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Am. J. Respir. Crit. Care Med., Volume 156, Number 6, December 1997, 1937-1944

Simultaneous or Delayed Administration of Hepatocyte Growth Factor Equally Represses the Fibrotic Changes in Murine Lung Injury Induced by Bleomycin
A Morphologic Study

MASAHIRO YAEKASHIWA, SHOICHI NAKAYAMA, KAZUYA OHNUMA, TOSHIHIKO SAKAI, TATSUYA ABE, KEN SATOH, KUNIO MATSUMOTO, TOSHIKAZU NAKAMURA, TOHRU TAKAHASHI, and TOSHIHIRO NUKIWA

Department of Respiratory Oncology and Molecular Medicine, Division of Cancer Control; Department of Pathology, Division of Organ Pathophysiology, Institute of Development, Aging and Cancer, Tohoku University, Sendai; and Division of Biochemistry, Department of Oncology, Biomedical Research Center, Osaka University Medical School, Osaka, Japan

Hepatocyte growth factor (HGF) is a humoral mediator of epithelial-mesenchymal interactions, acting on a variety of epithelial cells as mitogen, motogen, and morphogen. Exogenous HGF acts as a hepatotrophic factor and a renotrophic factor during experimental injury. To investigate whether HGF has a pulmotrophic function, human recombinant HGF was administered to C57BL/6 mice with severe lung injury by bleomycin (BLM). Low dose simultaneous and continuous administration of HGF (50 µg/mouse/7 d) with BLM (100 mg/mouse/7 d) repressed fibrotic morphological changes at 2 and 4 wk. Ashcroft score showed a significant difference in lung fibrosis with and without HGF at 4 wk (3.7 ± 0.4 versus 4.9 ± 0.3, p < 0.05). Furthermore, either simultaneous or delayed administration of high dose HGF (280 µg/mouse/14 d) equally repressed fibrotic changes by BLM when examined at 4 wk (Ashcroft score: 2.6 ± 0.4 and 2.4 ± 0.2 versus 4.1 ± 0.2, p < 0.01). Hydroxyproline content in the lungs was significantly lower in mice with either simultaneous or delayed administration of high dose HGF as compared to those administered BLM alone (121.8 ± 8.1% and 113.2 ± 6.2% versus 162.7 ± 4.6%, p < 0.001). These findings indicate that exogenous HGF acts as a pulmotrophic factor in vivo and prevents the progression of BLM-induced lung injury when administered in either a simultaneous or delayed fashion. HGF may be a potent candidate to prevent or treat lung fibrosis.




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