Gen Path 2
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What are the phases and mediators of increased vascular permeability?
- 1) Immediate/transient - lasts <30min, mediated by LTr and Hist
- 2) Delayed response, 2hrs - 8hrs, mediated by kinins and complement
- 3) Prolonged response - after direct endothelial injury (ie. burns)
Name 6 ways endothelium become leaky.
- 1) Endothelial gaps in venules (not caps and arterioles) (transient 20-30min) - hist, badykinin, LT, neuropeptide substance P
- - mediator binds to endothelial cell receptor --- leads to phosphorylation of contractile and cytoskelelon proteins --- contract endothelial cell
- - IL-1, TNFa, IFNg - also cause endothelial cells to retract d/t reorganiz of cytoskel but more delayed - 4-6hrs, lasts up to 24hr
- 2) Direct endothelial injury
- 3) Delayed prolonged leakage - begins 2-12 hrs and lasts for days, unclear mech, in venules and caps
- 4) WBC injury - neuts adhere, activate and release ROS and proteolytic enzymes
- 5) Increased transcytosis - clusters of interconnected vesicles and vacuoles, VEGF increases numbers of these channels - may also be increased by histamine
- 6) Leakage from new vessels - new vessels have incr receptors for VEGF, sub P and histamine
Name the sequence of events from the vessel lumen to extravasation of leukocytes:
- 1) Margination
- 2) Rolling
- 3) Adhesion
- 4) Transmigration
- 5) Migration in tissues towards chemotactic stimulus
What are the four families of adhesion molecules?
- 1) Selectins
- 2) Immunoglobulin superfamily
- 3) Integrins
- 4) Mucin-like glycoproteins
Name the selectins, where they are expressed and what they bind.
- 1) E-selectin - endothelial cells (cytokine activated - IL1, TNF) - bind ESL1, sLex, PSGL1, GlyCam (gran, mono, Tcells)
- 2) P-selectin - endothelial cells (WP bodies) and platelets (a granules) - bind same as E-selectin except not ESL1, stim by hist, thrombin, PAF for release from granules
- 3) L-selectin - lymphs and other leuks (home receptor for binding to HEVs), binds GlyCAM1 (HEVs), MadCAM1 (GALT endoth), CD34 (endoth and BM cells), PSGL-1
Name the Ig superfamily molecules, where they are expressed and what they bind.
- They are ligands for integrins on leukocytes:
- 1) ICAM-1 - endothel - binds to CD11/CD18 integrin on leukocytes (adhesion, arrest, transmigration)
- 2) VCAM-1 - endothel - binds to a4b1 (VLA4 - B1integrin), a4b7 (LPAM1) integrins on eos, mono, lymph (not neuts) - adhesion
- 3) MadCAM1 - endothel of GALT - binds L-selectin of lymphos
- 4) PECAM1 (CD31) - plts, leuk and endoth (?not clear) - NB for transmigration?
Name the integrins, where they are expressed and what they bind.
- Made of up a and b chains, expressed on many cell types - bind to endoth, leuk, ECM
- 1) B2 integrins (CD11/CD18) - all leukocytes - bind ICAM1 on endoth cells - adhesion, arrest, transmig
- CD11a-c/CD18, so CD11a is LFA1, a1; CD11b is Mac1, a2; CD11c is CR4 or p150,9; CD18 is b2 int
- LFA1: lymphs and other leuk with other cells, endoth
- Mac1 or CR4 - attachment of leuk to endoth and extravasation
- Mac1 also fib receptor and C receptor on phag cells allowing binding of optimized particles
- 2) B1 integrins (VLA4) - eos, monos,lymphs - bind VCAM1 - adhesion (not on neuts) to endothelium
- Some integrins bind RGD sequences of fibronectin, vitronectin, laminin and other ECM components
Name the mucin-like glycoproteins, where they are expressed and what they bind to.
- 1) Heparan sulfate - on cell surfaces and ECM - binds CD44 (leuk adhesion molecule)
- 2) GlyCAM1 - HEVs of LNs - binds L-selectin
- 3) CD34 - on endoth and BM cells - binds L-selectin
- 4) ESL1 and PSGL1 - on leukocytes?
What are the three steps to leukocyte recruitment to sites of injury/infection?
