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Inflammation

Inflammation

by CNeilson, Nov. 2015

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	What is the purpose of the inflammation response? What is the goal of inflammation?	To dilute, destroy, and neutralize harmful agents (microbes and toxins) To remove dead and damaged tissue To initiate repair Mediates the elimination of foreign invaders such as : infectious pathogens and damaged tissue DEFINITION - Protective response Eliminate the initial cause of cell injury Eliminate the necrotic cells and tissues from original insult It is part of the innate immunity What is the goal? Brings cells and molecules of host defense from the blood stream (circulation) to the site of where infection or tissue damage has happened
	What are the components of inflammation?	Cells and molecules that can leave the circulation such as: neutrophils, lymphoctyes, monocytes, platelets, and plasma proteins Tissue resident cells such as macrophages and mast cells but also fibroblasts and extracellular matrix proteins The endothelial and smooth muscle cells of the vessel wall
	Why does the inflammatory reaction need to be balanced?	The subsequent repair process can cause considerable harm and can cause injury of normal tissue. Therefore, pro-inflammatory reactions need to be balanced with anti-inflammatory responses. Pathology might become the dominant feature of the inflammatory reaction if: The reaction is very strong Reaction is prolonged The reaction is inappropriate
	What are the basic forms of inflammation? Give a brief description of inflammation.	Acute Inflammation Rapid onset and duration (min-days) Characterized by fluid and plasma protein exudation Predominantly neutrophilic leukocyte accumulation in inflamed tissues Chronic inflammation Is longer in duration (day-year) Characterized by influx of lymphocytes and macrophages Associated with vascular proliferation and fibrosis (scarring)
	What are the cardinal sings of acute inflammation?	Heat and redness - relate to vasodialtion and the increase in blood flow into an area of inflammation, accumulation of blood, both intra- and extra-vascular Redness - at the site and perhaps also to an increase in metabolic rate in the tissue cells Swelling - mainly due to the accumulation of exudate and the migration of inflammatory cells from the vessels out into the tissue spaces Pain - due to the increase in pressure as a result of the accumulation of cells and exudate (the pain varies with the site of inflammation) and due to the release of chemicals from damaged tissue cells which stimulate sensory nerve endings Loss of function - due to pain (muscle and joint movement), cell and tissue destruction, and to the effects of the vascular disturbances on normal physiological function (secretion of glandular tissues, eg under the udder)
	Define exudate. Define edema.	Exudate - extracellular fluid collection rich in proteins and/or cells Edema - an excess of watery fluid collecting in the cavities or tissues of the body
	What are possible stimulus of inflammation	Physical - cuts, burns, fracture, foreign bodies Chemical - acids, alkialis, industrial chemicals Microbial - bacterial/fungal toxins and products, viral induced cell death, parasites Immunological - normal immune response to infectious agents, hypersensitivity reactions (I-IV)
	What are the main changes occurring due to the acute inflammatory reactions?	Vascular Response Active hyperemia (increased blood flow into tissues) with change in vessel caliber Changes in vessel walls and swelling of the endothelial cells Gradual slowing of blood flow leading to stasis, clumping of erythrocytes (sludging), and margination (pavementing) of leukocytes (leukocytes stick to blood vessel wall) Exudation of Fluid - Inflammatory edema The increase in hydrostatic pressure (due to vasodilation and increased permeability) leading to increased passive filtration of fluid and electrolytes out of the blood vessels (edema) Escape of plasma proteins (albumins, globulins, and fibrinogen) from inflamed capillaries and venules thorough transient gaps between the endothelial cells
	What are inflammatory mediators? Where are they found? What is their job? What happens when their job is done? Give examples of cellular mediators.	Found Widely distributed in a sequestered or inactive form throughout the body Released or activated locally at sites of injury Some newly synthesized Job Some act directly on blood vessels while other act indirectly Mediators overlap in function and linked to give positive feedback effects or synergistic effects After they are used After release, they tend to be rapidly inactivated locally providing an important element of control of the inflammatory process
	Give examples of plasma mediators?
	What are some important inflammatory cytokines?	Tumor necrosis factor alpha (TNF-a) Key role in triggering inflammation Induces cardinal signs of inflammation Prolongs and amplifies inflammation Interleukin-1 (IL-1a and IL-1b) Responsible together with TNF-a for sickness behavior Causes fever, lethargy, malaise, and lack of appetite Interleukin-6 (IL-6) Produced by innate immune cells after stimulation with IL-1, TNF-a, or PAMPS Affects both inflammation and acquired immunity IL-6 is a major mediator of the acute-phase reaction and of septic shock
	How does histamine act as an inflammatory mediator? What is it? What are its effects? How is it made?	Rapidly acting vasoactive amine Found in the granules of mast cells and basophils Platelet granules contain a similarly acting substance called serotonin Main Effects Dilation of small blood vessels Increased vascular permeability (immediate - due to histamine or seratonin - and delayed - due to kinins, prostaglandinsm and leukotienes) Contraction of smooth muscle
	How do kinins act as an inflammatory mediator?What is it? What are its effects? How is it made?	Biologically active polypeptides produced by the action of enzymes called kallikreins on a precursor molecule call kininogen Most significant = bradykinin Effects of bradykinin Vascular effects Pain via an axon reflex Kalikrein enzymes exist in plasma as inactive precursor called prekallikreins Activated during blood clotting C2-kinin Generated from complement either via classical pathway activation or by the action of plasmin Plasmin Generated from an inactive precursor called plasminogen during blood clotting Functions - breaking down fibrin formed during blood clotting
	How do Prostaglandins (PG) and Leukotrienes (LT) act as an inflammatory mediator?What is it? What are its effects? How is it made?	Fatty acids produced from phospholipids in cell membranes Synthesized by activated cells rather than being stored ready fro release Phospholipase A2 Converts phospholipds to archidonic acid, In turn this is acted on by cyclo-oxygenase to produce PG and thromboxane molecules Or by lipoxygenaes to produce LT molecules Role of PG and LT in Delayed Phase Vasodialtion Increased vascular permeability Smooth muscle contraction Pain Neutrophil chemotaxis
	How do Platelet Activating Factors (PAF) act as an inflammatory mediator?What is it? What are its effects? How is it made?	Synthesized by activated mast cells from membrane phospholipds Causes platelets to degranulate
	How does the Complement System act as an inflammatory mediator? What is it? What are its effects? How is it made?	Activation of the complement system is inter-related with the kinin and coagulation/plasmin systems. Complement fragments C3a and C5a (anaphylotoxins) cause the release of histamine from mast cells, and are important in aggregate anaphylaxis and other immune complex lesions
	How do mediators released by neutrophils act as an inflammatory mediator? What is it? What are its effects? How is it made?	Two types of cytoplasmic granules Azurophilic lysosomal granules - contain proteolytic and other degradative enzymes that are important in tissue liquefaction and amplification of inflammation Specific granules - contain proteins with anti-bacterial properties and can cause mast cell degranulation
	How do mediators released by platelets act as an inflammatory mediator? What is it? How is it made?	Two types of granules Lysosomal granules - which contain proteolytic enzymes and cationic proteins Dense bodies - contain serotonin Activated During blood clotting and platelet activating factor (PAF) to release their granules and synthesize prostaglandins thus initiating inflammation following for examples of cuts and surgery
	How do peptides act as an inflammatory mediator? What is it? What are its effects? How is it made?	These result from the digestion of exudate proteins by proteolytic enzymes derived from plasma, tissue cells, and neturophils They are capable of increasing vascular permeability in some cases
	How do microbial products act as an inflammatory mediator? What is it? What are its effects? How is it made?	Bacteria may produce a variety of inflammatory products Kinases Hyaluronidase Vaso-activetoxins Hemolysins Leucocidins Proteases Some of these have substantial influence on the development of the associated inflammatory reaction
	How do cytokines act as an inflammatory mediator? What is it? What are its effects? How is it made?	These are protein mediators produced by local cells that are induced following tissue insults Action Paracrine way - activate adjacent cells or cells at a distance Autocrine way - stimulating the initial producing cell Pronounced effects on all stages of the inflammatory process Induce increased vascular dilation and permeability as well as the production of proteolytic enzyme Examples IL-1 TNF-a IFN-g
	How do cheomkines act as an inflammatory mediator? What is it? What are its effects?	These are also proteins and act as chemo attractants for leukocytes
	What are the phases of vascular dilation and permeability? How do mediators relate to these phases?
