Mechanisms of pulmonary fibrosis. Spontaneous release of the alveolar macrophage-derived growth factor in the interstitial lung disorder
Interstitial lung disorders are characterized both by a chronic inflammation of the lower respiratory tract that includes increased numbers of activated alveolar macrophages and by increased numbers of fibroblasts within the alveolar wall. Since alveolar macrophages from normal individuals can be activated to release a growth factor for lung fibroblasts (alveolar macrophage-derived growth factor [AMDGF]), we hypothesized that the activated alveolar macrophages within the lower respiratory tract of patients with fibrotic lung disorders might be spontaneously releasing AMDGF. To evaluate this hypothesis, alveolar macrophages (suspension culture, 4 h, 37 degrees) from 65 patients with interstitial lung disorders and 30 control subjects were examined for the spontaneous release of fibroblast growth-promoting activity, with human lung fibroblasts as the target. Whereas none of the controls had macrophages spontaneously releasing a growth-promoting activity for fibroblasts, 82% of the patients with interstitial lung disease had alveolar macrophages that were spontaneously releasing a growth-promoting activity for fibroblasts. In common with AMDGF, the fibroblast growth-promoting activity released by these macrophages eluted from DEAE cellulose at 270 mM NaCl, had a partition coefficient of 0.3 by gel filtration on Sephadex G-50, was distinct from other characterized growth factors, and acted as a progression factor for fibroblast replication in a serum-free complementation test. These data suggest that the expansion of fibroblast numbers within the alveolar structures in interstitial lung disorders may result, in part, from the release of AMDGF by alveolar macrophages stimulated in vivo.