Am. J. Respir. Crit. Care Med., Volume 162, Number 6, December 2000, 2302-2307

Hepatocyte Growth Factor Attenuates Collagen Accumulation in a Murine Model of Pulmonary Fibrosis

MAKOTO DOHI, TAKASHI HASEGAWA, KAZUHIKO YAMAMOTO, and BRUCE C. MARSHALL

Department of Allergy and Rheumatology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; and Salt Lake VA Medical Center and the Division of Respiratory, Critical Care, and Occupational Pulmonary Medicine, University of Utah Health Sciences Center, Salt Lake City, Utah

We investigated the in vivo effects of recombinant human hepatocyte growth factor (HGF) on epithelial cell proliferation in normal mouse lung and on the repair process that follows bleomycin-induced lung injury. Intratracheal administration of 100 µg of rhHGF to C57BL/6 mice led to proliferation of bronchial and alveolar epithelial cells as indicated by an increased number of cells staining for proliferating cell nuclear antigen (PCNA). The effect of HGF on the lung repair process was examined by administration of 100 µg of rhHGF on Day 3 and Day 6 after intratracheal injection of bleomycin to mice. We found that HGF significantly attenuated collagen accumulation induced by bleomycin as determined by quantitation of hydroxyproline content and by scoring of the extent of fibrosis. To explore the potential mechanisms involved in the beneficial effects of HGF, we performed in vitro studies with A549 pulmonary epithelial cells and found that HGF enhanced cell surface plasmin generation, expression of u-PA activity, and cell migration. In summary, HGF has potent in vivo and in vitro effects on epithelial cells, which suggests it may have a role in the therapy of pulmonary fibrosis.

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