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163 Cards in this Set
- Front
- Back
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Edema and high neutrophils are characteristic of what inflammation (acute or chronic)?
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acute
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3 major components of acute inflammation
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increase in blood flow, changes to vascular walls to increase permeability, plasma proteins and leukocytes leave blood/enter connective tissue to work
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What are some stimuli for acute inflammation?
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Infections, tissue necrosis, foreign bodies, immune response
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Why do auto-immune diseases lead to chronic inflammation?
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the stimulus for inflammation cannot be removed. the stimulus in the case of auto-immune disease is the patient's own tissues
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Why is it important that vascular membranes become permeable during an inflammatory response?
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The leukocytes must be able to enter the connective tissue from the blood
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What is exudate?
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extravascular fluid with high protein concentration, cellular debris; denotes increased membrane permeability in vasculature
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What is more characteristic of an inflammatory response, exudate or transudate?
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exudate. exudate has more plasma proteins, leukocytes and debris in it. transudate refers to mostly water
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What is transudate?
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extravascular fluid with little protein concentration; denotes fluid permeability in vasculature
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Which can lead to edema? Accumulation of exudate or transudate?
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Both cause edema, but have different causes
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What is pus? Is is exudate or transudate?
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extravascular fluid rich in leukocytes (neutrophils) and microbe debris after inflammation; exudate
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What major changes occur regarding blood vessels during acute inflammation?
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vasodilation, increased endothelial permeability, loss of colloid pressure, leukocytes adhere to endothelium
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What are 2 major mediators of vasodilation during acute inflammatory response?
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histamine and nitric oxide work on smooth muscle to vasodilate
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What is erythema? What causes it during inflammation?
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redness of skin; caused by vasodilation and increased blood flow to the inflamed area
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What is "stasis" referring to during an acute inflammatory reaction?
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as fluid leaves the blood vessels (after membrane permeability increases) and RBCs accumulate (increase viscosity), blood flow slows down
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Vascular permeability is key in inflammation. What are some mechanisms that occur to let neutrophils out of the vessels?
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retraction of the endothelium (caused by histamine/NO), neutrophils or microbes injure the endothelium, transcytosis
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One mechanism to let neutrophils out of blood vessels (into the extravascular tissue fluid) involves retraction of the endothelium. What chemicals directly stimulate this?
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histamine, nitric oxide
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What mechanism of increasing endothelial permeability is the fastest acting? (retraction, injury, transcytosis)
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retraction occurs quickly (within minutes)
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Sunburn leads to what type of increased vascular permeability?
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delayed prolonged leakage during retraction of endothelial cells
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An increase in VEGF levels would indicate what mechanism of vascular permeability?
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transcytosis; VEGF increase the size and # of channels in the endothelial cells, allowing more leukocytes to migrate through the cells
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In the process of transcytosis, during acute inflammation, how are leukocytes entering the tissue fluid?
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they are moving through the endothelial cells via channels
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Why is it important that lymphatics also dilate during inflammation?
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lymph system is responsible for draining the tissue fluids, which accumulate during inflammatory edema
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What is lymphangitis?
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inflammation of lymphatics
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What is lympadenitis?
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inflammation of lymph nodes; due to hyperplasia during acute inflammation elsewhere since we are making more immune cells
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What is extravasation?
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process of moving leukocytes from blood vessel lumen to the extravascular tissue fluid
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During acute inflammation, what is the process of margination?
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The movement of WBCs to a peripheral location in the blood vessel. more WBC can move towards the "margin" due to stasis (slowing of blood flow, due to decreased plasma volume). this is the 1st step in getting the leukocytes out of the vessel
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When leukocytes leave the blood vessel, where do they go?
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they enter the tissue fluid and move towards a chemotactic stimulus
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"Rolling" of leukocytes on the endothelium is mediated by what proteins?
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selectins
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3 types of selectins and on what cells are they expressed?
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L-selectin (leukocytes), E-selectin (endothelium), P-selectin (platelets and endothelium)
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On what cells are P-selectin expressed?
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platelets and endothelial cells
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Expression of selectin proteins is regulated by ...
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cytokines
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How do histamine, thrombin and platelet activating factor (PAF) support the binding of leukocytes to the endothelial walls?
