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85 Cards in this Set

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unresolved inflammatory response can yield what?
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)
Chemical Mediators of Inflammation
-of PLASMA origin:
-cell-derived:
ZYMOGENS = inactive pro-enzymes, require activation via proteolytic cleavage by serum proteases
Cell-derived: PRESTORED GRANULES (rapid); SYNTHESIZED DE NOVO (slower)
Interactions modulating effects of chemical mediators
SYNERGISM
POSITIVE FEEDBACK
ANTAGONISM
NEGATIVE FEEDBACK
Mechanisms of action of chemical mediators of inflammation
-Bind to receptors on target cells
-Direct enzymatic activity (e.g. lysosomal proteases)
-Oxidative damage (oxygen metabolites)
lifespan of mediators
short-lived, but can do damage if not adequately controlled
the hallmark of acute inflammation
Neutrophils: release many mediators of inflammation, stored in their granules
3 steps involved in Leukocyte extravastion?

Requires activation of what?
ROLLING, ADHESION, DIAPEDESIS

requires activation of both: The Leukocyte and endothelium
Preformed mediators in secretory granules

(Cellular Mediators)
HISTAMINE
SEROTONIN
LYSOSOMAL ENZYMES
Newly Synthesized mediators of inflammation

(Cellular Mediators)
PROSTAGLANDINS
LEUKOTRIENES
PLATELET-ACTIVATED FACTORS
ACTIVATED OXYGEN SPECIES
NITRIC OXIDE
CYTOKINES
Examples of mediators in plasma
FACTOR XII ACTIVATION:
bradykinin, coagulation/fibrinolysis system
COMPLEMENT ACTIVATION:
anaphylatoxins (C3a, C5a), C3b, C5b-9 (MAC)
Histamine:
synthesized by:
stored in:
synthesized and stored in mast cells in CT, adjacent to blood vessels, also found in circulating basophils, platelets
histamine is released in response to what?
-physical stimuli
-immune reactions (x-linking of surface bound IgE)
-anaphylatoxins (C3a, C5a)
-cytokines (IL-1, IL-8)
release of histamine leads to what?
(effects are through what receptors?)
dilation of arterioles,
increased vascular permeability
(effects on small vessels are through H1 receptors)
Serotonin (stored where?)
stored in platelets
Serotonin released by what?
released by platelet aggregation induced by collagen contact, thrombin, ADP, Ag-Ab complexes
Actions of Serotonin
actions, similar to histamine

increased vascular permeability
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
COMPLEMENT
examples of Complement mediated inflammatory actions
CYTOLYSIS by formation of the MAC, opsonization of foreign organisms, solubilizaztion and clearance of Ab-Ag complexes
In Classical pathway, complement is inactive in plasma until activated at localized sites by:
activated at localized sites by:
Ag-Ab complexes
In Alternative pathway, pathway, complement is inactive in plasma until activated at localized sites by:
activated at localized sites by:
surfaces of pathogens
central component of Complement Cascade
C3 is central component
both pathways generate different C3 convertase complexes that activate C3, converting it to C3a and C3b
C3b action
proteolytically cleaves C5; C5b + C6, C7, C8 C9 ---> C5-9 (MAC)

can also opsonize bacteria
C3a and C5a
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)
Histamine independent actions of C5a:
-activates lipoxygenase pathway in
PMN--> leukotrienes--> + permeability

-potent chemoattractant for and activator of PMNs

-increases leukocyte adhesion to endothelium
EICOSANOIDS
-local short range hormones; formed rapidly, local effects, short lived
where are eicosanoids formed?
formed in LIBID BODIES (specialized cellular domains, that have high concentration of the synthetic enzymes)
COX pathway-
Initiated by:
Results in:
Initiated by COX-1 or COX-2

Results in: formation of PROSTAGLANDINS
Tissue restricted enzymes involved in arachidonic acid cascade
IN PLATELETS: TxA2 synthase
(makes TxA2 = vasoconstrictor)
IN ENDOTHELIUM:
Prostacyclin synthase (makes PGI2= a vasodilator)
Diapedesis
“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.
chemokine responsible for initial "rolling" in leukocyte extravasation
SELECTINS expressed by endothelial cells, interact with glycoproteins on leukocyte to slow it down

cooperates with Integrin-ICAM interaction in "STICKING" adhesion
chemokines activate what structure on leukocyte surface, that is primarily responsible for diapedesis?
INTEGRIN: on Leukocyte surface aids in establishing stable adhestion "STICKING" (along with selectin)

and mediates migration through endothelium
chemokines
superfamily of small proteins that activate and chemoattract leukocytes
important characteristics of complement
-multiple proteolytic enzymes
-sequential activation
-amplification
-highly regulated
complement is inactive until activated by:
-Ag-Ab complexes "Classical pathway"
-Surfaces of pathogens "Alternative Pathway"
Effector Functions of Activated Complement
C3a C5a: INFLAMMATION
C3b: Opsonization/Phagocytosis
C3b cleaves C5--> C5-9 (MAC): Lysis of Microbe
MAC
C3b proteolytically cleaves C5

C5b + C6, C7, C8, C9 --> C5-9
Histamine dependent actions of anaphylatoxins
-bind to mast cells and release histamine
-dilation of arterioles
-increased vascular permeability of the venules
principal mediator of immediate vascular permeability
histamine
Histamine independent actions of anaphylatoxin(s)
C5a activates lipoxygenase pathway in PMN → leukotrienes → increased permeability
complement gone wrong...
SURVIVAL of sepsis dramatically increased with C5a BLOCKADE
(indicates strong potential for complement to drive disease)
Factor XIIa induces what two cascades?

