Pulmonary fibrosis is a chronic inflammatory disorder characterized by diffuse fibrous remodeling of alveolar spaces. Although much interest is focused on mechanisms of the inflammatory process in pulmonary fibrosis, little is known about the repair and regenerative process. Hepatocyte growth factor (HGF), originally discovered as a mitogen for hepatocyte regeneration, is now recognized as a multifunctional mesenchymal factor for epithelial regeneration, including the regeneration of alveolar type II epithelial cells. Involvement of HGF and its receptor (c-met) is evident in animal models of acute lung injury produced by hydrochloride inhalation. We studied the role of HGF in patients with idiopathic pulmonary fibrosis (IPF) (25 cases), lung fibrosis associated with rheumatoid arthritis (22 cases), and sarcoidosis (39 cases). Immunohistochemical evaluation demonstrated that hyperplastic alveolar type II epithelial cells, as well as alveolar macrophages, were strongly stained with anti-HGF antibody in tissues of patients with IPF. The concentration of HGF in bronchoalveolar lavage fluid (BALF) was significantly higher than in normal controls (0.23 +/- 0.09 pg/microg) in patients with IPF (0.77 +/- 0.88 pg of HGF/microg of albumin, P < 0.001), lung fibrosis associated with rheumatoid arthritis (0.50 +/- 0.64 pg/microg, P < 0.01), and sarcoidosis (0.41 +/- 0.61 pg/microg, P < 0.05). In situ hybridization revealed mRNA for HGF in alveolar macrophages (especially small monocytelike macrophages). These results indicate that the increase in HGF concentration in patients' peripheral air spaces is due to augmented HGF production by alveolar epithelial cells and alveolar macrophages. HGF, through a paracrine mechanism, may play an important role in the repair and healing of the inflammatory lung damage in pulmonary fibrosis.