Plasma-derived mediators of inflammation Flashcards
acute inflammatory response is orchestrated by
plasma derived and cell derived chemical mediators
plasma-derived mediators are produced mainly in the
liver
plasma-derived mediators are present in circulation as
inactive precursors
plasma contains 4 major protease cascade systems that contribute to inflammation
- complement
- kinin
- products of coagulation
- fibrinolysis
what is the complement system
a collection of soluble proteins and membrane receptors that function mainly in host defense against microbes and in pathologic inflammatory reactions
complement system consists of
more than 20 proteins, some numbered C1 through C9
does complement function in innate or adaptive immunity
both
in the process of complemetn activation, several celavage products of complement proteins are elaborated that cause
increased vascular permeability, chemotaxia, and opsonization
the critical step in complement activation is the
proteolysis of the 3fd component (C3)
Cleavage of C3 can occur by one of three pathways
classical, alternative, lectin
classical pathway
triggered by fixation of C1 to antibody (IgM, or IgG) that has combined with antigen
alternative pathway
can be triggered by microbial surface molecules, complex polysaccharaides, cobra venom, and other substances, in the absence of antibody
lectin pathway
plasma mannose-binding lectin binds to CHO on microbes and directly activates C1
all three pathways of complement activation lead to the formation of an active enzyme called
the C3 convertase
c3 convertase
splits C3 into 2 functionally distinct fragments, C3a and C3b
C3a
released
C3b
covalently attached to the cell or molecule where complement is being activated; more binds to previously generated fragments to form C5 convertase
c5 convertase
cleaves C5 to release C5a and leave C5b attached to the cell surface
C5b
binds to the late components C6-C9, culminating in the formation of membrane attack complex
MAC composed of
multiple C9 molecules
MAC formation of a sufficient number of these large pores or patches causes
an electrolyte imbalance in the target cell, a rapid loss of cell function ensues and lytic death usually results
the complement system has 3 main functions
inflamation
opsonization
cell lysis
anaphylatoxins
C3a, C5a, C4a are cleavage products of the corresponding complement components that stimulate histamine release from mast cells
C5a is also a chemotactic agent for
neutrophils, monocytes, eosinophils, and basophils
C5a activates
lipoxygenase pathway of AA metabolism in neutrophils nd monocytes, causing further release of inflammatory mediators
C3b and its cleavage product when fixed to a microbial cell wall, act as opsonins and promote
phagocytosis by neutrophils and macrophages; which bear cell surface receptors for the complement fragments
MAC is important in
killing of microbes with thin cell walls
kinin system is activated by
coagulation factor XII (Hageman factor)
what are kinins
vasoactive peptides derived from plasma proteins (kininogens) by the action of specific proteases (kallikreins)
the enzyme kallikrein cleaves
a plasma glycoprotien precursor, high-molecular-eight kinogen, to produce bradykinin
bradykinin
increases vascular permeability and causes contraction of smooth muscle, dilation of blood vessels, and pain when injected into the skin
action of bradykinin
short lived; quickly inactivated by an enzyme called kininase
coagulation system is responisble for
conversion of soluble fibrongen into fibrin
the ultimate goal of coag system is to
produce thrombin that can convert soluble fibrinogen into fibrin
fibrin is an important component of
inflammatory exudates
end product of fibrinolytic pathway is
plasmin
what is plasmin
a potent proteolytic enzyme with a broad spectrum of activity
plasmin is responsible for the
lysis of fibrin into fibrindegradation products, and plasmin acts on fibrin at over 5- sites, breaking down into tiny fibrin degradation products which can easily be removed
plasminogen activators are found in
plasma and in many tissues; also present in endothelial cells