	Describe serous exudate.	Abundant Watery, clear, or cloudy Low protein Low cell Observed in mild reactions involving serous (pleural, pericardial, and peritoneal) and synovial membranes and connective tissues Depending on its fibrinogen content, the exudate may coagulate at necropsy and form a loose jelly
	Describe fibrinous exudate.	Abundant Rich in fibrinogen Observed in more sever reactions involving serous membranes, the alveoli of the lungs, and sometimes connective tissues Most of the fibrinogen becomes converted to fibrin and is deposited as yellow/white elastic and often shaggy The serous component may be contained within pockets int he meshwork of fibrin fivers or become expressed to accumulate as collections of clear yellow watery exudate
	Describe catarrhal exudate.	Abundant Usually cloudy thin mucinous exudate to more restricted thick white sticky mucinous exudate Associated with the inflammation o the mucous membranes of the nasopharynx, airways, lower alimentary tract, uterus and mucous glands Exudate is rich in desquammated epithelial cells as well as in neutrophils
	Describe Suppurative/purulent exudate.	Associated with a bacterial infection by pyogenic organisms (streptococci, staphlyococci, etc) Characterized by the formation of large amounts of purulent exudate - pus Opaque fluid Variable color, viscosity, and odor Contains very large number of dying and dead neutrophils and necrotic tissue debris that has been partly liquified by various proteases, peptidases, and lipases liberated form dead cells and neutrophils. Cholesterol, lecithin, fats, soups, and other breakdown products are present Color of pus depends on the presence of erythrocytes and hemaglobin breakdown pigments and on pigments derived from chromogenic bacteria, and it may be characteristic for particular pyogenic infection in particular sites. The smells relates to breakdown products produced by particular organisms while the viscosity appears to relate to the DNA content. Suppurative inflammation usually occurs as a localized process, the pus accumulating in a closed cavity within the affected tissue - an abscess - but sometimes it occurs as a diffuse process extending through connective tissues and along fascial planes, when it is termed cellulitis - this tends to be associated with organisms such as beta-hemolytic streptococci and Clostirium oedematiens which produces large amounts of hyaluronidase and fibrinolysin (plasmin)
	Describe hemorrhagic exudate.	Frank hemorrhage may occur during the development of an inflammatory reaction and dominate the appearance of the exudate Especially in organs with a rich vascular supply - lung, udder, intestine, etc., Especially if the causal agent actively damages vessel walls and perhaps interferes with the coagulation mechanism
	Describe necrotising exudate.	Necrosis is a feature of all inflammatory reactions at a microscopic level by may become the major feature in the macriscopic lesison. The necrosis may be the result of ischemia following spasm or thrombosis of the vascular supply of the acute venous congestion and stasis following strangulation or thrombosis of the venous return. These vascular crises may result from and be combined with the action of potent necrotizing toxins produced by a certain bacteria and which rapidly diffuse through the tissues surrounding the sites of infection.
	What is the role of the lymphatics and lymph nodes in inflammation?	In Acute inflammation The distension of the tissue spaces with exudate results in the walls of the lymphatics bieng held widely open The flow of lymph is usually greatly increased In sever reactions Coagulation of fibrin within the lymphatics (fibrin thrombi) may interfer with the lymphatic drianage. In bacterial inflammation Increased lymph flow may result in considerable numbers of organisms, extra-cellular and intracellular, being carried off from the primary site of infection along the afferent lymphatics to the draining lymph node Secondary localization may take place in the lymphatic tissues and cause inflammation of nodes (lymphadenitis) Further spread along the lymphatic chain may occur in some cases and the infection eventually reaches the blood circulation (lymphahematgoenous dissemination) Lymphatic vessels may themselves become inflamed - caused by virulent bacteria (lymphangitis)
	What is leukocyte migration?	Active process of two stages. Margination of neutrophils on altered vascular endothelium (especially of venules) accompanying the slowing the blood flow (tethering, rolling, and arrest) The active emigration of these cells through gaps between the endothelial cells and then through the basement membrane and perivascular sheath out into the tissue spaces. Both endothelial cells and leukocytes undergo rapid changes in the presence of inflammatory mediators, elaborating a variety of cell adhesion molecules which determine the kinetcs of migration for each type of leukocyte
	How does the tethering and rolling portion of leukocyte migration work?	Involves the expression of selectin molecules by the endothelium which serve to tether passing leukocytes Chemoattractant molecules cause activation of the tether leukocyte which then express an adhesive form of an integrin molecules The latter then binds strongly to cell adhesion molecules of the immunoglobulin super family to cause final arrest of the leukocyte. The leukocytes then migrate through gaps between endothelial cells and traverse into the tissues
	What cells are involved in leukocyte migration and what is their timing?	The cells first involved in this process are emigrating in great numbers during acute inflammation They are the neutrophils (sometimes eosinophils) Intensity of the migration varies widely with the cause and severity of the tissue injury. About the same time or slightly later, monocytes emigrate into the tissues and beomce actively pagocytic macrophages
	What is neutrophil adhesion? What are the two basic pathways of neutrophil arrest in the circulation near inflammatory sties?	Immediate Pathway Minutes Involves rapid expression of P selectin on endothelial cells which interacts with P selectin receptors on neutrophils These rapid changes are mediated by histamine, C5a, and PAF Causes tethering and rolling Chemoattractants (ex C5a) released in the tissues causes neutrophil activation and expression of adhesive LFA-1 which then binds to ICAM-1 on the endothelium Delayed Pathways 2-4 hours Involves expression of E selctin by the endothelium This is brought about by the action of interleukin 1 (IL-1) and TNF-a on endothelial cells E selectin binds to an E selectin receptor expressed by neutrophils to mediate tethering and rolling All these molecules require to be synthesized the process is slower and develops over a period of about 2 hours Chemoattractants such as LTB4 and IL-8 cause neutrophils to express adhesive LFA-1 which then binds to ICAM-1 on the endothelium to mediate arrest Migration into the tissues follows
	What is monocyte adhesion?	Monocytes also express receptors for selectins which mediate tethering and rolling. Activation of blood monocytes is due to the action of the cytokine monocyte chemotactic factor I (MCP-1) synthesized and secreted by resident macrophages at the site of damage. Again, adhesive LFA-1 binds to ICAM-1 on the endothelium to mediate arrest and initiate monocyte migration into tissues This is a slower process than occurs with neutrophils, due to the slow production of MCP-1 and results in the delayed appearance of monocytes at the site of damage. Many more neutrophils than monocytes in tissues (in blood [PMN]>>>[Mo]) Monocytes differentiate into macropahges in tissues (24-72 hr)
	What is chemotaxis? How does it work? What is its purpose? Give examples of chemoattractants.	Examples A variety of chemotactic and migration promoting factors for neutrophils are known C3a C5a PGE1/2 LTB4 IL8 bacterial products HOW IT WORKS. Neutrophils follow chemoattractant gradient concentrations and hence move in the direction of the source of the chemoattractant Similarly, monocytes follow chemoattractant gradients of MCP-1 Purpose Draw neutrophils and monocytes to site of inflammation for phagocytosis of foreign particles, bacteria, debris, etc. Phagocytosis is promoted by opsonins such as antibodies and complement components and suitable scaffolding ex. a fibrin meshwork facilitates particles-phagocyte contact
	What are the pros and cons of neutrophils and macrophages as phagocytic cells?	Netrophils are short-lived end-stage cells and cannot resynthesize their lysosomal enzymes. Macrophages, however, are long-lived and resynthesize a variety of lysosomal enzymes, some of which are likely to be appropriate to the particular material which has been phagocytozed.
