Path (4/4) Mediators Of Inflammation

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unresolved inflammatory response can yield what?

Back 1

Pathologic conditions:
-aggregates of lymphocytes/M0s (GRANULOMA)
-Disortion of cell repair mechanism, e.g. too much collagen (FIBROSIS)
-Persistent inflammation can lead to neoplastic transformation (cancer)

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Chemical Mediators of Inflammation
-of PLASMA origin:
-cell-derived:

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ZYMOGENS = inactive pro-enzymes, require activation via proteolytic cleavage by serum proteases
Cell-derived: PRESTORED GRANULES (rapid); SYNTHESIZED DE NOVO (slower)

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Interactions modulating effects of chemical mediators

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SYNERGISM
POSITIVE FEEDBACK
ANTAGONISM
NEGATIVE FEEDBACK

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Mechanisms of action of chemical mediators of inflammation

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-Bind to receptors on target cells
-Direct enzymatic activity (e.g. lysosomal proteases)
-Oxidative damage (oxygen metabolites)

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lifespan of mediators

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short-lived, but can do damage if not adequately controlled

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the hallmark of acute inflammation

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Neutrophils: release many mediators of inflammation, stored in their granules

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3 steps involved in Leukocyte extravastion?

Requires activation of what?

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ROLLING, ADHESION, DIAPEDESIS

requires activation of both: The Leukocyte and endothelium

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Preformed mediators in secretory granules

(Cellular Mediators)

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HISTAMINE
SEROTONIN
LYSOSOMAL ENZYMES

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Newly Synthesized mediators of inflammation

(Cellular Mediators)

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PROSTAGLANDINS
LEUKOTRIENES
PLATELET-ACTIVATED FACTORS
ACTIVATED OXYGEN SPECIES
NITRIC OXIDE
CYTOKINES

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Examples of mediators in plasma

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FACTOR XII ACTIVATION:
bradykinin, coagulation/fibrinolysis system
COMPLEMENT ACTIVATION:
anaphylatoxins (C3a, C5a), C3b, C5b-9 (MAC)

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Histamine:
synthesized by:
stored in:

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synthesized and stored in mast cells in CT, adjacent to blood vessels, also found in circulating basophils, platelets

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histamine is released in response to what?

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-physical stimuli
-immune reactions (x-linking of surface bound IgE)
-anaphylatoxins (C3a, C5a)
-cytokines (IL-1, IL-8)

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release of histamine leads to what?
(effects are through what receptors?)

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dilation of arterioles,
increased vascular permeability
(effects on small vessels are through H1 receptors)

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Serotonin (stored where?)

Back 14

stored in platelets

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Serotonin released by what?

Back 15

released by platelet aggregation induced by collagen contact, thrombin, ADP, Ag-Ab complexes

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Actions of Serotonin

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actions, similar to histamine

increased vascular permeability

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system of functionally linked proteins that interact with one another in a highly regulated manner to provide many of the effector fucntions of humoral immunity and inflammation

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COMPLEMENT

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examples of Complement mediated inflammatory actions

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CYTOLYSIS by formation of the MAC, opsonization of foreign organisms, solubilizaztion and clearance of Ab-Ag complexes

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In Classical pathway, complement is inactive in plasma until activated at localized sites by:

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activated at localized sites by:
Ag-Ab complexes

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In Alternative pathway, pathway, complement is inactive in plasma until activated at localized sites by:

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activated at localized sites by:
surfaces of pathogens

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central component of Complement Cascade

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C3 is central component
both pathways generate different C3 convertase complexes that activate C3, converting it to C3a and C3b

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C3b action

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proteolytically cleaves C5; C5b + C6, C7, C8 C9 ---> C5-9 (MAC)

can also opsonize bacteria

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C3a and C5a

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anaphylatoxins, many of their actions are histamine dependent

bind to mast cells and release histamine, causing dilation of arterioles, increased vascular permeability of the venules (histamine is the principal mediator of immediate vascular permeability)

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Histamine independent actions of C5a:

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-activates lipoxygenase pathway in
PMN--> leukotrienes--> + permeability

-potent chemoattractant for and activator of PMNs

-increases leukocyte adhesion to endothelium

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EICOSANOIDS

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-local short range hormones; formed rapidly, local effects, short lived

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where are eicosanoids formed?