- 1) Induction of adhesion molecules
- PAF, hist, thrombin ---- release of P-selectin from WP and a granules
- IL1, TNF ---- expression of various adhesion molecules on leuk and endoth and ligands for integrins on endoth (VCAM, ICAM)
- 2) Activation of leukocytes: chemokines bind to endothelial cell hep sulfate - activate rolling leukocytes AND get conversion of VLA4 and LFA1 from low affinity to high affinity - SO ROLLING STOPS/FIRM ADHESION
- 3) Migration through endothelium: chemokines produce chemical concentration gradient, PECAM1 expressed on endoth cells near jxns binding to other PECAM1, leuk secrete collegenases to get through BM, once through they bind to ECM with B1 integrins and CD44
Name chemotactic factors:
- 1) Endogenous: C5a, LTB4, IL8 (others of these types also involved but these are most NB)
- 2) Exogenous: bacterial products - N-formyl-meth aa
How do chemotactic factors exert their effects?
- 1) Bind GProt coupled receptors on WBC
- 2) Recruit G protein
- 3) Activate effector molecules: PLC, PI3K, protein tyrosine kinases --- increase cytosolic Ca
- 4) This activates GTPases and kinases ---- polymerizes actin ---- WBC movement
- 5) Actin regulating proteins - filamin, gelsolin, profilin, calmodulin - interact with a and m to contract
What is the end result of signalling pathways triggered in leukocytes during activation?
- 1) Increase cytosolic Ca
- 2) Activation of protein kinase C and phospolipase A2
What are the functional responses of leukocyte activiation?
- 1) Prod of AA metabolites from PLs - d/t activation of PL A2 by incr. Ca
- 2) Degran and secretion of lysosomal enz and activation of oxidative burst
- 3) Secretion of cytokines
- 4) Modulation of adhesion mol, increased avidity of intergrins allowing for firm adhesion
Name the receptors involved in leukocyte activation.
- 1) TLRs - activate leukocytes in response to infectious agents
- 2) GPCRs - on most leukocytes, have diverse ligands ex. C5a, chemokines, NFM residues,
- When ligand binds receptor - GTP replaces GDP (in resting recetor) - activates enzymes - incl PLC which degrades inositol PLs -- incr Ca --- activates protein kinase C
- GPCR - also stim cytoskel changes (see prev Q) and increase motility
- 3) Cytokine receptors: ex. IFNg - secreted by NK cells and Tcells --- macrophage activation
- 4) Opsonin receptors: best opsonins - IgG, C3, but also: MBL, fibronectin, fib, CRP
What are the three steps of phagocytosis?
- 1) Recognition
- Mannose receptor: binds sugars (mannose and fructose) of microbial cell walls (not found at terminals of mammalian cells)
- Scavenger receptors: bind variety of microbes and LDL
- Integrins ex. CD11b/CD18 (MAC1) binds microbes
- 2) Engulfment: pseudopods (polymerizing actin filaments) form around particle, engulf, then fuse with lysosome (phagolys), note that pinocytosis not dependent on actin (instead via clathrin coated pits - Tf)
- 3) Killing: O2 dep mech, phag stim bust in O2 consumption, glycogenolysis, glucose oxidation --- ROS
Explain how bacterial killing occurs after phagocytosis (O2 dep).
- 1) Activation of NADPH oxidase - pulls e off NADPH ---- NADP and gives to O2 leaving O2-
- 2) O2- dismutates to H2O2 which then reacts with Fe2+ and results in OH- or with MPO and Cl (halide) it is converted to hypoclorite and destroys organisms by halogenation or lipid peroxidation
- Resting neuts have NADPH oxidase in plasma mem and cyto but when activated they go to membrane and phagosome membrane
- ROS and NO produced in the phagolysosome protecting the cell
Explain O2 independent mech of bacterial killing.
- Within leuk granules are:
- 1)BPI - PL activation, PL degredation, incr. membrane perm
- 2) Lysosyme - hydrolyses glycopeptide of bacteria
- 3) Lactoferrin - Iron binding prot
- 4) MBP - eos - cytotox to parasites - NOT bacteria
- 5) Defensins - cytotoxic to microorganisms
- 6) Other enz - elastase
How are leukocyte products released causing tissue injury?