	Why does phagocytosis not always work for bacterial infections?	In bacterial infections, it is important to appreciate that phagocytosis is not automatically followed by bacterial disintegration Some organisms cause rapid death of the ingesting cell (via release of toxins) whilst other adapt to the intracellular environment, and such infected cells (esp macrophages) may plan an important role in the dissemination of infection in the body.
	What is the role of macrophages in acute inflammation and host defense?	To phagocytoze pathogens via scavenger receptors, Fc-receptors, and complement receptors (ex. pathogens opsonized with antibodies or complement) To secrete toxic factors that kill pathogens (ex. H2O2, nitric oxide, proteases) To secrete cytokines and chemokines which alert other immune effector cells (ex. IL-1, TNF-a, IL-6) To secrete colony stimulating factors that promote differentiation of recruited immature granulocytes and monocytes
	What is the function of exudate?	Dilutes toxins and other active molecules Distributes clotting factors and mediators around injured tissues - clots obstruct bacterial spread and aid in phagocytosis; mucus traps microorganisms Antibodies and complement opsonize pathogens for phagocytosis and antibodies neutralize toxins Exudate continuously drains off to lymphatic vessels - carries bacterial antigens and toxins to lymph nodes where specific immune responses can be mounted or amplified
	What are the main cell types involved in acute inflammation? What type of cells are they?
	What is a PMN?	Polymorphonuclear neutrophil granulocyte Major cell population of blook leukocytes Important host defence cells of the innate immune system
	Summarize what happens during inflammation.	Vasodilation - increased regional flow Increased vascular permeability - exudation Expression of adhesion molecules - circulating cells can stick to endothelium Increased neutrophils - phagocytosis Increased monocytes - phagocytosis
	Summarize the types of inflammatory mediators.
	What are eicosanoids?	Lipid mediators 20 carbons Role in homeostasis and inflammation Effects mediated primarily thorugh GPCR (G protein coupled receptors) 2 key eicosanoids - prostaglandins and leukotrienes
	What are essential fatty acids (EFAs)?	Short chain polyunsaturated fatty acids (PUFAs) Form buildignclocks for long chain PUFAs Omega 3 = antiinflammatroy Omega 6 = proinflammatory
	What is arachidonic acid (AA)?	An EFA - most mammals synthesize AA from Linoleic acid (exception: cats) Main mammalian precursor for eicasonoid production
	How are prostaglandins synthesized?	Cyclooxygenase (COX) COX is responsible for the formation of the prostaglandin intermediary PGH2 COS is therefore a target for drugs to inhibit PG production (ex. aspirin) Two isoforms: COX-1 and COX-2 Theoretically COX-1 is involved in homeostasis and COX-2 is involved in inflammation
	Give examples of prostaglandins.
	What is the mechanism of action for prostaglandin? Which prostaglandin is produced when?	Order of diagram: Cell Type, Produce Produced; Effect; Result Effects are mediated through GPCR (Gs > cAMP^; Gq> PLC^ and Ca2+^; Gi > cAMPv) PGs transported out of the cell Act very locally as extremely short half life Which prostaglandin? Particular prostaglandin produced depends on the cell type Platelets produce Thromboxane A2 which acts on the platelets themselves and the vascular smooth muscle to cause platelet aggregation and vasoconstriction Vascular smooth muscle produces PGI2 which prevents the platelets from sticking and causes vasorelaxation
	What are leukotrienes?	Eicosanoids Certain cells associated with production PMNL (polymorphonuclear leukocytes) Mast Cell Macrophage
	How are leukotrienes synthesized?	AA within cell wall PLA2 and trigger activates and releases AA FLAP = 5 lipooxygenase activator protein
	What are the mechanisms of action and effects of leukotrienes?	Effects mediated through GPCR 4 Receptors identified to date Not all effects of leukotrienes have been elucidated
	Which drugs modify the PGs and LTs?	Prostaglandin production NSAIDs target teh COX enzyme COX isofroms COX-1 and COX-2 COX-1 homeostasis COX-2 inflammation COXIBs designed to be COX-2 selective These drugs are widely used in Vet Med Anti-inflammatory, analgesic and antipyretic 5-Lipoxygenase inhibitors and receptor antagonist Used to manage asthma (non-responders) Use in Vet Med largely unexplored
	What is histamine?	Biogenic amine Involved in: inflammation-acute mainly; anaphylaxis; allergies; drug reactions; gastric secretion; neurotransmission Has its effect via H1-4 receptors There are species differences but in general histamine causes: smooth muscle contraction of bronchi, gut, and large vessels; smooth muscle relaxation in small arterioles (significant fall in BP); increased vascular permeability; increased secretion of gastric acid
	How is histamine produced?	Widely distributed in bodies - high levels in goats and rabbits, relatively lower levels in horse, dog, cat, and humans Histidine goes to histamine in the presence of the enzyme L-histidine decarboxylase CNS neurons, gastric mucosa, parietal cells, and lymphocytes also produce histamine
	How is histamine stored?	Mast cell is the main storage site for histamine-basophil in the blood - concentration particularly high in tissues with high concentrations of mast cells (skin, bronchial, and intestinal mucosa) Histamine in mast cells synthesized slowly and stored - turnover is slow and depletion can occur (mast cell pool is the one that participate in inflammation allergic reactions, drug reactions) Other sites of histamine production have a much more rapid turnover (ex. of this site includes gastric mucosa and gastric acid production control)
	What are the effects after histamine is released?	There are species differences Carnivores - hypotension Rabbits - bronchoconstriction and right heart dilation Guinea pigs - bronchoconstriction and asphyxiation Right heart is a thin muscles which is a low pressure system Bronchoconstriction increases BP in lungs, causing increased pressure that R heart cannot cope, leading to R heart failure
	How is histamine released from its storage granules?	Antigen reacts with IgE on mast cell surface This causes an increase in intracellular Ca2+ This causes a release of complexed histamine (an active process) This releases histamine from the granules. Causes anaphylaxis and allergy
	How do drugs and other chemicals effect histamine?	Certain drugs may cause direct degranulation and release of histamine from mast cells Neuromuscular blocking agents Pethidine Codeine Polypeptide antibiotics (polymixin) Endogenous mediators such as bradykinin, kallidin, and substance P
	How does histamine respond to physical injury?	Example of scraping/scratching the surface of the skin Redness, urtication due to the local release of histamine Causes "triple response": redness to swelling/wheal to flare