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formed in LIBID BODIES (specialized cellular domains, that have high concentration of the synthetic enzymes)

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COX pathway-
Initiated by:
Results in:

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Initiated by COX-1 or COX-2

Results in: formation of PROSTAGLANDINS

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Tissue restricted enzymes involved in arachidonic acid cascade

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IN PLATELETS: TxA2 synthase
(makes TxA2 = vasoconstrictor)
IN ENDOTHELIUM:
Prostacyclin synthase (makes PGI2= a vasodilator)

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Diapedesis

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“the passage of blood, or any of its formed elements, through the intact walls of blood vessels.”
eg:Leukocytes have to get out of the blood vessels and into the interstitium.

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chemokine responsible for initial "rolling" in leukocyte extravasation

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SELECTINS expressed by endothelial cells, interact with glycoproteins on leukocyte to slow it down

cooperates with Integrin-ICAM interaction in "STICKING" adhesion

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chemokines activate what structure on leukocyte surface, that is primarily responsible for diapedesis?

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INTEGRIN: on Leukocyte surface aids in establishing stable adhestion "STICKING" (along with selectin)

and mediates migration through endothelium

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chemokines

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superfamily of small proteins that activate and chemoattract leukocytes

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important characteristics of complement

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-multiple proteolytic enzymes
-sequential activation
-amplification
-highly regulated

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complement is inactive until activated by:

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-Ag-Ab complexes "Classical pathway"
-Surfaces of pathogens "Alternative Pathway"

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Effector Functions of Activated Complement

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C3a C5a: INFLAMMATION
C3b: Opsonization/Phagocytosis
C3b cleaves C5--> C5-9 (MAC): Lysis of Microbe

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MAC

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C3b proteolytically cleaves C5

C5b + C6, C7, C8, C9 --> C5-9

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Histamine dependent actions of anaphylatoxins

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-bind to mast cells and release histamine
-dilation of arterioles
-increased vascular permeability of the venules

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principal mediator of immediate vascular permeability

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histamine

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Histamine independent actions of anaphylatoxin(s)

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C5a activates lipoxygenase pathway in PMN → leukotrienes → increased permeability

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complement gone wrong...

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SURVIVAL of sepsis dramatically increased with C5a BLOCKADE
(indicates strong potential for complement to drive disease)

Front 41

Factor XIIa induces what two cascades?

Both these cascades interact and induce what downstream cascade?

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Kinin cascade and Clotting Cascade

both lead (indirectly) to activation of complement cascade

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how do steroids exert their anti-inflammatory properties?

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inhibit phospholipases that liberate arachidonic acid from cell membrane phospholipids

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how do COX-1 and COX-2 inhibitors exert their anti-inflammatory properties?

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inhibit cyclooxygenase involved in the conversion of ARACHIDONIC ACID to Prostaglandin G2 (PGG2)

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PGI2 causes:
opposes action of?

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causes vasodilation, inhibits platelet aggregation

opposes action of TxA2

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TXA2 action:

opposes action of what?

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causes vasoconstriction, promotes platelet aggregation

opposes action of PGI2

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5-Lipoxygenase

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Neutrophil specific enzyme
involved in branch of arachidonic acid cascade that generates various Lipoxins, and Leukotrienes (some pro-, some anti-inflammatory

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Products of Arachidonic Acid Cascade

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EICOSDINOIDS

formed in specialized cellular domains called lipid bodies, that have high concentration of synthetic enzymes

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examples of eicosanoid metabolites involved in:
->vasoconstriction:

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TxA2, LTC4, D4, E4

eicosanoid metabolites involved in what action:

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examples of eicosanoid metabolites involved in:
->vasodilation

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PGI2, E1, E2, D2
eicosanoid metabolites involved in what action:

Front 50

examples of eicosanoid metabolites involved in:
->+ vascular permeability

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LTC4, D4, E4
eicosanoid metabolites involved in what action:

Front 51

examples of eicosanoid metabolites involved in:
->chemotaxis, leukocyte adhesion

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LTB4, HETE, Lipoxins

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Lipoxins

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example of transcellular metabolism
some are pro-others are anti-inflammatory,
LTA4 produced by 5-lipoxygenase in Neutrophil, metabolized by adjacent platelet to Lipoxin and LTC4

(Inhibit Neutrophil chemotaxis, via negative feedback?)

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chemokines are secreted and bind to what?

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cell surface proteoglycans (immobilized to form gradients)

bind to 7transmembrane receptors and activate --> G PROTEINS

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HIV co-receptor = what kind of receptor?

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a chemokine receptor

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NO is released from what type of cells?

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Endothelial cells

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NO action on vessels

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vasodilator

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NO action as hormone

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local paracrine factor

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NO lifespan

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SHORT LIVED

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NO forms adducts with what?