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stimulate redistribution of P-selectin from intracellular Weibel-Palade bodies to surface proteins that leukocytes can now bind to
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L-selectin on leukocytes serve as a ligand to what receptors on the endothelial surface?
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E-selectin and P-selectin
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What is the purpose of the weak selectin interactions leading to leukocyte "rolling"?
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to slow down the leukocytes until they bind to high-affinity receptors (integrins)
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High-affinity binding of leukocytes to endothelium is mediated by what proteins?
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integrins
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How do chemokines support the binding of leukocytes to the endothelial walls?
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chemokines increase avidity of integrins on the leukocyte. integrins are responsible for the high-affinity binding of leukocytes to endothelium
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Which interaction is stronger? L-selectin to E-selectin or integrin to ICAM-1?
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intergrins binding to ICAM-1 are responsible for securing the leukocytes to the endothelial wall. selectins are low affinity interactions to slow the leukocyte down during rolling
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How do cytokines (TNF, IL-1) support the binding of leukocytes to the endothelial walls?
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they increase expression of selectin and integrin proteins; selectins are responsible for slowing the leukocytes down during "rolling". integrins are responsible for securing the leukocytes to endothelium
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What is ICAM-1?
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intercellular adhesion molecule. binds integrins expressed on leukocytes to secure the leukocyte to the endothelium before moving into the tissue fluid
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Chemokines "activate" leukocytes by expressing what integrins in a high-affinity state?
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VLA-1 and LFA-1
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What is diapedesis?
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Migration of the leukocytes between the endothelium
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During diapedesis, leukocytes use what enzymes to pierce the basement membrane?
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collagenases
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Once in the extravascular tissue fluid, leukocytes are retained where they are needed by binding what proteins?
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integrins and CD44
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What is sialyl-Lewis X-modified glycoprotein?
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L-selectin on the leukocyte that binds to E or P selectin on the endothelium
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In a patient with leukocyte adhesion deficit type 1, why can they not bind leukocytes?
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deficit in synthesis of LFA-1 and MAC-1 integrins; no stable,high-affinity binding of leukocyte to endothelium
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In a patient with leukocyte adhesion deficit type 2, why can they not bind leukocytes?
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defect in fucosyl transferase leads to poor sialyl-Lewis X protein (contains fucose); leads to poor rolling
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Most common exogenous agents acting as chemotactic agents?
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bacterial products
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Most common endogenous agents acting as chemotactic agents?
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cytokines, C5a, Leukotriene B4 (Arachodonic acid metabolite)
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The process of chemotaxis uses what biochemical signaling mechanism to activate actin?
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G-protein/cAMP mechanism
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Why are neutrophils the usually the first to scene of inflammation?
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higher # in blood, respond quickly to chemokines, better attachment to selectins
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In chronic inflammation, would we expect higher levels of neutrophils or monocytes?
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monocytes. neutrophils are short-lived for quick responses (acute)
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Successful treatment for chronic inflammation blocks what cytokine?
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TNF (tumor necrosis factor)
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Once leukocytes have arrived at the site of inflammation, leukocytes use what receptors to recognize external stimuli?
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toll-like receptors (TLR), G-protein receptors, opsonin receptors, cytokine receptors
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What is opsonization?
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process of opsonins coating foreign particles with antibodies to mark them for destruction
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What are opsonins?
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substances that coat the foreign particles and signal them for leukocyte destruction (antibodies, lectins, complement proteins)
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Bacterial infection with elevated levels of LPS would likely activate which leukocyte membrane receptors?
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Toll-like receptors respond to LPS (lipopolysaccharides) or endotoxins
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Bacterial infection with elevated levels of short bacterial peptides would likely activate which leukocyte membrane receptors?
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G-protein receptors
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What is the function of lectins in the inflammatory response?
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serve as opsonins that bind to foreign particles and signal them for destruction by leukocytes
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Bacterial infection with elevated levels of interferons would likely activate which leukocyte membrane receptors?
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cytokine receptors
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During phagocytosis, scavenger receptors bind to ...
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LDL particles or microbes
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Why does it make sense that the same signals that trigger chemotaxis also trigger phagocytosis?
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both rely on polymerization of actin
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Why does pinocytosis not need actin polymerization?
