04 - September 19, 2013.docx

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University of Toronto St. George
Laboratory Medicine and Pathobiology

LMP September 19, 2013 Inflammatory Mediators Virtually anything could be an inflammatory mediator If given substance X, would characteristics/tests would tell us it is an inflammatory mediator? Inject substance X, does it induce inflammatory response? Should be able to see it at the site of inflammation Found at sites of tissue damage Injection of purified substance induces inflammatory response Inflammatory effects of this substance inhibited by antagonist or receptor antagonist Biological effects of these mediators Prolonged inflammation can damage tissue – thus short-lived Where they are often found? In blood – if not rapidly inactivated, will not have local inflammation – to keep inflammation local Stimulate target cells to produce secondary mediators – amplification of the response Vasodilation to increase blood flow (increase delivery of mediators and leukocytes to site of tissue injury or infection) Increased vessel permeability (allow mediators into tissue) Emigration of leukocytes into tissues These called vascular events of inflammation Smooth muscle cells line the smooth muscle walls – Exogenous inflammatory mediators Chemnotaxin – recruitment of leukocytes Endogenous mediators – products of host released in response to the pathogen – plasma derived, meaning they are inactive until cleaved Cell derived – in response to pathogen – Plasma derived mediators – largely produced by liver, circulate in plasma as INACTIVE precursor Factor 12 – important activator of all four inflammatory cascades that form the Inactive until in contact with collagen, BM, and activated platelets – this happens when there is damge to vessel wall, pathogen, some tissue injurty that exposes BM Co-factor as well, together cleave – so 12a is active inflammatory mediator – BOUND TO VESSEL WALL, LOCALIZED TO SITE OF TISSUE INJURY – can activate all four arms of plasma derived mediators Braykini First system Activated factor 12a – cleaves prekallikrein into kallikrein Kallikrein cleaves HMWK to form bradykinin, the active inflammatory mediator of kinin system Bradykinine major component of bee venome, wasp venom – that’s why they hurt Activate fibinoloytic pathway – activates other plasma derived mediators Plasma-derived inflammatory mediators The coagulation system Clotting cascade – forms protective protein mesh over sites of injurty – mediated by the protein thrombin?? Variety of factors can activate thrombin cascade Extrinsic pathway that involves tissue factor Intrinsic pathway involves factor 12 a – activate factor 10a – 10a cleaves prothrombin to produce thrombin – cleaves soluble plasma fibrinogen to produce fibrin, fibrin aggregates and forms blood clot – can also act as inflammatory mediator by par1 receptor – induce other cells to produce inflammatory mediators – Other inflammatory mediators production can also be induced Plasma derived – 4 Fibrinolytic system – acts in opposition to coagulation system Plasmin – protein derived from plasminogen – breaks down fibrin clots – thrombin makes thrombin clots – fibrin degradation products can have plasma permeability effects Another effect is can cleave complement c3 Amplifying the process Complement cascade Fourth system Circulate as pro-enzymes in plasma C3 cleaved by enzyme to form peptides – C3 A and B This is the case for all complement proteins – A is soluble, has inflammatory effects B is the active fragments, cleaves the next zymogen in the cascade Activation occurs on pathogen surface – active enzyme – localize complement response – inflammatory effect of the complement cascade include c3a and c5a – these are soluble mediators – they are often called anaphylatoxins Act on blood vessels to increase vascular permeability – c5a is also chemoattractant for neutrophils to site of infection – c3b is opsonin is a molecule that binds to pathogen and targets it for phagocytosis – and then c5b to 9 forms MAC Complement cascade – three arms on the left – three different pathways for activation of complement cascade Microbe has C3b deposited Formation of c3 convertase is important for effector production C3 convertatse critical for effector production Generation of C3 converstase on the left Generation of effectors on the right C3b – opsonin – binds to the pathogen, targets it for phagocytosis and then also downstream is MAC Complement cascade Lead to generation of C3 convertase Triggered enzyme cascades Classical pathway – C1 activated when antibody binds to antigen on pathogen; C1 is soluble, binds to this complex, undergoes conformation change that activates it; now activated C1 – C4 can now bind to C1; makes C4a soluble; C4b binds to the pathogen; when C4b is bound to pathogen, now C2 can bind; activating C1 can cleave C2, get C2a; C2b remains bound to pathogen; C4b2b bound to surface (this is the classical C3 convertase – covalently linked to pathogen surface – can cleave many C3, over a thousand) C3 – when cleaved, forms C3a which is soluble – C3b can bind to pathogen as opsonin or it can bind to C3 convertase to make C4b2b3b (this is C5 convertase) C5b initiates formation of MAC This General pathway is true for all three pathways – just the initiating aspect that is different For example, lectin pathway – it is the mannose-binding lectin binds to mannose residue; human mannose are often covered by other residues, not available for lectin to bind; Alternate pathway – in this case, there is no involvement of the C1 – spontaneous hydrolysis of these proteins in the blood – C3 binds to microbial surfaces polysachcardies and becomes spontaneously hydrolyzed to form C3a and C3b – once bound to pathogen, other factors in plasma, like factor B that is cleaved by D – leading to C3bBb – This only happens on pathogens, not host cells, because there are host regulatory protines that can stabilize the complex Properdin will stabilize C3b complex if bound to pathogen, NOT IF BOUND TO HOST CELL CL1 proteins will dissociated this from a host cell; decay-accelerating factor wil dissociate this from a host cell Membrane Attack Complex After the C5 convertase was formed – cleaved C5 into C5a and b C5b associates with C6 and C7 – this whole complex binds to pathogen membrane via C7 – C8 then binds, inserting itself into cell membrane; then C9 binds – many molecules of C9, forming pore in the membrane Disrupt bacterial membrane – lead to destruction of bacterial membrane This cannot happen to host cells – regulatory proteins that prevent (CD59) that inhibits binding of C9 molecule Interactions between kinin, fibrin, coagulation, and complement cascades Factor 12 – binding to collagen – can activate kinin and clotting cascade Kini cascade can activate fibrinolyit csystem – act in opposition to each other to induce formation and breakdown of clots Plasmin can activate C3 to produce C3a – all four of these pathways There is feedback amplifccation; can initiate production of inflammatory mediators PLASMA to FIBRIN arrow should be inhibitory – BREAKING DOWN FIBRIN CELL DERIVED MEDIATORS Vasoactive amines – histamine, serotonin Histamine is a vasoactive amine – formed by decarboxylation of L-histidine Mast cells Stain of WBC smear; with basophil, mast cells –stains dark purple – filled with granules for release Black circles – granules full of histamine Histamine relase from cultured mast cells stimulated with complement proteins and bradykinin Had cultured mast cells – look for substances that will cause release of these granules C5a , C3a, and braykinin causes releases of histamine Histamine and allergic rhinitis How histamine might contribute to allergic rhinitis Ragweed binds to and activates B cell – IgE against ragweed – binds to ragweed, waiting for second time to see ragweed Second time – ragweed binds to surface of mast cells, which is primed and relases histamine – get allergic response Blood vessels dilate – increased permeability of blood vessels Antihistamines bind to H1 receptor, histamine receptors – do not prevent release of histamine – histamine blockers REACTIVE OXYGEN SPECIES Unpaired electron – try to get another electron – so oxideize lipids, proteins, enzymes In unstimulated neutrophil, NADPH inactive Cytoplasmic portion of oxidase – waiting for phagocyte to engulf pathooen Once this appens, goes to membrane of phagocytic vacuole where associates with membrane component of vacuole – production of superoxide ra
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