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169 Cards in this Set
- Front
- Back
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the holy trinity of acute inflammation
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vasodilation
increased vascular permeability leukocyte infiltration |
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stasis
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caused by increased viscosity due to loss of plasma
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six ways to increase vascular permeability
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1. detachment of cell-cell junctions due to histamine (immediate transient) and IL-1 / TNF (6 hours to 24)
2. delayed prolonged response - this begins at 2-8 hours and may last days. due to secondary cytokines or perhaps endothelial apoptosis due to uv damage 3. endothelial cell injury (burns, radiation) 4. leukocyte mediated damage 5. vesiculovacuolar organelle increases transcytosis 6. leakage from new blood vessels (w/o cell-cell yet) |
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the beta 2 integrins
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lfa-1 and mac-1
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receptor for p selectin
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sialyl lewis x
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receptor for e selectin
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sialyl lewis x
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ligand for beta 2 integrins
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lfa-1 and mac-1 bind to
ICAM-1 |
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ligand for the beta 1 integrin
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VLA-4 binds to
VCAM-1 |
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the beta 1 integrin
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VLA-4
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examples of Immunoglobulin family molecules on endothelial cells
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ICAM-1
VCAM-1 |
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histamine exposure causes redistrubtion of ____ to the endothelial cell surface
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P selectin
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IL-1 and TNF cause increased expression of __, __, and __ in endothelial cells
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ICAM1
VCAM1 E Selectin |
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in leukocytes, chemokines cause increased affinity of ___ for their ligands
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LFA-1 and Mac-1
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homotypic interaction between ___ molecules on endothelium and leukocytes mediate extravasation
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PECAM-1
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in acute inflammation, neutophils dominate in hours ___ to ___, and monocytes dominate in hours ___ to ___
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6-24;
24-48 |
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exogenous bacterial products
complement arachadonic acid breakdown produccts chemokines are all chemotactic for ____ |
neutrophils
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what are some components of leukocyte activation?
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production of cytokines
production of arachadonic acid metabolites degranulation / secretion of lysosomal enzymes increased cell adhesion molecule expression / increased affinity of integrins |
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2 major opsonins and key difference
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immunoglobulins (Fc fragment)
C3b complement is covalent! |
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scavenger receptor
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expressed on macrophages helps them recognize bacteria for phagocytosis
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major basic protein
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produced by eosinophils
works especially on parasites increases permeability to kill them |
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what do lactoferrin and defensins have in common?
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they are secreted by leukocytes to increase membrane permeability of bacteria to kill them
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how can urate crystals cause lysosomal enzyme release?
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they puncture lysosomes when engested
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chronic granulomatous disease
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reccurent bacterial infections because of a defect in the NADPH oxidase
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lad-1
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defect in the beta 2 integrins, leukocytes cant bind tightly
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lad-2
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defect in fucose metabolism, and no sialyl lewis x, leukocytes cannot roll
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chediak-higashi
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defect in vesicle trafficking
lysome cant fuse with phagosome recurrent infections also hypopigmentation |
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most common clinical cause of neutrophil deficiency?
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neutropenia - cuased by cancer chemotherapy or metastatic tumor replacing bone marrow
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what are some anti-inflammatory molecules produced to end the inflammatory response?
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tgf-beta (anti inflammatory cytokine) and lipoxins
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primary inducer of cytokines?
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MICROBIAL PRODUCTS!
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what things can activate platelets to release serotonin (and just generally activate them?)
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PAF (platelet activating factor)
ADP thrombin collagen antigen-antibody complexes |
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what activates complement in the lectin pathway
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plasma MBL
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which complement component activates arachonic acid metabolism?
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C5a
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which complement component is a powerful leukocyte chemoattractant?
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C5a
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which complement component is an opsonin?
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C3b
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2 molecules that inhbit complement activation?
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c1 inhibitor
decay activating factor |
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paroxysmal nocturnal hemoglobinuria
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defect in decay activating factor causes activation of complement -> hemolysis and anemia
your red cells "decay" |
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hereditary angioneurotic edema
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defect in c1 inhibitor -> episodic life threatening edema b/c complement gets activated
c1 inhibitor is neurotic |
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effects of bradykinin
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vasodilation
increased permeability pain |
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fibrinopeptides
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increase vascular permeability
chemotactic for leukocytes |
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how does thrombin increase leukocyte attachment to endothelium
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via PARs (dont know which cells these are on...)
