[Complement activation and inflammation].
The complement system not only plays an important role in the defense system, but also contributes to the amplification of inflammation if activated in excess or inappropriately controlled. Complement activation through one of three pathways is tightly controlled by various regulators of complement activation (RCA) which are constitutively expressed on various cells in order to restrict excessive activation. Complement activation may generate polypeptides, so-called anaphylatoxins, and membrane attack complex (MAC) with large molecular mass. Anaphylatoxins (C3a, C4a, and C5a) produced by activation of the complement is considered to bridge innate and acquired immunity. Considering that C5a is more potent than C3a, but the serum concentration of C3 is 10 times higher than that of C5, the overall effects of C3a may be comparative with those of C5a. Since both anaphylatoxins are considered to exert their actions through rhodopsin-typed receptors, their receptor antagonists are targets for the discovery of anti-inflammatory and immune-modulating drugs. Complement activation may be related to the pathophysiology of various refractory disorders including ARDS, asthma, septic syndrome, SLE, rheumatoid arthritis, ischemia-reperfusion injury, and psoriasis etc. Pharmacological manipulation of the complement system may consist of various strategies including (1) inhibitors of complement activation at various levels, (2) receptor antagonists of anaphylatoxins, C3a and C5a, and (3) inhibitors of C5a including monoclonal antibody. Candidate agents concerning the above-mentioned manipulations have being produced and some are now in progress toward clinical trials in patients with certain diseases.
Abe
Masayoshi
M
Department of Pharmacology, Faculty of Medicine, Fukuoka University, Fukuoka.
D000818:Animals; D001249:Asthma / Q000276:immunology; D003167:Complement Activation / Q000502:physiology*; D003176:Complement C3 / Q000037:antagonists & inhibitors; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D044087:Receptor, Anaphylatoxin C5a / Q000037:antagonists & inhibitors; D012128:Respiratory Distress Syndrome / Q000276:immunology
C038245:C3 protein, human; D003176:Complement C3; D044087:Receptor, Anaphylatoxin C5a