Turbulence and stasis contribute to thrombosis in several clinical settings. Ulcerated atherosclerotic plaques not only expose subendothelial ECM but also cause turbulence. Abnormal aortic and arterial dilations, called aneurysms, create local stasis and consequently a fertile site for thrombosis. Acute myocardial infarction results in focally noncontractile myocardium; ventricular remodeling after more remote infarction can lead to aneurysm formation. In both cases cardiac mural thrombi

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form more easily because of the local blood stasis. Mitral valve stenosis (e.g., after rheumatic heart disease) results in left atrial dilation. In conjunction with atrial fibrillation, a dilated atrium is a site of profound stasis and a prime location for development of thrombi. Hyperviscosity syndromes increase resistance to flow and cause small vessel stasis; the deformed red cells in sickle cell anemia cause vascular occlusions, with the resultant stasis also predisposing to thrombosis. Fate of the Thrombus If a patient survives the initial thrombosis, in the ensuing days or weeks thrombi undergo some combination of the following four events: 1 Propagation. Thrombi accumulate additional platelets and fibrin, eventually causing vessel obstruction. 2 Embolization. Thrombi dislodge or fragment and are transported elsewhere in the vasculature. 3 Dissolution. Thrombi are removed by fibrinolytic activity 4 Organization and recanalization. Thrombi induce inflammation and fibrosis (organization). These can eventually recanalize (re-establishing some degree of flow), or they can be incorporated into a thickened vessel wall. Clinical Correlations: Venous versus Arterial Thrombosis Thrombi are significant because they cause obstruction of arteries and veins and are potential sources of emboli. Which effect is most important depends on the site of thrombosis. Venous thrombi can cause congestion and edema in vascular beds distal to an obstruction, but they are most worrisome for their capacity to embolize to the lungs and cause death (see below). Conversely, while arterial thrombi can embolize and even cause downstream tissue infarction (see below), their role in vascular obstruction at critical sites (e.g., coronary and cerebral vessels) is much more significant clinically.

26)EMBOLISMEmbolus is a free mass in the blood which can occlude any vessel at any time. If it occludes an artery it will lead to tissue necrosis.Embolism: an embolism occurs when an object migrates from one part of the body andcausesa blockage of a blood vessel in another part of the body. MATERIAL 1.Thromboembolism embolism of thrombus or blood clot. 2.Fat embolism embolism of fat droplets. 3.Air embolism (also known as a gas embolism) embolism of air bubbles. 4.Septic embolism embolism of pus-containing bacteria. 5.Tissue embolism embolism of small fragments of tissue. 6.Foreign body embolism embolism of foreign materials such as talc and other smallobjects. 7.Amniotic fluid embolism embolism of amniotic fluid, foetal cells, hair, or other debristhat enters the mother's bloodstream via the placental bed of the uterus and triggers anallergic reaction PATHWAY 1.Anterograde 2.Retrograde 3.Paradoxica CAUSES & Pathophysiology A.Thromboembolism ,This is when a part of a blood clot (thrombus) blocks blood flow to a major organ such asthe heart or lungs. Itsthe most common type of embolism. B.Fat embolism usually occurs when 26

Endogenous :1.Thefracture of tubular bones (such as the femur), which will lead to theleakage of fat tissue within the bone marrow into ruptured vessels.2.Trauma of burns of a fatty area. Exogenous:(from sources of external origin) causes such as intravenousinjection of emulsions. C. Air embolism is usually always caused by exogenic factors. the rupture of alveoli, and inhaled air can be leaked into the blood vessels. The puncture of the subclavian vein by accident or during operation where thereis negative pressure.Air is then sucked into the veins by the negative pressure caused by thoracicexpansion during the inhalation phase of respiration.Intravenoustherapy, when air is leaked into the system (however this iatrogenicerror in modern medicine is extremely rare).

Gas embolism is a common concern for deep-sea divers because the gasesin our blood (usually nitrogen and helium) can be easily dissolved at higheramounts during the descent into deep sea. However, when the diver ascends tothe normal atmospheric pressure, the gases become insoluble, causing theformation of small bubbles in the blood. This is also known as decompressionsickness or the Bends. D.Septic embolism happens when a purulent tissue (pus-containing tissue) is dislodged fromits original focus. E.Tissue embolism is a near-equivalent to cancer metastasis, which happens when cancertissue infiltrates blood vessels, and small fragments of them are released into the blood stream. F. Foreign-body embolism happens when exo