	What are the receptor subtypes and system effects of histamine?	Designation/delineation of the specific effects of histamine to a specific receptor subtype is difficult Cardiovascular System Traditionally considered to by H1 but at higher doses/amounts H2 receptor also involved Generally constriction of large vessels Dilation of arterioles and microcirculation Species variation (rabbits - pressor effects dominate v.s. carnivores where vasodialtion of microcirculation is the dominant effect) Respiratory Bronchoconstriction - guinea pigs especially sensitive Tracheal relaxation in cats Bronchial relaxation in sheep (H2 mediated) Intestinal smooth muscle Generally contracted Uterine smooth muscle generally contracted (except rat) Exocrine glands Gastric acid secretion mediated by H2 receptors Other system effects Increased vascular permeability - associated with phophorylation (by histamine) of an intercellular adhesion molecule called cadherin; leads to gaps between the vascular endothelial cells Effects on other leucocytes - histamine may trigger the release of cytokines and other inflammatory mediators
	How do H1 and H2 receptors work? What type of receptors are they?	H1 GPCR - G protein coupled receptor coupled to phosphlipase C resulting in increased intracellular calcium H2 Also GPCR - seems to be linked in this case to activation of adenylyl cyclase and increases in cAMP
	What does a GPCR look like?
	How does a GPCR effect calcium levels?
	What is the effect of histamine on chronic inflammation?	Histamine can affect the function of macropahges, T lymphocytes, B lymphocytes, cytokine production, expression of MHC class II antigens on cell surface
	How is histamine metabolized?
	What are anti-histamines? How are they received in the animal?	Most of the classic anti-histamines are H1 receptor antagonists They physically block the H1 receptor preventing access to histamine Distinguish from physiological antagonism Pharmacokinetics and Pharmacodynamics In monogastrics well absrobed after oral administration - not in ruminants Side effects more pronounced if givein i/v Generally more effective if given pre-emptively NB- DO NOT INHIBIT THE RELEASE OF HISTAMINE
	What is the purpose of anti-histamines?	Counteract the effects of Allergic type reactions (ex. itching) Bronchial, uterine, intestinal, and vascular effects of histamine during anaphylactic type reactions Have no effect on H2 receptor mediated effects Gastric acid secretion Some of the H2 mediated vascular effects
	What are some specific anti-histamines? What are they used for?	Diphenhyramine Cyproheptadine Chlorphenamine Levocabastine Iodoxamine Uses For CNS effects - travel anxiety Allergic conjunctivitis Feline asthma Skins? (excessive grooming in cats)
	What is Serotonin?	Serotonin = 5-hydroxytryptamine (5-HT) 5-HT derived from dietary tryptophan high levels of 5-HT in pineapples, plums, and bananas but not orally availalbe Also present in some venoms and stings Concentrated in enterochromaffin cells in the GI tract, in platelets, and in the CNS
	How is serotonin synthesized and metabolized?	Synthesis Tryptophan to 5-hydroxytryptophan to 5-HT Two steps involved are hydroxylation followed by decarboxylation Metabolism 5-HT to 5-hydroxyindolacetic acid (5-HIAA) This is catabolized by monoamine oxidase (MAO)
	What are the receptors for serotonin?	Four subgroups of receptor with additional subtypes within each family 5HT1-4 The majority are GPCRs Exception - 5HT3 is ion gated
	What are the effects of serotonin?	Platelets Platelets store but do not synthesize 5-HT Release of 5HT from the platelet promotes platelet aggregation and local vasoconstriciton and increased vascular permeability GI tract Produced and stored locally in the enterochromaffin cells - main source of 5-HT Helps control gastrointestincal function May be excitatory or inhibitory Depends on location and subtype of receptor CNS Multiple effects in the CNS affecting sleep/wake cycle, behavior, anxiety, etc. Role in Inflammation Precise pathways are poorly understood Know that it increases platelet aggregation and vascualr permeability Also plays an important role in autoimmunity (ex. rheumatoid arthritis) Experimental studies suggest that stimulation of COX-2 leading to increased production of inflammatory mediators may play an important role May be mediated by certain receptor subtypes
	How are agonists and antagoinsts of serotonin used in the clinical setting?	5HT1 agonists (such as sumatriptan) are used in the management of migraines Ondansetron (5HT3 antagonist) is used in the management of chemotherapy induced emesis SSRIs (serotonin reuptake inhibitors) are used in the management of depression - ex. fluoxetine and sertraline
	What is leukocytosis?	An increase in the concentration of leukocytes in blood. Compenstation mechanism to replace cells lost in inflammatory reactions This usually occurs with specific types of leukocyte depending on the cause of the inflammation Ex. neutrophil leukocytosis (=neutrophilia) occurs when the inflammation is caused by local bacterial or viral infection or by trauma Monocytes - monocytosis Eosinophils - eosinophilia
	What is the process the results in neutrophil leucocytosis? What happens if this process is prolonged?	In infections by pyogenic bacteria and fungi, emigration of neutrophils causes rapidly depletion of the levels of cells in the circulating blood and results in temporary neutropenia (neutrophil deficiency in the blood) Within a few hours, the release of large numbers of relatively mature cells from the reserves (in the hematopoietic tissues - bone marrow) results in a neutrophilia. This release is induced by cytokines such as IL-1, TNF-a, IL-8, and various colony stimulating factors (CSFs) synthesized by lymphocytes and macrophages in response to antigens or bacterial endotoxins. Increased production of both neutrophils and monocytes is soon required and this appears to occur in response to the further action of CSFs. If this process is prolonged, immature neutrophils are released into the blood resulting in a "shift to the left" The immature cells with differentiate into mature forms once the cells emigrate into the inflamed tissues and come in contact with CSFs produced locally. Similar mobilization of monocytes occurs resulting in monocytosis. In parasite infections, the main leukocytes involved in protection is the eosinophil. Results in eosinophilia in blood
	What are the systemic effects of acute inflammation?	Leukocytosis Induction of fever Acute phase response Anemia Septic shock
	What is pyrexia? What are its benefits? How is it induced?	Fever! Often a feature of the general response of the body in more sever inflammatory reactions Especially associated with viral, bacterial, and parasitic infections Benefits Decreased microbial replication efficiency Increased phagocytosis and killing by neutrophils and macrophages (aka increased leukocyte function) Increased antigen presentation efficiency Induction - two main ways By stimulation of macrophages by infection or microbial products. Ex. lipopolysaccharides resulting in synthesis and secretion of IL-1 and TNF-a (endogenous pyrogens). These cytokines act on the brain to induce PGE2, which causes an increase in the hypothalamic thermostat thus inducing fever. Byinteraction of microbial products with TLF on brain endothelial cells. PGE2 is induced and fever results.