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how does plasmin contribute to complement cascade
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it cleaves C3 (c3 tickover)
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transcellular biosynthesis
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occurs in leukotriene and lipoxin synth
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what produces PAF?
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MAST CELLS!!! (after an activating stimulus such as IgE activation)
and other leukocytes |
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what does PAF do?
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PAF can elicit most of signs of acute inflammation
platelet activation and release vasodilation increased vascular permeability increased leukocyte adhesion bronchoconstriction leukocyte chemotaxis IT DOES IT ALL!!! |
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the major cytokines of inflammation
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IL-1 and TNF
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what is the major source of IL1 and TNF
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activated macrophages
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systemic acute phase response
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initiated in response to IL-1 and TNF
1. fever 2. anorexia 3. lethargy 4. neutrophilia 5. release of corticotropin from pituitary and corticosteroids from adrenal 6. hemodynamic effects of septic shock (3) |
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what are the hemodynamic effects of septic shock?
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1. hypotension
2. tachycardia (brr) 3. acidosis |
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cachexia is associated with which cytokine
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tnf
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4 classes of chemokine receptors?
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CXC, CC, C, CX3C
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CXC chemokines recruit ____
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neutrophils
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IL-8 is a ____ chemokine
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CXC
recruits neutrophils |
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CC chemokines recruit ____
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all but neutrophils
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C chemokines recruit _____
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lymphocytes
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a C chemokine
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lymphotactin
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a CX3C chemokine
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fractalkinin -recruits monocytes and lymphocytes
soluble and membrane bound version |
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eotaxin is a ____ chemokine
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CC
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NO's effects on platelets
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decreases platelet aggregation / activation / adhesion
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what activates eNOS and nNOS
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increased cytoplasmic calcium
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what induces iNOS?
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IFN-gamma - think granuloma and activated macrophages
IL-1 and TNF - think septic shock |
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which NOS is important in septic shock and why?
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cytokines IL-1 and TNF induce iNOS in activated macrophages, and this helps lead to the widespread vasodilation
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what holds proteases in check
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serum and tissue antiproteases such as alpha 1 antitrypsin
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2 serum proteins that protect from ROS?
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ceruloplasmin
transferrin |
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hypoxia-induced factor 1-alpha
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produced by cells deprived of oxygen, can induce an inflammatory response (think reperfusion injury)
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how do necrotic cells cause inflammation
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uric acid
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serous inflammation
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eg blister, pleural effusion
modest increase in permeability with low specific gravity transudate |
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fibrinous inflammation
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eg fibrinous pericarditis, fibrinous pleuritis
marked increase in vasc perm which allows leakage of fibrinogen which is turned into fibrin by coagulation cascade and is deposited on serosal surface |
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suppurative purulent inflammation
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=pus = exudate with high protein content, neutrophils, and cell debris
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abscess
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localized collection of purulent inflammatory exudate accompanied by liquefactive necrosis
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ulcer
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erosion of EPITHELIUM due to sloughing off of inflammed necrotic tissue
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holy trinity of chronic inflammation
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1. infiltration by macrophages, lymphocytes, and plasma cells (mononuclear cells)
2. tissue destruction due to persistent injury and the inflammatory cells 3. attempts at healing - neovasculization and fibrosis |
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what is the best macrophage activator
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interferon gamma - they love this shit - it's like crack
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what do macrophages make that TH1 cells love the shit out of?
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IL-12
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granuloma
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a focal accumulation of activated macrophages walled off by t-lymphocytes.
the t-lymphocytes produce interferon gamma and the macrophages produce IL12 |
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giant cell
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activated macrophages -> epithelioid macrophage -> fuse to form giant cells
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foreign body granuloma
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foreign body cannot be gotten rid of and thus causes chronic inflammation in the form of a granuloma
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can a granuloma be acute inflammation
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no!!
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what is a tubercle?
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an immune granuloma with a core of central caseous necrosis
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lymphadenitis
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inflammation of the lymph nodes
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lymphangitis
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inflammation of the lymphatics - can make red lymphangitic streaks
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what is the first line of defense in bacteremia?
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phagocytes in the spleen, liver, and bone marrow
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SIRS
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systemic inflammatory response syndrome is a very severe activation of the acute phase response
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what causes the acute phase response?
what are components of the acute phase response |
acute phase response is due to the systemic effects of cytokines
1.fever 2.acute phase proteins 3.leukocytosis 4. increased pulse and blood pressure, rigors, chills, anorexia, somulence, malaise, lethargy too? |
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how do IL1 and TNF cause fever?