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uses clatharin-coated vesicles, don't need actin polymerization
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What is the "respiratory burst" in neutrophils?
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increase in reactive oxygen species in the phagolysosome by phagocyte oxidase activity; accompanied by phagocytosis
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Since H2O2 cannot kill microbes, what enzyme in azurophilic granules converts H2O2 into ClO*?
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myeloperoxidase
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What is the most efficient bactericidal system of neutrophils?
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Halogenation of microbes using ClO* (hypochlorite) created by myeloperoxidase in azurophilic granules of neutrophils
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What enzyme converts arginine into NO (nitric oxide)?
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NOS (nitric oxide synthase)
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How does nitric oxide contribute to phagocytosis in the lysosome?
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NO reacts with O2* to create very dangerous peroxynitrite (ONOO*)
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Why will a patient with defective nitric oxide synthase be more likely to get infections?
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they will be making less NO = less peroxynitrite (ONOO*) = less ability to kill microbes
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Why will a patient with defective phagocyte oxidase (NADPH oxidase) be more likely to get infections?
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they cannot create reactive oxygen species and will have a lesser ability to kill microbes
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A "classically" activated macrophage serves what purpose?
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inflammation, phagocytosis
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What types of molecules stimulate a macrophage to become "classically" activated?
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T-cell cytokines (interferons) or bacterial products (TLR ligands, LPS)
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An "alternatively" activated macrophage serves what purpose?
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Wound repair/fibrosis, ANTI-inflammatory response
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What types of molecules stimulate a macrophage to become "alternatively" activated?
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IL-4, IL-13 (cytokines)
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What are some ways leukocytes can end up being damaging to humans?
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prolonged host response, collateral damage to normal cells, auto-immune disease, excessive response
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What is "frustrated phagocytosis"?
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If a leukocyte is unable to degrade a cell by traditional phagocytosis, it will release its reactive species (lysosomal enzymes) into the extracellular environment
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Why are urate crystals in the extracellular space dangerous to a patient under going inflammation?
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urate crystals can rupture the phagolysosome membrane and cause lysosomal granules to be released into the tissue (contains very reactive species)
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Where might "frustrated phagocytosis" occur?
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Areas where the leukocyte cannot adequately surround the target for phagocytosis; against a wall like in the glomerular basement membrane
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What is Chediak-Higashi syndrome?
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defective fusion of phagosomes and lysosomes during phagocytosis due to poor lysosomal trafficking (defective LYST gene); increased risk of prolonged infection
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How is Chediak-Higashi syndrome inherited?
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autosomal-recessive
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Why do patients with chronic granulomatous disease have recurrent infections?
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defects in phagocyte oxidase means they cannot degrade microbial agents
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Why does bone marrow suppression lead to recurrent infection?
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bone marrow suppressed = leukocyte production suppressed
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TGF-B, resolvins, protectins all work to ...
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shut off inflammatory response
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5 characteristics of inflammatory mediators
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derived from plasma proteins, respond to varying stimuli, can stimulate other mediators, work on various targets, short-lived
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Where is histamine found in greatest abundance?
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in mast cells in connective tissue near blood vessels (histamine is vasodilator)
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Histamine function
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vasodilation and increase endothelium permeability to leukocytes
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What is the function of serotonin in the inflammatory response?
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vasodilator
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Where is serotonin stored?
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platelets
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Why is there a relationship between coagulation and increased vascular permeability?
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serotonin and histamine are stored in platelets. when platelets are activated (during clotting) they release their components. histamine increases vascular permeability
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Prostaglandins and leukotrienes (eicosanoids) are derived from what compound?
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Arachidonic acid
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Prostaglandins are made by the actions of which enzymes on Arachidonic acid?
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cyclooxygenases (COX-1, COX-2)
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During a period of inflammation, which enzyme's activity is increased more? (COX-1 or COX-2)
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COX-2. COX-1 is always on, COX-2 is induced by inflammation
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Prostacyclin is written as PGI2. What does the 2 signify?
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the number of double bonds in the compound
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Arachidonic acid is a fatty acid derived from what part of the cell? What enzyme makes it?
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form the cell membrane; made by phospholipases
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What type of drugs can be given to prevent Arachidonic acid formation from the cell membrane?