	What is acute phase response? How does it differ between acute and chronic inflammation? What is its mechanism of action?	Systemic manifestation that occurs in most forms of inflammation, infection, and tissue injury Involves the induction of increased synthesis of several host proteins involved in attracting leukocytes into tissues (serum amyloid A= SAA), clearing microorganisms (C-reactive protein, complement components), blood clotting, and controlling proteases released during inflammation. Species specific and great diagnostic value - the serum concentration and the type of acute phase respnse proteins released differ in species Acute inflammation These proteins are synthesized rapidly by the liver until the infection or reaction is halted when their production return to normal. Chronic Inflammation Their production is usually elevated for long period Mechanism of Action The response is mediated by IL-6 released by activated macrophages acting on hepatocytes and initiating synthesis of the acute phase proteins and more IL-6 (autocrine mechanism)
	What is anemia? What is its mechanism of action? What happens during acute inflammation?	Transient reduction in erythrocytes in blood. Mechanism Occurs as a result of the action of inflammatory mediators on the liver, causing the liver to synthesize and secrete hepcidin Hepcidin binds a membrane bound iron transporter protein (ferroportin) on gut epithelial cells, macrophages, and hepatocytes. Hepcidin/ferroportin complex is internalized by the cells and destroyed. Ferroportin is required to transport iron from Gut epithelial cells (dietary iron) Macrophages, (iron recycled from red blood cells) Hepatocytes (iron stores) into plasma where it would normally be picked up by transferrin and taken to the bone marrow for incorporation into hemoglobin and erythocytes. Without ferroportin: no iron is released into plasma and red blood cell production is shut off. In acute inflammation, resolution of the inflammation results in hepcidin production being switched off, allowing ferroportin expression and normal iron release into plasma resumes.
	What is septic shock? What are some characteristic features of septic shock? What are its mechanisms of action? What induces septic shock? How can it be controlled?	Infection-induced syndrome characterized by a generalized inflammatory state Excessive or poorlyregualted immune response to gram -/+ bacteria, fungi, viruses, or microbial toxins. Unbalanced reaction may harm the host through a a maladaptive release of endogenously generated inflammatory compounds. Characteristic features Fever Acute phase response Metabolic acidosis, hypglycemia Increased vascular permeability/ exudate/ hemorrhage Interstitial pneumonitis Organ dysfunction Hypotensive shock Mechanisms Release of cytokines Activation of neutrophils, monocytes, and microvascular endothelial cells Activation of neuroendocrine reflexes and plasma protein cascade systems (complement system, intrinsic and extrinsic pathways of coagulation, and the fibrinolytic system) Reaction progresses from sepsis and septic shock to multiple organ dysfunction syndrome and multiple organ failure Induction Infection, which may either invade the blood stream, leading to dissemination and positive blood cultures, or proliferate locally and release various microbial products into bloodstream Generalized inflammatory response ensues characterized clinically by fever, increased heart rate, hyperventiliation, and low or high blood leukocyte counts Mediated by pro-inflammatory cytokines, lipid mediators, and other factors released by macrophages which serve to activate neutrophils, platelets, and endothelial cells This causes microthrombi and neturophil aggregations which induce tissue ischaemia due to vascular blockage (big contributor to tissue ischemia is disseminated intravascular coagulation - DIC) This results in tissue damage, resulting in multiple organ dysfunction and multiple organ failure often with fatal consequences. Also induced are fever, acute phase responses, and increased vascular dilation and permeability (this results in massive exudation and emigration of neutrophils into tissue). Control Pro-inflammatory reactions in the developing sepsis can be controlled by endogenously released glucocorticoid and other hormones as part of a stress response.
	What is disseminated intravascular coagulation?	DIC Sepsis disturbs the normal homeostatic balance between the pro coagulant pathway and the anticoagulant pathways leading to widespread thrombosis and impaired tissue perfusion This results in tissue damage, resulting in multiple organ dysfunction and multiple organ failure often with fatal consequences.
	What is hypotensive shock? How is it induced?	Lack of blood to brain The action of TNF-a on endothelial cells causes the production of nitric oxide which induces vascular smooth muscle to relax
	What are the sequelae of acute inflammation? What determines the sequelae which follow an acute inflammatory reaction?	Healing Progression to Suppuration Progression to Chronic Inflammation What follows The extent of damage caused to the tissue cells Whether the causal agent is eliminated or whether it persists and continues to cause further damage and provoke further repsosnes
	What are the two outcomes of healing sequelae?	Resolution - return to normal architecture and removal of dead cellular debris If inflammatory reaction is mild, elimination of the causes may lead to a reversal of the inflammatory changes and non-appreciable necrosis may occur. It is an active process involving not only the elimination of the cause of inflammation, but also the activation of the "resolution" program Followed by demolition and regeneration phases Repair - formation of scar tissue if inflammatory reaction is extensive Lost tissue is replaced by fibrous scar If inflammatory reaction is severe it is produced by granulation tissue
	How does the Resolution program work and lead to the healing process?	There is a switch from production of inflammatory mediators (prostaglandins and leukotrienes to lipoxins, resolvines, and protectins) These mediators actively antagonize the infiltration of neutrophils into the tissues, promote neutrophil apoptosis, and stimulate the regeneration of damaged tissue components. Phagocytosis of apoptotic neutrophils by macrophages induces the macrophages to switch from being pro-inflammatory to being pro-resolution. Macrophages coordinate the healing process
	What is the demolition phase? How does it work?	Part of healing sequelae - resolution process Clearing up process Is accompanied by reinstatement of normal permeability and blood flow within the vessels. Macrophages remove dead cells (erythrocytes, neutrophils, and tissue cells), cell debris, fibrin, lipids, hemosiderin, bacteria, and foreign material Fibrinolysis may also assist in the removal of larger masses of fibrin and the excess cells and exudate pass out of the area along the lymphatics
	What are the anti-inflammatory mediators involved in the resolution phase?	Lipoxins Fatty acid mediators Produced by the action of lipoxygenase on precursors derived from arachidonic acid Induced when the inflammatory reaction is beginning to subside Serve to switch off many of the pro-inflammatory pathways activated by the pro-inflammatory mediators Resolvines and Protectins Derived from fatty acid precursors Produced during an ongoing inflammatory reaction Serve to inhibit the inflammation and promote resolution of the inflammation Other factors Such as TGF-b Inhibit the immune responses and promote tissue regeneration
	How is the site regenerated during the healing sequelae -resolution phase?	Lost tissue is replaced by proliferation of cells of the same type Mediated by wound cytokines secreted by Mphi TGF-b, PDGF, FGF, VEGF Wound cytokines act as growth factors for: Endothelial cells Epithelial cells Smooth muscle cells Fibroblasts Original architecture is reconstructed
	What is granulation tissue?	Small, red, granular foci which bleed easily Newly formed fragile capillary blood vessels which proliferate (angiogenesis) Fibroblast proliferation New connective tissue production
	How is the site repaired during the healing sequelae - repair phase?	Proliferative response coordinated by wound cytokines produced by Mphi Tissue architecture replaced with avascular fibrous scar tissue (leads to loss of tissue function) Scar tissue remodels and contracts over time Sometimes adhesions form between internal organs
	What is fibrosis?	Sign of connective tissue replacement of function tissue Occurs with serious protein exudates, lots of fibrin exudation from plasma, and areas where the exudate cannot be adequate absorbed.
