Approaches to the design of anti-fibrotic drugs

Introduction Progressive fibro-proliferative diseases (FPDs), such as liver cirrhosis, pulmonary fibrosis, scleroderma, ankylosing spondylitis and rheumatoid arthritis, exhibit excessive production of connective tissue and the resulting destruction of normal tissue architecture and function. It is generally recognized that most treatments for these diseases have little effect upon the inexorable pathological progression. Elimination of the initiating cause, where it is known, can be helpful. For example, abstinence from alcohol improves survival in liver cirrhosis [ 13 and removal of patients with early silicosis of the lungs from the silica-dust-laden environment has long been known to be of major benefit. In cases of liver fibrosis resulting from chronic infection with hepatitis C, suppression of viral activity by interferon-a appears to slow the fibrogenic process in a proportion of patients [2]. In most FPDs a chronic inflammatory process may provide a continuing stimulus to fibrogenesis. Treatment of alcoholic liver disease with anti-inflammatory steroids benefits some patients [ 11 and this form of treatment is occasionally dramatically successful for scleroderma and pulmonary fibrosis [ 31. Anti-inflammatory therapy of joint disease generally provides only symptomatic relief. The possibility of a direct attack on the growth and proliferation of the connective tissue has been raised many times. Cytotoxic drugs have been used in pulmonary fibrosis in the hope of slowing the proliferation of fibroblasts [4]. These drugs are also used in the treatment of rheumatoid arthritis, and methotrexate, for example, shows particular promise although its mode of action is uncertain and may involve suppression of some aspects of immune function [S]. There is increasing interest in the possibility of modulating the functions of cytokines, believed to regulate the proliferative and biosynthetic activities of connective tissue [6]. These include transforming growth factor (TGF)-P, platelet-derived growth factor (PDGF), epidermal growth factor (EGF) and interieukin1. However, there are formidable technical obstacles to be overcome in the design and development of