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steroids
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Function of Thromboxane A2
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vasoconstriction, promote platelet aggregation
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Function of prostacyclin (PGI2)
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vasodilation, inhibit platelet aggregation
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Thrombus formation can occur due to an imbalance of which mediators of the inflammatory response?
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prostacyclin vs. thromboxane; more thromboxane = likely clot formation
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How does aspirin help relieve pain and fever?
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inhibits COX-1 and COX-2, less prostaglandins = less pain/fever
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What enzyme makes leukotrienes from Arachidonic acid?
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lipoxygenases
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How could a lack of prostacyclin synthase lead to a heart attack?
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low prostacyclin synthase = low prostacyclin = greater effect of thromboxane = more platelet aggregation/vasoconstriction = high risk of thrombus. prostacyclin and thromboxane have opposite effects and must have a balance to maintain proper clotting. if levels of prostacyclin fall too low, then thromboxane's promotion of clotting and vasoconstriction will prevail
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Why would a decrease in 12-lipoxygenase activity lead to chronic inflammatory disease?
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12-lipoxygenase creates lipoxin A and B which inhibit neutrophil adhesion and chemotaxis; if we cannot stop the chemotaxis/adhesion (defective LXA and LXB, then the inflammatory response is less regulated
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Eicosanoids (prostaglandins and leukotrienes) are made by what 2 major classes of enzymes?
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cyclooxygenases (for prostaglandins) and lipoxygenases (for leukotrienes)
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Which is more powerful in increasing vascular permeability? histamine or leukotrienes?
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leukotrienes
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Histamine causes vascular leakage in what types of vessels?
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venules
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Leukotrienes and histamine both increase vascular permeability, a key component of inflammation, but what functions are different?
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histamine is a vasodilator; leukotrienes vasoconstrict
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What class of compounds function to limit the recruitment of neutrophils to inflammation site?
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the lipoxins
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Why is research so involved with finding aspirins that are only COX-2 inhibitors, and don't work on COX-1?
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COX-1 is always expressed and is implicated in normal homeostatic function, whereas COX-2 is really the problem during inflammation. want to limit the collateral damage
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What dangers have been seen with aspirins that are only COX-2 inhibitors?
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COX-1 is still available to make thromboxanes, and COX-2 cannot make prostacyclin now that the drug has limited it. thromboxane's clotting function will not be regulated by prostacyclin any longer. high risk of heart attack/clotting
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Why are lipoxygenase inhibitors useful in treating asthma?
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leukotrienes can cause bronchospasm. less lipoxygenase = less leukotrienes = less bronchospasm
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Why are fish oils useful in patients with chronic inflammation?
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fish oils are a poor substrate for COX and lipoxygenase enzymes, so we have less promoters of inflammation. fish oils are a good substrate to create resolvins/protectins that decrease inflammation
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How does platelet activating factor (PAF) enhance inflammation?
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high vascular permeability (10,000x histamine). more adhesion, chemotaxis, and degranulation also
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Aside from creating reactive species, how does nitric oxide enhance the inflammatory response?
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vasodilation
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Nitric oxide helps inflammation in many ways, but how does nitric oxide inhibit inflammation?
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inhibit leukocyte recruitment, less platelet binding
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What is "endothelial activation"?
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expression of leukocyte binding proteins on the endothelium; activated by TNF, IL-1 cytokines
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What is Mediterranean fever?
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auto-inflammatory syndrome; high caspase activity constantly activates IL-1
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Why do patients with chronic high levels of TNF have cachexia?
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high TNF = low appetite. patients lose weight and are anorexic
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Main function of chemokines
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serve as attractants during chemotaxis
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What group of chemokines work mostly on neutrophils?
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C-X-C chemokines
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Chemokines bind to what type of receptors?
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heptahelical G-protein receptors
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What neutrophil enzyme does α-1-antitrypsin work on?
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elastase
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Fun Fact: neuropeptides can be secreted by neurons to initiate an inflammatory response.
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substance P and neurokinin A are examples
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What triggers the "classical pathway" of C3 cleavage in the complement system?
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binding of C1 to antibody/antigen complex
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What triggers the "alternative pathway" of C3 cleavage in the complement system?
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microbial substances without antibodies (endotoxins, LPS)
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What triggers the "lectin pathway" of C3 cleavage in the complement system?