	What is suppuration?	Pus formation Caused by pyogenic bacteria that resist uptake or destruction Caused by the production of potent toxins which damage severely both the tissue cells at the site (causing necrosis) and the adjoining vessels (causing massive leakage of exudate and often thrombosis and stasis) Can also follow the local action of irritant chemicals which can cause substantial tissue necrosis and vascular damage Characterized by an intense and prolonged neutrophil emigration resulting in the accumulation of large numbers of these cells in the tissues at the site of damage. Following emigration, neutrophils have a lifespand of 24 hrs But, because of the concentration of bacterial toxins in the area and the effects other impaired circulation (causing anoxia and acidosis) many of the neutrophils are killed before the end of their lifespan They release their lysosomal enzymes which digest and liquefy the dead cells and tissue framework
	How is an abscess formed?	Liquefaction (caused by dead neutrophils) results in the formation of a potential space (the abscess cavity) at the center of the lesion which is filled with highly cellular fluid exudate (pus) composing mainly of dead and dying neutrophils with necrotic tissue cells ,debris, fibrin, erythocytes, and bacteria. The conditions in the cavity favors continued multiplication of the bacteria and further toxin production and the resultant release of inflammatory mediators (C5a, LTB4, bacterial toxins) is responsible for continued emigration of neutrophils. The accumulation of dead cells, digested cell and tissue debris, and plasma proteins within the abscess cavity tends to raise the osmotic pressure of the contents as compared with that of the adjoining tissues resulting in further movement of fluid into the abscess. This process is accentuated by the inadequacy or absence of lymphatic drainage from the cavity. The hydrostatic pressure within the cavity rises rapidly and because of this, the cavity enlarges and extends along tissue planes in the direction of least resistance The parenchymatous cells in the tissue around the cavity undergo atrophy as a result of the increase in pressure and the diffusion of toxins, while the stromal tissue becomes condensed forming the beginnings of a capsule This condensation is soon reinforced by fibroblast proliferation and the laying down of new collagen fibers, and the formation of new blood vessels (angiogenesis). Within the tissue, the rising pressure in the direction of least peripheral resistance continues to cause degrees of ischemia with atrophy or necrosis and the abscess is said to "point" to a surface Once this process reaches the final layer of the overlying epidermis, epithelium, or mesothelium, the effects of the ischemia soon result in necrosis and rupture of the membrane and the abscess discharges its purulent contents through the opening onto the free surface
	What is a sinus track?	Where the site of surface discharge is at some distance from the original abscess cavity, the tube-like connecting track is called a "sinus track"
	How does the direction of abscess pointing impact healing?	Gravitational pointing Drainage of its contents and elimination of bacterial infection is usually prompt and effective Clears the way for the process of repair to fill in the now empty cavity Anti-gravitational Only a proportion of the abscess contents may be discharged over the sinus track opening Owing to the persistnec of infection within the cavity, the whole process may then recur and sometimes this may take place several times over Externally- end infection Internally - spread infection
	What is granulation tissue? Describe the encapsulation process.	If the growth of bacteria is checked during the development of the abscess, (either by natural defenses or with the help of antibiotic drugs) the abscess will stop enlarging and the accumulated pus will become enclosed by a layer of new cellular and vascular tissue - granulation tissue Encapsulation Process A pyogenic membrane will form around the exudate. As the new tissue matures, it becomes a support tissue with many collagen fibers being formed with in It is gradually transformed into a relatively acellular and avascular fibrous tissue capsule New granulation tissue continues to be formed on the inner face of the capsule but because of the stretching effect of the pressure of the purulent exudate, the volume of the cavity may not become reduced This innermost layer of granulation tissue is vascular and cellular, with continuing emigration of neturophls and accumulation of macrophges, while further out in the capsule there may by prominent aggregation of lymphocytes and plasma cells Such encapsulated abscess may persist for many months and even years and with the elimination of bacterial infection, the purulent exudate may slowly become transformed either into a clear fluid resulting in a cyst like structure or with the resorption of water, the contents may become inspissated (firm, cheesy, granular, and even calcified)
	How do abscess heal?	Initiated by granulation tissue - angiogenesis, fibroblast proliferation, leukocyte filtration (Mphi) Mphi secret TGF-b, PDGF, FGF, VEGF New connective tissue secrete by fibrobalsts By resolution if abscess is small By repair if abscess is large (avascular scar tissue)
	How does an injury progress to chronic inflammation? How does the nature of the causal agent impact response?	When tissue injury is due to: Prolonged or repeated action of a low-grade irritant The causal agent fails to be eliminated during the acute phase of their inflammatory reaction and persists The features of the reaction become altered Proliferative changes resembling attempts at repair occur Formation of substantial amounts of vascular granulation tissue (which matures to fibrous tissue) then dominates the lesion. Some chemical agents give rise to prolonged low-grade irritation Leading to proliferative changes with increasing fibrosis There may be little or no acute exudate phase Other agents- particularly some bacteria and fungi (which persist as large aggregated colonies)- give rise to lesions in which acute suppurative inflammation occurs inn the immediate vicinity of the colonizing pathogens
	What is the mechanism that allows acute inflammation to develop into chronic inflammation?	Thought to involve chronic production of IL-6 in the acute phase response. A complex of IL-6 and shed IL-6 receptors can activate local endothelial cells and local macrophages to release MCP-1 MCP-1 continually attracts more monocyte/macrophages into the tissues These cells contribute to the IL-6 production on activation and set the scene for ensuing chronic inflammation.
	What is chronic inflammation?	Definition: immune reactions of prolonged duration (weeks to months to years) in which active inflammation, tissue injury, and healing proceed simultaneously. Associated with: The persistence of an irritant substance or infection or of an antigen (autoimmune). Prolonged continuation of acute inflammation Transition from neutorphil dominance to mixed infiltrate of neutorphils and mononuclear cells Slow moving, harmful induction of chronic inflammation process (most forms) Some infections may initiate chronic inflammatory reactions without a prior acute inflammatory reaction.
