CHEMICAL MEDIATORS OF INFLAMMATION

( PLASMA PROTEIN DERIVED )

BY : Izatty Lim (0308188)

LEARNING OUTCOMES Able to describe the 3 systems of the plasma

protein-derived mediator of inflammation. Identify the plasma protein-derived mediator in

the 3 systems and their actions.

CHEMICAL MEDIATORS OF INFLAMMATION

Definition : any messenger that acts on blood vessels, inflammatory cells or other cells to contribute to an inflammatory response.

MEDIATORS

PLASMA PROTEIN-DERIVED MEDIATORS

Circulating protein of 3 interrelated system :o Complement systemo Kinin systemo Coagulation system

COMPLEMENT SYSTEM

Consist of plasma protein that play important role in host defense & inflammation. C1 – C9 Activated by proteolysis to acquire their own proteolytic activity, thus setting up an

enzymatic cascade. Critical step : activation of 3rd component, C3, by

o Classical pathway • By fixation of C1 to antigen-antibody complexes

o Alternative pathway• Triggered by bacterial polysaccharides (eg. Endotoxin) & other bacterial cell

wall component• Involving distinct set of plasma protein including properdin & factors B and D.

o Lectin pathway• Plasma lectin bind to mannose residues on microbes & activates the early

component of classical pathway

COMPLEMENT SYSTEM

CLASSICAL PATHWAY

ALTERNATIVE PATHWAY

LECTIN PATHWAY

Formation of C3 Convertase

C 3 a C 3 b

C6 – C9

Formation of C5 Convertase

C 5 bC 5 a

Deposit on cell/microbial surface & bind with C3 convertase

(4) MAC (made up of multiple copies of final component C9) create pores disrupt osmotic balance cell lysis

(1) VASCULAR EFFECTS:-C3a & C5a induce release of histamine-↑ vascular permeability & cause vasodilation-C5a also activates lipoxygenase pathway of AA

(2) LEUKOCYTE ACTIVATION, ADHESION & CHEMOTAXIS:-C5a, C3a & C4a (lesser extent)-potent chemotatic agent for neutrophils, monocytes, eosinophil & basophil.

(3) PHAGOCYTOSIS:-C3b & iC3b act as opsonins- ↑ phagocytosis

Vascular effects (C3a & C5a) Leukocyte activation, adhesion, chemotaxis

(C5a) Phagocytosis (C3b,iC3b) MAC ( C9)

COAGULATION & KININ SYSTEM

Hageman factor ( Factor XII )o A protein synthesized by the livero Circulate in inactive form in plasmao Activated by collagen, basement membrane or activated

plateletso Activated Hageman factor (factor XIIa) further actives:

• Kinin system (vasoactive kinins)• Clotting system (activation of thrombin, fibrinopeptides & factor

X)• Fibrinolytic system (plasmin production & inactivating thrombin)• Complement system (anaphylatoxins C3a & C5a)

(High molecular-weight kininogen)

KININ SYSTEM

Bradykinino ↑ vascular permeabilityo Arteriolar dilationo Branchial smooth muscle contractiono Pain

Kallikreino Chemotatic activityo Potent activator of Hageman factor link with clotting

system

HMW KININOGEN BRADYKININ

KALLIKREIN

CLOTTING SYSTEM

Activated thrombino Fibrin cloto Enhance leukocytes adhesiono Cleave C5 C5a ( link with complement system )

Fibrinopeptideo ↑ vascular permeabilityo Chemotatic for leukocytes

Factor Xa (intermediate in clotting cascade)o ↑ vascular permeability & leukocyte emigration

Fibrinogen

Activated thrombin

Thrombin

Fibrin Clot

Fibrinopeptide

FIBRINOLYTIC SYSTEM

Plasmin o Multifunctional protease that cleaves fibrino Fibrin degradation product will ↑ permeabilityo Cleaves C3 C3a (vasodilation & ↑ vascular permeability)o Activate Hageman factor, thus amplify the entire set of

responses

• Activated concurrently with activation of clotting system

• Serve to limit clotting

The end.