- 1) Regurg during feeding - phag vacuole remains open
- 2) Frustrated phag - ex. Ig-complexes on immovable surfaces
- 3) Phagocytosis of membranolytic substances - cytotoxic release
- 4) Exocytosis
Describe the types/categories of defects in leukocyte fxn:
- 1) Adhesion: BLAD, CLAD (CD18)
- 2) Phagolysosome fxn: C-H - abherent organelle fusion
- 3) Defects in microbial activity ex. defect in NADPH oxidase - NB to generate superoxide
- 4) BM suppression
What is missing in LAD type 1?
What is missing in LAD type 2
receptor for selectins d/t no fucosyl transferase
What is problem with chronic granulomatous dz?
Decr oxidative burst either d/t NADPH oxidase def (x-linked - membrane component gp91phox) OR (aut rec - cyto component missing p47phox)
What is problem in C-H syndrome
Missing protein needed for organelle membrane docking and fusion
What are some acquired leukocyte function abn?
- 1) Decreased chemotaxis: heat, DM, malignancy, sepsis, immunodef
- 2) Decreased adhesion: hemodialysis, DM
- 3) Decreased phag and microbicidal: leukemia, sepsis, DM, neonates, malnutrition
What terminates the acute inflammatory rxn?
- 1) short lived mediators
- 2) switch from pro to anti-infl mediators
- 3) release of anti-infl TGF-b from macs
- 4) neural impulses that inh TNF prod by macs
Name the mediators of inflammation.
- 1) Vasoactive amines: histamine, serotonin
- 2) Plasma proteins: complement system, kinin system, clotting system
- 3) Arachidonic acid metabolites: cyclooxygenase pathway, lipoxygenase pathway
- 4) Platelet activating factor
- 5) Cytokines and chemokines
- 6) Nitric oxide
- 7) Lysosomal constituents of leukocytes
- 8) Oxygen derived free radicals
- 9) Neuropeptides
- 10) Others - ex. hypoxia-induced factor 1a, uric acid
What are the first mediators of inflammation to be released?
Vasoactive amines - histamine, serotonin - since they are preformed
Where is histamine found and what are its effects?
- Widely distributed, mostly in mast cells, also in basos and plts (dense)
- Released from MC in response to: 1) trauma, 2) Abi binding to MC 3) anaphylatoxins (C3a, C5a) 4) histamine releasing proteins from leukocytes 5) Substance P 6) cytokines (IL1, IL8)
- Actions: dilates arterioles, increases permeability of venules, binds to H1 receptors on endo cells
Where is serotonin found and what are its effects?
- Platelets (dense) and enterochromaffin cells (mast cells in rodents but not people)
- Release stim by plt aggregation d/t collagen, thrombin, ADP and Ag-Abi AND by PAF released form MC after IgE binding
Describe the steps of the classical path of complement system.
- 1) Ag-Abi complex activates C1
- 2) AC1 cleaves C4 + C2 ------ C4b2b (C3 convertase)
- 3) C3 convertase then activates C3 to C3a and C3b
- 4) C3b combines with C4b2b to produce C4b2b3b (C5 convertase)
- 5) C5 convertase activates C5 to C5a and C5b
- 6) C5b combines with C6,7,8,9 to form C5-9 (MAC)
- NOTE: plasmin also generates C3a and C5a from C3 and C5
Describe the steps of the lectin path of complement system.
Same as classical but C1 is activated by mannose-binding lectin which binds to CHO on microbes.
Describe the steps of the alternative path of complement system.
- 1) C3 is cleaved to C3b by microbial surface polysaccharides
- 2) C3bBb (alt path C3 convertase) is formed from C3b with Factor B and Factor D
- 3) C3bBb3b (alt path C5 converstase) is formed by combining C3bBb with C3b
What are the actions of the completment proteins?
- C3a, C5a and some C4a: increase vascular perm (via histamine release from mast cells)
- C5a also: activates lipooxygenase path, leuk adhesion, chemotaxis and activation
- C3b: opsonization (coats bacteria, phag by neut and mac with C3R (CD11b/CD18 or Mac1)
What is the critical step of the complement system?
Activation of C3
How is the complement system regulated? ie. What are its inhibitors?
- DAF - accelerates decay of C3 and 5 convertases
- Factor H and I - cleave C3b
- C1INH - inhibits C1 activation, as well as kallikrein and factor XII
- CD59 - inhibits MAC
What are the actions of bradykinin? How is it produced?