	What are the dominant leukocytes in chronic inflammation?	Tend to be lymphocytes and macrophage, though neutrophils persist in some forms as for example in chronic abscesses.
	How do mononuclear cells migrate into tissues?	Lymphocytes adhere to endothelia through E selectin expressed by endothelial cells and VLA4 expressed by lymphocytes. (Only lymphocytes that have been recently activated by antigen in lymph nodes will express VLA4 and so are of the memory phenotype.) Chemokines such as IL-8 and RANTES induce lymphocytes to express the adhesive form of LFA-1 and so bind to ICAM-1 on endothelial cells. They then migrate into tissues and follow chemokine gradients to the source of the inflammation. During the inflammatory reaction IL-6 and soluble IL-6 receptor are released and form and IL-6/sIL-6R complex which can bind to a signalling receptor (called gp130) on the membranes of macrophages and endothelial cells resulting in production of MCP-1. MCP-1 acts as a chemokine for more lymphocytes and monocytes to enter the tissues, hence initiating the chronic inflammatory process.
	What are the cellular events of chronic inflammation?	Mphi and DC present antigen to T cells T helper cells become activated and secrete cytokines (IFN-y, IL-4, IL-6) T helper cells activate B cells (IL-4) and cytotoxic T lymphocytes (IFN-y) Plasma cells secrete antibodies locally Facilitates Ag/Ab complex formation and Ag removal by Mphi (Mph become activated) Target infected cells for killing via ADC by Mphi and NK cells Cytotoxic T cells and NK cells kill infected cells IGN-y secreted by T cells and NK cells is pro-inflammatory Promotes lymphocyte/monocyte migration through endothelia Activates Mphi - increasing intracellular killing; increasing IL1-b, TNF-a, IL-6, and CSFs; increasing PG and LT
	What are the characteristic features of most types of chronic inflammation?	Dense cellular infiltration and proliferation of lymphocytes and macrophages rather than exudation Begins as a cuffing reaction around blood vessels Progresses to a diffuse infiltration pattern Local lymphoproliferation takes place, which greatly increases lymphocytes numbers In some cases, lymphoid aggregates resembling the lymphoid follicles and germinal centers of lymph nodes occur Granulomas (tight collection of Mphi) The tissue becomes thickened Angiogenesis Epithelial cells and fibroblasts Local stromal cells are also induced to proliferate under the action of cytokines and growth factors
	What are granulomas?	Granulation tissue may occur and in some cases granulomas may develop. Granulomas consist of aggregation of T cells and macrophages. The macrophages may differentiate into epitheloid cells, which appear to function as secreting cells, or they may fuse to form "giant cells". Granulomas may develop a surrounding fibrous wall, presumably to prevent spread of any pathogens contained within the structure. These structures may become necrotic through a process called caseation. Healing will usually be by repair with resultant scarring/fibrosis
	What are giant cells?	Giant cells may contain up to 200 nuclei due to fusion of macropahges. Their function is unknown, though they are thought to be more efficient than macrophages at clearing infection.
	What happens during a foreign body response? What are the monocellular functional pathway in response to a foreign body?	The reaction is mediated mainly by macrophage, since the irritant material is not antigenic (for example silica or asbestos) However, lymphocytes are also involved through the action of pro-inflammatory cytokines. Granulomas can form around the foreign body The persistent nature of such irritant materials results in persistent activation of macrophages and lymphocytes, and leads to widespread scarring
	How is tissue damage mediated in chronic infections?	The tissue damage is often mediated by macrophage and T cell cytotoxic reactions, but can involve humoral immune responses. However, in some infection and some types of autoimmune disease, tissue damage is mediated by long-term production of auto-antibodies (Type II hypersensitivity) or antigen/antibody complexes (Type III hypersensitivity) via complement activation and involvement of neutorphils predominantly.
	What are the systemic manifestations of chronic inflammation?	Leukocytosis Chronic inflammation results in increased production of cytokines (IL-1, TNF-a, IL-8) These stimulate the bone marrow to produce and release lymphocytes and monocytes into the blood Higher concentrations gives rise to lymphocytosis, monosytosis, eosinophilia, or neutrophilia Pyrexia Fever can occur in chronic inflammatory conditions But it tends to be low grade in comparison to acute inflammation Acute Phase Response Systemic reaction can be elevated for prolonged periods of time The same acute phase proteins are produced by the liver as discussed in acute inflammation Cachexia Wasting Chronic weight loss is common in chronic inflammatory disease Mediated by continual production of TNF-a TNF-a causes skeletal muscle breakdown and fat resorption by inhibiting adipose cell differentiation and enzymes involved in lipogenesis Induces anorexia Anemia Chronic production of IL-6 results in hepatocytes producing hepcidin which causes destruction of ferroportin Plasma iron levels drop resulting in decrease hemoglobin and erythocytes Observed in many disease such as chronic infection, autoimmune disease, and cancer Amyloidosis Can occur as a primary disease or secondary to certain type of chronic infection of disease (TB or rheumatoid arthritis) In primary amyloidosis - the host protein involved is immunoglobulin light chain (deposition of light chain or light chain fragments in tissues - usually heart, tongue, alimentary tract, and skin) In secondary, several host proteins have been implicated, but the main on is serum amyloid A (SAA) protein with serum amyloid P protein constituting a minor component. (Deposition of SAA fragments in liver, kidney, spleen, and adrenals) All amyloid-forming proteins appear to require proteolytic processing before they adopt the characteristic beta-sheet polymer structure of the tissue deposits Amyloid deposits appear to be resistant to proteolytic breakdown and so deposition is cumulative in chronic disease The deposits interfere with normal tissue function can be life threatening (cell death due to compression and induce inflammation) It is thought that secondary amyloidosis might be mediated by a prolonged acute phase response in response to continued production of excess IL-6
	What are hypersensitivity diseases?	Inflammation and injury mediated by the immune system Inappropriate reaction to antigens by the immune system - cause tissue injury and disease Immune reactions are controlled inadequately Reactions target the host tissue Caused by humoral or cell mediated immune mechanisms
	What are some general characteristics of hypersensitivity reactions?	Sensitation Phase Previous exposure to an antigen Development of a specific immune response against that particular antigen Effector Phase Pathology associated with hypersenstivity
	What are the four types of hypersensitivity reactions? What are they mediated by?	Type I - mediated by IgE antibodies Type II - mediated by IgG or IgM antibodies Type III - mediated by Ag/Ab complexes (IgG or IgM Ab) Type IV - mediated by antigen-specific T cells and macrophages (Th1 cells, Th2 cells, cytotoxic CD8+ T cells)
	What is Type I Hypersensitivity? What are the different types of Type I? What are general causes of Type I?	Immediate anaphylactic reactions Form of acute inflammatory reaction mediated by IgE antibodies Occur within 15-20 min of antigen or allergen exposure Mediated via interaction of the allergen with IgE antibodies bout to tissue mast cells (local anayphylaxis) or blood basophils (general anaphylacis) causing the release of soluble mediators Types of Type I Genetically predisposed to make high levels of IgE antibodies (=atopic); often inherited Not genetically predisposed but are subject to repeated exposure to the allergen (=non-atopic) Typical allergens: Pollens Insect bites/stings/feces Animal danders Food Components (Eggs, shellfish, milk) Drugs Endoparasites
	How do genetic mechanisms regulate Type I responses?	They regulate: Total IgE levels Allergen-specific IgE responses General hyper-responsivenss
	Give examples of Type I atopic allergies.	Atopic dermatitis (eczema) Allergic rhinits (hay fever or seasonal and year-round or perennial symptoms) Allergic asthma Food allergy
	What is general or systemic anaphylaxis? What organs are commonly effected?	A condition that occurs relatively rarely, but is often fatal Shock reaction due to bronchoconstriction, contraction of smooth muscle, and increase in vascular permeability Involves mast cells and basophils Shock organs Lungs - horses and cattle GI tract - dogs Heart -rabbits
	What is local anaphylaxis? What are common causes of local anaphylaxis?	Operates via the binding of the allergen to IgE antibodies on the surface of mast cells or basophils resulting in degranulation Mechanism The release of histamine results in vascular permeability changes or smooth muscle spasm causing the clinical signs of acute inflammation (edema, bronchoconstriction) Eosinophils attracted to the site by LTB4 Eosinophils recognize IgE/allergen complexes via IgE Fc receptors, then degranulate to release more mediators (major basic protein, peroxidase) which damage cells Activated mast cells and eosinophils synthesize PGs and LTs are responsible for the late phase Type I reaction. Common causes Hay fever (rhinits, conjunctivitis) Allergic asthma (bronchospasm) Skin rashes (eczema, dermatitis) GI tract (vomiting, diarrhea)
	What is the mechanism for Type I hypersensitivity?
