Mechanisms of pulmonary fibrosis. Spontaneous release of the alveolar macrophage-derived growth factor in the interstitial lung disorders.

Abstract

A B S T R A C T 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, 370) 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 growthpromoting 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 serumfree 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.

Induction of Macrophage Insulin-Like Growth Factor-I Expression by the Th2 Cytokines IL-4 and IL-13

“…As discussed earlier, IGF-I stimulates many responses that are consistent with its proposed role in the pathogenesis and progression of IPF including acting as a progression factor for fibroblast proliferation (8) and stimulating collagen matrix synthesis (22). However, recent studies have also revealed the importance of IGF-I as a survival factor that acts to inhibit apoptosis in a wide variety of cell types including myofibroblasts, and skeletal and smooth muscle cells (54,55).…”

“…In 1983, Bitterman et al (8) found that alveolar macrophages from patients with IPF spontaneously released a peptide growth factor capable of promoting fibroblast proliferation. The growth factor was found to function as a progression factor for fibroblast proliferation and was termed AMDGF.…”

A Profibrotic Function of IL-12p40 in Experimental Pulmonary Fibrosis

“…Pulmonary macrophages play an important role in the pathogenesis of lung fibrosis by promoting inflammation and fibrotic responses (19,20). IL-12p70, composed of p35 and p40 subunits, is a major Th1-driving cytokine establishing cell-mediated immunity (6) and preferentially expressed by APC cells such as pulmonary macrophages (21,22).…”

Pulmonary immune responses induced in BALB/c mice by Paracoccidioides brasiliensis conidia

“…It may also be the result of cryptogenic processes [142][143][144]. In these diseases, fibrosis shares common characteristics, including fibroblast proliferation and extracellular matrix deposition [145][146][147]. Lung fibrosis often follows a series of chronic granulomatous processes.…”