A variety of airborne particulates and pollutant gases cause lung inflammation by oxidative injury. Our laboratory has focused on the mechanisms by which inhaled particulates such as asbestos cause nonresolving inflammation that leads to pulmonary fibrogenesis. A key feature of these lesions is mesenchymal cell (fibroblast and smooth muscle cell) hyperplasia. We have previously reported that rat alveolar macrophages activated by inorganic particulates secrete platelet-derived growth factor (PDGF)-like molecules that are potent mitogens and chemoattractants for rat lung fibroblasts. These activated macrophages also secrete increased levels of transforming growth factor-beta (TGF-beta) and we have shown that TGF-beta increases the gene expression of extracellular matrix proteins (fibronectin and type I collagen) by fibroblasts. Thus, we have identified two macrophage-derived mediators, PDGF and TGF-beta, that promote fibroblast growth and extracellular matrix deposition, respectively. These two factors are essential for normal lung development and tissue repair following injury and inflammation. However, because their aberrant expression is thought to lead to fibroproliferative lung disease, their activity must be precisely regulated. We have discovered that PDGF action is regulated at several different levels. These include 1) macrophage activation for PDGF gene expression and secretion, 2) association of PDGF with its binding protein, alpha2- macroglobulin (alpha2M) and subsequent activation of the PDGF/alpha2M complex by proteinases, and 3) expression of PDGF receptors on fibroblasts. Asbestos fibers appear to interfere with at least some of these regulatory mechanisms in the following ways. First, asbestos fibers increase PDGF secretion by macrophages by as much as 10-fold, while alpha2M secretion is increased by only 2-fold. This could be due in part to the observation that oxidants generated by activated phagocytes functionally inactivate alpha2M. Secondly, fibroblasts exposed to asbestos up-regulate their pDGF- alpha receptors, which renders these cells more responsive to the pDGF-AA isoform. Asbestos fibers also stimulate fibroblasts to express the gene for PDGF-A chain and secrete PDGF-AA. The mechanism by which asbestos induces this PDGF-AA autocrine growth loop is currently under investigation. Most recently, we have shown that interleukin-1beta (IL- 1beta) induces a dramatic PDGF-alpha receptor upregulation on fibroblasts and we have postulated that asbestos fibers cause receptor transmodulation by first increasing IL-1beta release from fibroblasts.