Both these cascades interact and induce what downstream cascade?
Kinin cascade and Clotting Cascade

both lead (indirectly) to activation of complement cascade
how do steroids exert their anti-inflammatory properties?
inhibit phospholipases that liberate arachidonic acid from cell membrane phospholipids
how do COX-1 and COX-2 inhibitors exert their anti-inflammatory properties?
inhibit cyclooxygenase involved in the conversion of ARACHIDONIC ACID to Prostaglandin G2 (PGG2)
PGI2 causes:
opposes action of?
causes vasodilation, inhibits platelet aggregation

opposes action of TxA2
TXA2 action:

opposes action of what?
causes vasoconstriction, promotes platelet aggregation

opposes action of PGI2
5-Lipoxygenase
Neutrophil specific enzyme
involved in branch of arachidonic acid cascade that generates various Lipoxins, and Leukotrienes (some pro-, some anti-inflammatory
Products of Arachidonic Acid Cascade
EICOSDINOIDS

formed in specialized cellular domains called lipid bodies, that have high concentration of synthetic enzymes
examples of eicosanoid metabolites involved in:
->vasoconstriction:
TxA2, LTC4, D4, E4

eicosanoid metabolites involved in what action:
examples of eicosanoid metabolites involved in:
->vasodilation
PGI2, E1, E2, D2
eicosanoid metabolites involved in what action:
examples of eicosanoid metabolites involved in:
->+ vascular permeability
LTC4, D4, E4
eicosanoid metabolites involved in what action:
examples of eicosanoid metabolites involved in:
->chemotaxis, leukocyte adhesion
LTB4, HETE, Lipoxins
Lipoxins
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?)
chemokines are secreted and bind to what?
cell surface proteoglycans (immobilized to form gradients)

bind to 7transmembrane receptors and activate --> G PROTEINS
HIV co-receptor = what kind of receptor?
a chemokine receptor
NO is released from what type of cells?
Endothelial cells
NO action on vessels
vasodilator
NO action as hormone
local paracrine factor
NO lifespan
SHORT LIVED
NO forms adducts with what?
froms adducts with thiol groups on Proteins (S-Nitrosoproteins)

(Hemoglobin : NO sing, may be an important function of Hb)
NO synthesized from what?
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
Types of NOS
enzyme NITRIC OXIDE SYNTHASE (NOS)
-constitutive (eNOS, nNOS) low levels, ca++ activated
-inducible (iNOS) produced by M0s, requires denovo synthesis, no ca++ needed
Importance of NO in host defense
can be used for killing of intracellular bacteria
eNOS constitutively expressed, activated by what?
activated by movement of Ca2+ into cell, results in reduced platelet adhesion, reduced leukocyte adhesion
iNOS not produced by macrophage until appropriate stimuli available, release can result in
-cytotoxic killing of engulfed pathogens, or secretion into tissues

vascular SM relaxation/vasodilation
IL1/TNF cytokines produced by
MACROPHAGE (and other cell) activation by: bacterial products, immune complexes, toxins, physical injury and other cytokines
IL1/TNF effects
ACUTE-PHASE REACTIONS
ENDOTHELIAL EFFECTS
FIBROBLASTS EFFECTS
LEUKOCYTE EFFECTS
IL1/TNF induced ACUTE-PHASE REACTIONS
fever
+ sleep
- appetite
+ Acute phase proteins
hemodynamic effects (shock)
neutrophilia
IL1/TNF induced ENDOTHELIAL EFFECTS
+ Leukocyte adherence
+ PGI synthesis
+ Procoagulant activity
- anticoagulant activity
+ IL1, IL8, IL6, PDGF
IL1/TNF induced FIBROBLASTS EFFECTS
+ proliferation
+ collagen synthesis
+ collagenase
+ protease
+ PGE synthesis
IL1/TNF induced LEUKOCYTE EFFECTS
+ cytokine secretion (IL-1, IL-6)
chemokine specificity
-eotaxin attracts what?
whereas
-IL-8 attracts what?
eotaxin attracts EOSINOPHILS

IL-8 attracts NEUTROPHILS
NF-kB
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
Stimuli that activate NF-kB
TNFalpha
IL-1beta
Lipopolysaccharide
Genes/proteins that are induced by NF-kB
TNFalpha
IL-1beta
NFkappaB activation by LBP and CD14 involves what type of receptor?
TLR4
TOLL LIKE RECEPTOR 4
IL-1, LPS, Spatzle all interact with TLRs to activate
NFkappaB
Amplification of inflammation via NFkappaB activity
inflammatory gene products promoted by p50 and p65 induce inflammatory signals that increase NFkappaB activation
Glucocorticoid effects on NFkappaB activity
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)
aspirin can inhibit inflammation via COX inhibition and also through what action on NFkappaB pathway
inhibits IkB kinases (responsible for degradation/activation of NFkB and release of transcription factors)
Entanercept and Infliximab/Remicade
both inhibit what?
the share what region?
both inhibit TNFa

both have Fc receptor of IgG1
Entanercept
soluble TNF-alpha receptor

Fc Region of Human IgG1
EC Domain of Human p75 TNF receptor
Infliximab/Remicade (cA2)
monoclonal antibody with Fc Region of Human IgG1

essentially mops up TNF
what is the central mediator in Rheumatoid Arthritis?
what is it secreted by?
what cells does it activate?
TNF- (secreted by monocytes) activates
-Endothelial Cells
-Monocytes (also secrete IL-1)
-Synovial Fibroblasts (secrete various factors)
Drugs useful in treating RA
methotrexate
+ Entanercept (soluble TNF-a receptor, fusion protein)
or
+ Infliximab; remicade (TNF-alpha monoclonal Ab)
cA2 showed what in Crohn's patients
higher rates of remission than those who received placebo