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lectin binds carbohydrates on microbe to activate C1
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What enzyme converts C3 into C3a and C3b?
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C3 convertase
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Function of C3a in the complement system of inflammation activation
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C3a activates and recruits leukocytes
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Function of C3b in the complement system of inflammation activation
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C3b stays on the microbe and acts as an opsonin to signal phagocytosis
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Function of C5a in the complement system of inflammation activation
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activate leukocyte, activate lipoxygenases, supports neutrophil chemotaxis
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What is the purpose of the complement system regarding inflammation?
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allows inflammation to be initiated by plasma proteins involved in immune response. connection between antibody binding and inflammation
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C5 becomes C5a and C5b by action of which enzyme?
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C5 convertase
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How does inflammation lead to activation of Hageman factor (XII), therefore leading to clotting?
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increased vascular permeability and exposed endothelium basement membrane create negative charged that activate factor XII
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Clotting (thrombin) engages protease activated receptors. How do these work to initiate inflammation?
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mobilize P-selectin, produce cytokines, express integrins, induce COX,
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What are kallikreins?
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proteases that activate kinins; also create C3a and C5a
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What activates prekallikrein into kallikrein?
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Factor XIIa (activated Hageman factor)
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Function of Bradykinin
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vasodilate, increase vascular permeability
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What are 2 general ways activated Hageman factor (which initiates clotting) also initiates inflammation?
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XIIa activates thrombin= protease activated receptors; XIIa activates kallikrein = bradykinin
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Why is bradykinin short-lived?
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kininase quickly kills it; ACE (angiotensin converting enzyme) also inactivates it
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Fun Fact: Kallikrein is autocatalytic. It is activated by XIIa, but kallikrein can also activate XIIa.
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redonkulous
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What is kallikrein's function in clotting?
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creates plasmin (which can also cleave C3, C5 to induce inflammation)
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What is kallikrein's function in inflammation?
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increase bradykinin, cleave C3 & C5, create plasmin (which also cleaves C3, C5)
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Activated Hageman Factor (XIIa) initiates which 4 cascades involved with inflammation?
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Kinin, Fibrinolytic, Clotting (thrombin), Complement
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What is the process of "organization" after acute inflammation?
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conversion of accumulated exudate into fibrous tissue; fibrosis
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Effusion occurs when inflammation is seen in what tissues?
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mesothelium/serous tissue; e.g. pericardium, pleura
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What are abcesses?
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localized collections of pus related inflammatory tissue
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What is an ulcer?
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local excavation/defect in an organ produced by shedding of necrotic/inflamed tissue
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What is silicosis?
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chronic inflammatory disease by accumulation of silica in lungs over long period of time
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Macrophages are dominant in which type of inflammation? (chronic or acute)
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chronic
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Kupffer cells are macrophages found in which organ?
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liver
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When do monocytes become macrophages?
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after they leave the blood vessel
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Tissue destruction is a hallmark of _____ inflammation. (chronic or acute)
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chronic; due to high macrophage power
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Aside from macrophages, what other immune cells characterize a chronic response?
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lymphocytes, plasma cells, mast cells, eosinophils
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"Immune inflammation" leads to what type of inflammation? chronic or acute?
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chronic. if the real immune system gets involved, you're fucked. macrophages are very powerful and are activated by the real immune system
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Function of plasma cells
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create antibodies
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Eosinophils are seen in immune reactions initiated by ...
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IgE (allergies) or parasites
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How do eosinophils damage host tissue in major allergic reactions?
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by releasing "major basic protein"
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How are mast cells activated?
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they bind IgE
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Macrophages can lead to tissue repair when stimulated by which specific cytokine?
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IL-4
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What is a granuloma?
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aggregation of macrophages with particles that cannot be eradicated
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Foreign body granulomas are caused by foreign bodies. What are immune granulomas caused by?
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poorly degradable material
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Tuberculosis forms what type of granuloma?
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immune
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What is the acute phase response of inflammation?
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immediate symptoms (fever etc.)
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High levels of hepcidin, as seen in acute phase of inflammation, lead to anemia. Why?
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hepcidin reduces the availibility of iron
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A "shift to the left" in the immune response refers to ....
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high level of immature neutrophils (bands) in the blood
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What is leukopenia?
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low WBC in blood
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