	What is the role of eosinophils in Type I hypersensitivity?
	What is the difference between immediate and late phase responses to allergic reactions?	Immediate 15-20 min Vascular dilation Vascular permeability changes Contraction of smooth muscle Mediated by histamine Late 2-8 hours Vascular dilation Vascular permeability changes Contraction of smooth muscle LTC4, LTD4, LTE4 Mediated by leukotriens, cytokines, and chemokines
	What is Type II Hypersensitivity? What are the 4 main modes of cell destruction?	Cytotoxic Caused by antibodies which react with cell surface antigens or haptens Host cell damage by IgG or IgM Abs directed against cell surface Ags or chemicals attached to cell surface proteins (drugs) There is genetic susceptibility to autoimmunity or reactivity to particular drugs 4 main modes of cell destruction Phagocytosis of antibody-coated (or opsonized) cells by liver, splenic, or tissue macrophages Complement-mediated lysis of antibody-coated cells Antibody-dependent cell-mediated cytotoxicity (ADCC) by killer cells Surface receptor endocytosis or down regulation (e.g. hemolytic anemias, autoimmune thyroid disease, myasthenia gravis)
	What is the mechanism for Type II Hypersensitivity via opsonization by IgG Abs?
	What is the mechanism for Type II Hypersensitivity via opsonization or lysis by complement (IgG and IgM)?
	What is the mechanism for Type II Hypersensitivity via ADCC (IgG)?
	What is the mechanism for Type II Hypersensitivity via receptor blockade/removal?
	What is Type III Hypersensitivity?	Immune Complex Disease Basis is combination of soluble antigen with circulating IgG or IgM antibodies to form "immune complexes" Source of the antigen is either an infectious agent or is host derived The immune complexes either form in the blood and get deposited in blood vessel walls and underlying tissues or are formed locally in blood vessel and tissues (in which case the reaction is called an Arthus reaction) In both cases, the blood vessels are inflamed and damaged Produces characteristic lesions (=vasculitis) often affecting the vessels of the kidneys, joints, skin, and heart Tends to occur in individuals who mount weak Ab response or make low affinity Abs This type of reaction occurs with certain types of chronic infection and in some autoimmune diseases.
	What is the pathogenesis of Type III Hypersensitivity?	Immune complexes bind to Fc gamma receptors on tissue macrophages Activate these cells to synthesize cytokines which attract neutrophils These cells phagocytoze the immune complexes and release proteolytic enzymes These enzymes damage cells and vessels causing a hemorrhagic edematous reaction which leads to necrosis
	What are the different types of Type III Hypersensitivity?	Examples of extrinsic IC disease: Chronic obstructive pulmonary disease (COPD) in horse caused by exposure to dusty stable air and poor-quality hay Serum sickness - use of anti-sera for passive immunisation
	What determines where the immune complex ( of Type III Hypersensitivity) will be deposited?	Hemodynamic Process Blood Filtration High Pressure Turbulence Antigen/antibody ratio Slight antigen excess gives small ICs Small IC more likely to persist in circulation
	What is the mechanism that causes an Arthus reaction?	Immune complex forms in tissues Complement fixation Mast cell degranulation Neutrophil degranulation Vasculitis (reaction peaks around 6 hours)
	What is Type IV Hypersensitivity? What are the different types of Type IV? What causes Type IV?	Cell Mediated Delayed Type Hypersensitivity or DTF When injected into the skin, some antigens induce a slowly developing inflammatory response Mediated by T cells and Mphi Infections are eliminated via T cell cytotoxic action and activation of macrophages DTH reactions are due to an inflammatory response which develops in sensitized individuals 24-48 hours after contact with antigen. Types of DTH reactions Jones Mote (cutaneous basophil hypersnesitivity) Contact sensitivity Tuberculin reaction Granuloma formation Causes: Bacteria Viruses Fungi Contact with simple chemicals (nickle, dyes)
	What is the mechanism for Type IV Hypersensitivity?	Illustrated by the tuberculin reaction Tuberculin injected intradermally into a sensitized animal gives rise to an eryhtematous and indurated lesion 24-48 hours later Reaction is due to the activation of tuberculin-specific T cells which release lymphokines that attract macropahges and more lymphocytes and retain them at the injection site Other lymphokines such as IFN-y activate the macropahges, which then adopt an aggressive killing function The lesion progresses with ischemia due to the intense infiltration by lympohocytes and macrophages and tissue damage due to the actions of mediators released by activated macorphages (IL-1, TNF-a)
	What happens in chronic Type IV Hypersensitivity reactions?	Due to persistent infection Lesion may progress with the development of epitheloid cells and giant cells from the pool of activated macrophages These cell types (along with the T cells) are involved in killing infected cells and causing an area of caseous necrosis at the center of reaction If the infectious organism is killed then the lesion is repaired by fibrosis If not, then the area of caseous necrosis is walled off by connective tissue secreted by the granulation reaction The ensuing granuloma may eventually result in killing the microorganism In some cases, the lesion can become calcified (=mineralization), while in others liquefaction occurs (due to proteolytic enzymes results in bursting of the tubercles) thus enabling live bacteria to escape and spread

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