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 matri x protein synthesis and degradation, which in turn is controlled by the bal ance between proteases and antiproteases. Recent evidence has suggested tha t antiproteases may also exert direct effects on cell function, including i nfluencing cell migration and proliferation. The antiprotease, alpha (1)-an titrypsin, is the major circulating serine protease inhibitor which protect s tissues from neutrophil elastase attack. Its deficiency is associated wit h the destruction of connective tissue in the lung and the development of e mphysema, whereas accumulation of mutant alpha (1)-antitrypsin within hepat ocytes often leads to liver fibrosis. In this study, we report that alpha ( 1)-antitrypsin, at physiologically relevant concentrations, promotes fibrob last proliferation, with maximal stimulatory effects of 118 +/- 2% (n = 6, P < 0.02) above media controls for cells exposed to 60 <mu>M. We further sh ow that alpha (1)-antitrypsin also stimulates fibroblast procollagen produc tion, independently of its effects on cell proliferation, with values maxim ally increased by 34 +/- 3% (n = 6, P < 0.01) above media controls at 30 <m u>M. Finally, mechanistic studies to examine the mechanism by which alpha ( 1)-antitrypsin acts, showed that alpha (1)-antitrypsin induced the rapid ac tivation of p42(MAPK) and p44(MAPK) (also known as ERK1/2) and that the spe cific MEK1 inhibitor PD98059 totally blocked alpha (1)-antitrypsin's mitoge nic effects. These results support the hypothesis that alpha (1)-antitrypsi n may play a role in influencing tissue repair in vivo by directly stimulat ing fibroblast proliferation and extracellular matrix production via classi cal mitogen-activated signalling pathways. J. Cell. Physiol. 186:73-81, 200 1. (C) 2001 Wiley-Liss, Inc.