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they increase the production of PGE2 in the hypothalamus and increase the temperature set point
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how does endotoxin cause such systemic effects?
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it causes massive release of IL1 and TNF
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what are some of the acute phase proteins that are increased in the systemic response to IL1 and TNF?
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serum amyloid A
C reactive protein fibrinogen |
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what is a shift to the left?
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it occurs in the acute phase response. immature neutrophils mobilize from the bone marrow, and thus there are more of them in the blood
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leukemoid reaction
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when leukocyte levels are more than 40,000 / mL
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viral infections cause what shift in leukocyte #
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lymphocytosis
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bacterial infections cause what shift in leukocyte #
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neutrophilia
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parasitic infections cause what shift in leukocyte #
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eosinophilia
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allergic reactions cause what shift in leukocyte #
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eosinophilia
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what do SAA and CRP do?
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they bind to microbial cell walls and act as opsonins
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what is the clinical triad of septic shock?
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1. cardiovascular failure (hypotension, decreased CO, etc)
2. DIC 3. hypoglycemia |
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why does diabetes result in problems with WBC adhesion?
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glycated receptors!
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how do cirrhosis and sarcoidosis affect chemotaxis?
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they increase C5 inactivators
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what do mbl, saa, and crp all have in common
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they are plasma proteins and are opsonins. they have receptors on macrophages
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which mediators of inflammation are preformed?
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histamine
serotonin lysosomal proteases (3!!) |
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what are 1st, 2nd, and 3rd waves of inflammatory mediators
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1. presynthesized cellular
2. newly synthesized cellular 3. hepatic synthesized (acute phase proteins like complement) |
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why do alcoholics have diminished response to infection?
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their liver is damaged and doesnt make acute phase proteins like it should!
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which inflammatory mediators are not premade and must by synthesized?
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cytokines,
NO, AA products, PAF ROS |
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what enzyme do steroids downregulate in inflammation?
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phospholipase
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indomethacin
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blocks cyclooxygenase
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relation b/t fibrinous pericarditus and friction rub?
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kidney failure
friction rub irritation of pericardium fibrinous pericarditis |
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hemorrhagic exudate?
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rickettsial infection that infects the endothelial cells
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pseudomembranous exudate?
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clostridium diphtheria (DIPHTERIA!)
diphtheria toxin kills epithelial cells layer of necrotic debris forms on top of the epithelium (pseudomembrane) |
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when can acute inflammation form a scar
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in tissue that can't regenerate (heart)- it was never chronic inflammation
in an abscess - it was neutrophils so it was never chronic . they can do enough damage to for m a sacr |
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histiocytes
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macrophages in connective tissue
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langerhans cells
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macrophages in skin
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is granulomatous inflammation a kind of chronic inflammation
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maybe, but Dr. Anderson says there are 3 kinds, acute , chronic, and granulomatous
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acute tubular necrosis
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when the proximal convoluted tubule epithelial cells die but leave the BM behind. they can repopulate and re-line the BM. just put the pt on dialysis and they will survive
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when hepatocytes repopulate in cirrhosis, what is wrong with the new tissue?
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bile duct has no superstructure, so biliary epithelium doesnt know where to regrow. you just have green nodules full of bile and bile stasis
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difference b/t healing by primary and secondary intention?
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healing of a surgical incision vs healing of a large tissue defect with lots of scar tissue created
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granulation tissue
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fibroblasts and endothelial cells in ECM matrix.
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transition in collagen types in wound healing
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III -> I
III is seen early on I is the tough crosslinked stuff |
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when will wound reach 70-80% of orig strength
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3 months
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where is procollagen cleaved and crosslinked
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extracellularly
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where are lysines oxidized in collagen formation
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extracellularly
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where are lysine and proline hydroxylated in collagen synthesis
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intracellularly
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why is vitamin C needed for collagen synth?
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hydroxylation of proline and lysine
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what is a formyl methyl protein?
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a bacterial protein which dendritic cells and macrophages, etc have receptors for
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what are lipotechoic acids?
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associated with gram pos bacteria, and we have receptors for them on innate immune system cells
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dsRNA
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Toll-like Receptors bind (innate immune sys)
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CD14
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LPS receptor
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which receptor activates NFkB?
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Toll like receptor
promotes survival |
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which cells express TLR?
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macrophages
dendritic cells neutrophils mucosal epithelium endothelium all these cells come in contact with invaders |
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what binds to flagellin and zymosan?
