Therapeutic approaches to organ fibrosis.
Scarring of superficial tissues and chronic fibroses of major organs present major medical problems ranging from disfigurement to progressive disability and death. Growing understanding of the cellular and molecular events, which are common to these intractable disorders, now provides a favourable basis for the development of effective drug therapies. Much attention is focussed on the roles of the many cytokines and growth factors, which contribute to the fibrogenic process. The transforming growth factor (TGF)-beta 1 and 2 isoforms are among the most significant of these and approaches to control their activity include blocking the activation of latent TGF-beta, preventing the ligand-receptor interactions and the inhibition of down-stream signal transduction. Concerns regarding possible risks of the long-term suppression of TGF-beta function point to connective tissue growth factor (CTGF) as a possible alternative target. CTGF is induced by and appears to mediate at least some of the fibrogenic actions of TGF-beta, although not its important antimitogenic activity on epithelial cells. The fibrogenic effects of endothelins and angiotensin II have aroused considerable interest in the anti-fibrotic potential of antihypertensive agents designed primarily to limit the vasoconstrictive activities of these peptides. Polypeptides including interferons alpha and gamma, relaxin, TGF-beta 3 and hepatocyte growth factor, all show an ability to limit fibrogenesis in either clinical or experimental situations. Finally, inhibitors of the enzymes required for the post-translational processing of collagens, including prolyl 4-hydroxylase, C-proteinase and lysyl oxidase provide a more direct means of reducing the deposition of fibrillar collagens into the extracellular matrix although the potentially adverse effects of sustained manipulation of collagen metabolism remain to be investigated.
Franklin
T J
TJ
Zeneca Pharmaceuticals, Alderley Park, Macclesfield, U.K.
D000818:Animals; D003094:Collagen / Q000378:metabolism; D016207:Cytokines / Q000502:physiology; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000502:physiology; D005355:Fibrosis / Q000209:etiology / Q000503:physiopathology / Q000628:therapy*; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000503:physiopathology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000502:physiology
D016207:Cytokines; D016212:Transforming Growth Factor beta; D003094:Collagen