Alpha‐1‐antitrypsin stimulates fibroblast proliferation and procollagen production and activates classical MAP kinase signalling pathways

Connective tissue formation at sites of tissue repair is regulated by matrix protein synthesis and degradation, which in turn is controlled by the balance between proteases and antiproteases. Recent evidence has suggested that antiproteases may also exert direct effects on cell function, including influencing cell migration and proliferation. The antiprotease, α 1 ‐antitrypsin, is the major circulating serine protease inhibitor which protects tissues from neutrophil elastase attack. Its deficiency is associated with the destruction of connective tissue in the lung and the development of emphysema, whereas accumulation of mutant α 1 ‐antitrypsin within hepatocytes often leads to liver fibrosis. In this study, we report that α 1 ‐antitrypsin, at physiologically relevant concentrations, promotes fibroblast proliferation, with maximal stimulatory effects of 118 ± 2% (n = 6, P  < 0.02) above media controls for cells exposed to 60 μM. We further show that α 1 ‐antitrypsin also stimulates fibroblast procollagen production, independently of its effects on cell proliferation, with values maximally increased by 34 ± 3% (n = 6, P  < 0.01) above media controls at 30 μM. Finally, mechanistic studies to examine the mechanism by which α 1 ‐antitrypsin acts, showed that α 1 ‐antitrypsin induced the rapid activation of p42 MAPK and p44 MAPK (also known as ERK1/2) and that the specific MEK1 inhibitor PD98059 totally blocked α 1 ‐antitrypsin's mitogenic effects. These results support the hypothesis that α 1 ‐antitrypsin may play a role in influencing tissue repair in vivo by directly stimulating fibroblast proliferation and extracellular matrix production via classical mitogen‐activated signalling pathways. J. Cell. Physiol. 186:73–81, 2001. © 2001 Wiley‐Liss, Inc.