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TLR
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CpG DNA
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bacterial DNA which TLR's recognize
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why do dendritic cells express TLRs?
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they kick off the innate immune system
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NOD proteins
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like TLR but are intracellular and recognize intracellular organisms and pieces of phagocytosed organisms
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why is C reactive protein reactive?
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it opsonizes and activates complement!
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where are cytokines of innate immunity produced? adaptive immunity?
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innate - activated macrophages (and NK cells too)
adaptive - lymphocytes |
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is IL-1 more adaptive or innate?
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innate
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is TNF more adaptive or innate?
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innate
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is IL-12 more adaptive or innate?
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innate
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is IL-2 more adaptive or innate?
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adaptive
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is IL-4 more adaptive or innate?
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adaptive
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is IL-5 more adaptive or innate?
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adaptive
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what inhibits synthesis of IL-1, TNF, and IL-12?
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CORTICOSTEROIDS
this is part of the antiinflammatory effect |
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what makes the adaptive immune system's cytokines?
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TH1 and TH2 cells. and in much lower concentrations
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are adaptive or innate cytokines local acting?
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adaptive are in lower conc and more locally acting
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what is the synthesis inhibitor of adaptive imm sys cytokines?
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cyclosporin
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how does cyclosporin decrease immune rejection
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it decreases the synthesis of adaptive immune system cytokines by T cells such as IL-2, IL-4, and IL-5
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what is the typical cytokine signal transduction mechanism?
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jak stat
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what makes TNF?
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activated macrophages
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what stimulates macrophages to make TNF?
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LPS
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which 2 cytokines are endogenous pyrogens?
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IL-1 and TNF
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what does TNF do to endothelium?
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it activates it and upregulates expression of cell adhesion molecules
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what is TNF's effect on the liver
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it increases acute phase protein production
CRP SAA fibrinogen |
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what effect do high concentrations of TNF have on myocardial contractility and the blood vessels?
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they decrease myocardial contractility and cause profound vasodilation. this leads to cardiovascular collapse
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what 2 diseases are treated with anti-TNF antibodies?
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rheumatoid arthritis
crohn's disease |
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what is complication to anti-TNF therapy?
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susceptibility to infection, esp TB and histoplasmosis
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what stimulates IL-1 production
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LPS and TNF (waves)
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what is one critical difference between IL-1 and TNF?
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TNF has apoptotic effects but IL-1 does not
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why does prostate cancer like to metastasize to bone?
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prostate cancer cells express chemokine receptors for a bone chemokine.
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what are the salient features of IL-12
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IL-12 is the gateway b/t the innate and adaptive immune responses
APC's (like activated macrophages and dendritic cells) respond to pathogens with their TLR's and then produce IL-12 to activate lymphocytes effects: stimulates production of interferon gamma (which activates macrophages) increases cytolytic function of NK and CTL stimulates differentiation of TH into TH1 cells, effecting a cellular response it activates TH1 lymphocytes to produce more cytokines |
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what is the gateway from the innate to the adaptive immune system?
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IL-12 produced by macrophages upon interacting with T cells
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what cytokine stimulates differentiation of TH to TH1 cells?
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IL-12
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what is the difference between IFN alpha and beta
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alpha is a family of interferons produced by one cell type
beta is one interferon produced by many cell types they both signal thru the same receptor activating a jak/stat pathway |
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effects of type I interferon?
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1. inhibit viral replication
2. increase expression of MHC type I 3. antiproliferative |
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how do type I IFN stop viral infection?
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1. inhbit viral reproduction
2. antiproliferative 3. increase expr of MHC I |
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IFN alpha is used to treat ____
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hepatitis C
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IFN beta is used to treat ____
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multiple sclerosis
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what 2 cell types produce IFN gamma?
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NK cells and TH1 cells
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what is a fun enzyme that IFN gamma induces?
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iNOS (increases NO killing by macrophages)
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IL-10
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anti inflammatory cytokine
1. inhibits immune activation 2. decreases macrophage activation |
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IL-6
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comes 3rd right after TNF and IL-1
increases acute phase proteins and neutrophilia *shown to be stimulatory to innate and inhibitory to adaptive immune response -weird. definitely strong innate |
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IL-15
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IL-15 is important for viral infection!! IT is an early stimulator of NK proliferation in response to viral infection
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IL-18
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synergizes with IL-12 to increase IFN-gamma production
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