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froms adducts with thiol groups on Proteins (S-Nitrosoproteins)

(Hemoglobin : NO sing, may be an important function of Hb)

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NO synthesized from what?

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synthesized from L-arginine by enzyime NITRIC OXIDE SYNTHASE (NOS)
-constitutive (eNOS, nNOS) low levels, ca++ activated
-inducible (iNOS) produced by M0s, requires denovo synthesis, no ca++ needed

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Types of NOS

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enzyme NITRIC OXIDE SYNTHASE (NOS)
-constitutive (eNOS, nNOS) low levels, ca++ activated
-inducible (iNOS) produced by M0s, requires denovo synthesis, no ca++ needed

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Importance of NO in host defense

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can be used for killing of intracellular bacteria

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eNOS constitutively expressed, activated by what?

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activated by movement of Ca2+ into cell, results in reduced platelet adhesion, reduced leukocyte adhesion

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iNOS not produced by macrophage until appropriate stimuli available, release can result in

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-cytotoxic killing of engulfed pathogens, or secretion into tissues

vascular SM relaxation/vasodilation

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IL1/TNF cytokines produced by

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MACROPHAGE (and other cell) activation by: bacterial products, immune complexes, toxins, physical injury and other cytokines

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IL1/TNF effects

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ACUTE-PHASE REACTIONS
ENDOTHELIAL EFFECTS
FIBROBLASTS EFFECTS
LEUKOCYTE EFFECTS

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IL1/TNF induced ACUTE-PHASE REACTIONS

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fever
+ sleep
- appetite
+ Acute phase proteins
hemodynamic effects (shock)
neutrophilia

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IL1/TNF induced ENDOTHELIAL EFFECTS

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+ Leukocyte adherence
+ PGI synthesis
+ Procoagulant activity
- anticoagulant activity
+ IL1, IL8, IL6, PDGF

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IL1/TNF induced FIBROBLASTS EFFECTS

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+ proliferation
+ collagen synthesis
+ collagenase
+ protease
+ PGE synthesis

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IL1/TNF induced LEUKOCYTE EFFECTS

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+ cytokine secretion (IL-1, IL-6)

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chemokine specificity
-eotaxin attracts what?
whereas
-IL-8 attracts what?

Back 71

eotaxin attracts EOSINOPHILS

IL-8 attracts NEUTROPHILS

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NF-kB

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complex of IkBa+p50+p65 found in cytoplasm

p50 and p65, when released from Ikba-- act as transcription factors binding to promoter of inflammatory gene

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Stimuli that activate NF-kB

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TNFalpha
IL-1beta
Lipopolysaccharide

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Genes/proteins that are induced by NF-kB

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TNFalpha
IL-1beta

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NFkappaB activation by LBP and CD14 involves what type of receptor?

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TLR4
TOLL LIKE RECEPTOR 4

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IL-1, LPS, Spatzle all interact with TLRs to activate

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NFkappaB

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Amplification of inflammation via NFkappaB activity

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inflammatory gene products promoted by p50 and p65 induce inflammatory signals that increase NFkappaB activation

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Glucocorticoid effects on NFkappaB activity

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glucocorticoid binds to glucocorticoid receptor in cytoplasm, complex enters nucleus and either:
-directly inhibits NF-kB to prevent action of TFs on inflammatory gene
or
-promotes IkBa gene (anti-inflammatory gene)

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aspirin can inhibit inflammation via COX inhibition and also through what action on NFkappaB pathway

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inhibits IkB kinases (responsible for degradation/activation of NFkB and release of transcription factors)

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Entanercept and Infliximab/Remicade
both inhibit what?
the share what region?

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both inhibit TNFa

both have Fc receptor of IgG1

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Entanercept

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soluble TNF-alpha receptor

Fc Region of Human IgG1
EC Domain of Human p75 TNF receptor

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Infliximab/Remicade (cA2)

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monoclonal antibody with Fc Region of Human IgG1

essentially mops up TNF

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what is the central mediator in Rheumatoid Arthritis?
what is it secreted by?
what cells does it activate?

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TNF- (secreted by monocytes) activates
-Endothelial Cells
-Monocytes (also secrete IL-1)
-Synovial Fibroblasts (secrete various factors)

Front 84

Drugs useful in treating RA

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methotrexate
+ Entanercept (soluble TNF-a receptor, fusion protein)
or
+ Infliximab; remicade (TNF-alpha monoclonal Ab)

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cA2 showed what in Crohn's patients

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higher rates of remission than those who received placebo