Page 155 - Textbook of Pathology, 6th Edition

producing them or on other cells. Although over 200 Hageman factor (factor XII) of clotting system plays a key role 139
cytokines have been described, major cytokines acting as in interactions of the four systems. Activation of factor XII in
mediators of inflammation are: interleukin-1 (IL-1), tumour vivo by contact with basement membrane and bacterial
necrosis factor (TNF)-α and β, interferon (IFN)-γ, and endotoxins, and in vitro with glass or kaolin, leads to
chemokines (IL-8, PF-4). activation of clotting, fibrinolytic and kinin systems. In
IL-1 and TNF-α are formed by activated macrophages inflammation, activation of factor XII is brought about by
while TNF-β and IFN-γ are produced by activated T cells. contact of the factor leaking through the endothelial gaps. CHAPTER 6
The chemokines include interleukin 8 (released from The end-products of the activated clotting, fibrinolytic and
activated macrophages) and platelet factor-4 from activated kinin systems activate the complement system that generate
platelets, both of which are potent chemoattractant for permeability factors. These permeability factors, in turn,
inflammatory cells and hence their name. further activate clotting system.
The actions of various cytokines as mediator of The inter-relationship among 4 systems is summarised
inflammation are as under: in Fig. 6.10.
i) IL-1 and TNF-αα αα α, TNF-ββ ββ β induce endothelial effects in the 1. THE KININ SYSTEM. This system on activation by
form of increased leucocyte adherence, thrombogenicity, factor Xlla generates bradykinin, so named because of the
elaboration of other cytokines, fibroblastic proliferation and slow contraction of smooth muscle induced by it. First,
acute phase reactions. kallikrein is formed from plasma prekallikrein by the action Inflammation and Healing
ii) IFN-γγ γγ γ causes activation of macrophages and neutrophils of prekallikrein activator which is a fragment of factor Xlla.
and is associated with synthesis of nitric acid synthase. Kallikrein then acts on high molecular weight kininogen to
iii) Chemokines are a family of chemoattractants for form bradykinin (Fig. 6.11).
inflammatory cells (as discussed above) and include: Bradykinin acts in the early stage of inflammation and
IL-8 chemotactic for neutrophils; its effects include:
platelet factor-4 chemotactic for neutrophils, monocytes smooth muscle contraction;
and eosinophils; vasodilatation;
MCP-1 chemotactic for monocytes; and increased vascular permeability; and
eotaxin chemotactic for eosinophils. pain.

6. FREE RADICALS: OXYGEN METABOLITES AND 2. THE CLOTTING SYSTEM. Factor Xlla initiates the
NITRIC OXIDE. Free radicals act as potent mediator of cascade of the clotting system resulting in formation of
inflammation: fibrinogen which is acted upon by thrombin to form fibrin
i) Oxygen-derived metabolites are released from activated and fibrinopeptides (Fig. 6.12).
neutrophils and macrophages and include superoxide The actions of fibrinopeptides in inflammation are:
oxygen (O’ ), H O , OH’ and toxic NO products. These increased vascular permeability;
2
2
2
oxygen-derived free radicals have the following action in chemotaxis for leucocyte; and
inflammation: anticoagulant activity.
Endothelial cell damage and thereby increased vascular 3. THE FIBRINOLYTIC SYSTEM. This system is activated
permeability. by plasminogen activator, the sources of which include
Activation of protease and inactivation of antiprotease kallikrein of the kinin system, endothelial cells and
causing tissue matrix damage. leucocytes. Plasminogen activator acts on plasminogen
Damage to other cells. present as component of plasma proteins to form plasmin.
The actions of free radicals are counteracted by Further breakdown of fibrin by plasmin forms fibrino-
antioxidants present in tissues and serum which play a peptides or fibrin split products (Fig. 6.13).
protective role (page 33). The actions of plasmin in inflammation are as follows:
ii) Nitric oxide (NO) was originally described as vascular activation of factor XII to form prekallikrein activator that
relaxation factor produced by endothelial cells. Now it is stimulates the kinin system to generate bradykinin;
known that NO is formed by activated macrophages during splits off complement C to form C which is a
the oxidation of arginine by the action of enzyme, NO permeability factor; and 3 3a
synthase. NO plays the following role in mediating degrades fibrin to form fibrin split products which
inflammation: increase vascular permeability and are chemotactic to
Vasodilatation leucocytes.
Anti-platelet activating agent
Possibly microbicidal action. 4. THE COMPLEMENT SYSTEM. The activation of
complement system can occur either:
II. Plasma-derived Mediators (Plasma Proteases) i) by classic pathway through antigen-antibody complexes;

These include the various products derived from activation or
and interaction of 4 interlinked systems: kinin, clotting, ii) by alternate pathway via non-immunologic agents such as
fibrinolytic and complement. Each of these systems has its bacterial toxins, cobra venoms and IgA.
inhibitors and accelerators in plasma with negative and Complement system on activation by either of these two
positive feedback mechanisms respectively. pathways yields activated products which include