- Actions: increase vascular perm, smooth muscle contraction, vasodil, pain
- Production: factor XIIa converts prekallikrein to kallikrein which cleaves HMWK to bradykinin
- Inactivated by kininase and angiotensin converting enzyme and inhibited by C1INH (via inh of kallikrein and HMWK)
What form is aa found in the body?
Esterified in PLs - released via the action of phospolipases.
What activates PL A2?
Increase cytosolic Ca and activation of kinases by external stimuli
Describe the steps of the AA pathway.
- 1) Membrane PL ---- PLipases ---- AA
- 3) AA ----COX1/2----PGG2 ---- PGH2 ---- PGI2 (vasodil, inh plt ag), TXA2 (vasocons, incr plt ag), PGD2, E2 and F2 (vasodil, edema)
- 4) AA --- 5-LO --- 5 HPETE --- 5 HETE (chemotaxis) --- LTB4
- 5) or 5 HPETE --- LTA4 --- LTC4 ---- LTD4 ---- LTE4 (last three cause vasocon, bronchosp, incr. perm)
- 6) or 5 HPETE --- 12 LO --- Lipoxins -LXA4 and B4 (vasodilation, inh neut chemotax, stim mono adhesion)
How do COX1 and 2 differ?
- COX 1 is constitutively expressed and NB in homeostatic functions - ie. fluid/elec balance in kid, GI prot
- COX 2 induced by: PGs - D, E, F, G and H
What are resolvins?
New cat of AA derived mediators only found in animals treated with ASA so anti-infl may be d/t COX inh as well as prod of resolvins.
Name the effects of TNF/IL1 on endothelial cells.
- 1) Incr leukocyte adherence
- 2) PGI synthesis
- 3) Incr Procoag activity
- 4) Decr anticoag activity
- 5) Incr IL1, IL8, IL6, PDGF
Name the fibroblastic effects of TNF/IL1.
- 1) Proliferation
- 2) Collagen synth
- 3) Collagenase
- 4) Protease
- 5) PGE synthesis
Name the leukocyte effects of TNF/IL1.
Incr cytokine secretion: IL1, IL6
What are the 4 groups of chemokines?
- 1) CXC (a) - must have ELR sequence to attract neuts, ex. IL8
- 2) C-C (b) - ex. Mono chemoattract prot (MCP-1), Mac inflam prot (MIP-1a), eotaxin, RANTES (attracts all but neuts)
- 3) C (g): lymphotactin
- 4) CX3C: only one - Fractalkine - chemo for monos and T cells - can be mem bound on endo or soluble in plasma
Where is NO produced and what are its effects?
- Produced by endo, macs and some neurons
- 1) smooth mm relax
- 2) inh plt aggregation and adhesion
- 3) inh mast cell inflammation
- 4) blocks leukocyte recruitment
- NOTE: some constitutively expressed and some inducible by action of cytokines on macs
Name lysosomal enzymes and what their actions are.
- 1) Acid proteases - degrad bact and debris in phagolysosomes
- 2) Neutral proteases - degrade ECM AND can cleave C3, C5 and kininogen
- NOTE: a1-antitrypsin and a2-mac both inhibit proteases (anti-inflam)
Which mediators cause vasodilation?
Which mediators cause incr. vascular perm?
- Vasoactive amines
- C3a, C5a
- LT C4, D4 and E4
- Substance P
Which mediators are chemotactic, activate and recruit leukocytes?
- IL1, TNF
- Bacterial products
Which mediators cause Fever?
IL1, TNF, PGs
Which mediators cause pain?
Which mediators cause tissue damage?
- Lysosomal enz
- O2 metabolites
Name the mediators which are chemotactic for monos in chronic inflammation.
MCP-1, C5a, PDGF, TGFa, fragments from broken down ECM
Name the systemic effects of inflammation.
- 1) Fever: PGs (esp PGE) - reset temp set pt, IL1 and TNF are pyrogens work by increase COX --- incr. PGs
- 2) APP: synthesis upreg by IL6 (CRP and fib), IL1 or TNF (SAA)
- 3) Leukocytosis- incr. BM release by IL1/TNF and later get incr prod as well
- 4) Incr pulse, BP, decr sweating
- 5) Sepsis results in massive release of IL1 and TNF d/t LPS
- Incr endo TF, decr TFPI and thrombomodulin --- DIC
- Liver damage results in hypogly and decr coag factors
- Overprod of NO --- hemodynamic shock
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