Hepatocyte growth factor is elevated in chronic lung injury and inhibits surfactant metabolism

Adult respiratory distress syndrome may incorporate in its pathogenesis the hyperplastic proliferation of alveolar epithelial type II cells and derang ement in synthesis of pulmonary surfactant. Previous studies have demonstra ted that hepatocyte growth factor (HGF) in the presence of serum is a poten tial mitogen for adult type II cells (R. J. Panos, J. S. Rubin, S. A. Aaron son, and R. J. Mason. J. Clin. Invest. 92: 969-977, 1993) and that it is pr oduced by fetal mesenchymal lung cells (J. S. Rubin, A. M.-L. Chan, D. P. B otarro, W. H. Burgess, W. G. Taylor, A. C. Cech, D. W. Hirschfield, J. Wong , T Miki, P. W. Finch, and S. A. Aaronson. Proc. Natl. Acad. Sci. USA 88: 4 15-419, 1991). In these studies, we expand on this possible involvement of HGF in chronic lung injury by showing the following. First, normal adult lu ng fibroblasts transcribe only small amounts of HGF mRNA, but the steady-st ate levels of this message rise substantially in lung fibroblasts obtained from animals exposed to oxidative stress. Second, inflammatory cytokines pr oduced early in the injury stimulate the transcription of HGF in isolated f ibroblasts, providing a plausible mechanism for the increased amounts of HG F seen in vivo. Third, HGF is capable of significantly inhibiting the synth esis and secretion of the phosphatidylcholines of pulmonary surfactant. Fou rth, HGF inhibits the rate-limiting enzyme in de novo phosphatidylcholine s ynthesis, CTP:choline-phosphate cytidylyltransferase (EC 2.7.7.15). Our dat a indicate that fibroblast-derived HGF could be partially responsible for t he changes in surfactant dysfunction seen in adult respiratory distress syn drome, including the decreases seen in surfactant phosphatidylcholines.