PRESENCE OF PLATELET-DERIVED GROWTH-FACTOR IN NORMAL AND FIBROTIC LUNG IS SPECIFICALLY ASSOCIATED WITH INTERSTITIAL MACROPHAGES, WHILE BOTH INTERSTITIAL MACROPHAGES AND ALVEOLAR EPITHELIAL-CELLS EXPRESS THE C-SIS PROTOONCOGENE

Normal lung structure is maintained by the presence of mesenchymal cells and their extracellular matrix products. The slow normal turnover of these cells is disrupted in fibrotic disorders, resulting in the in situ accumulation of mesenchymal cells and their extracellular matrix leading to a progressive alveolar wall thickening. Idiopathic pulmonary fibrosis (IPF) is a chronic fibrotic disorder of the lung characterized by a diffuse interstitial and intra-alveolar inflammation dominated by macrophages and polymorphonuclear neutrophils. Evaluation of alveolar macrophages (AM) obtained by bronchoalveolar lavage has previously shown that AM from normal individuals spontaneously release small amounts of platelet-derived growth factor (PDGF), a chemotactic and growth factor for mesenchymal cells, whereas AM from IPF patients spontaneously release increased amounts of biologically active PDGF, suggesting its involvement in mesenchymal cell accumulation. However, other cells such as endothelial cells and vascular smooth muscle cells can also release PDGF in vitro. In order to specify PDGF location in lung parenchyma, open lung biopsies from normal individuals and IPF patients were examined by immunohistochemistry using an anti-PDGF antibody and by in situ hybridization using PDGF A-chain and B-chain gene probes. In normal as well as in fibrotic lung, PDGF was only present in relation with interstitial macrophages but not with any other inflammatory cells or mesenchymal cells. Furthermore, the percent-age of PDGF-positive macrophages in IPF was 3-fold increased in comparison to normal lung. In addition, the percentage of PDGF-positive macrophages was the same in fibrotic and nonfibrotic areas of IPF lungs. Finally, although no PDGF A-chain transcript was detected, PDGF B-chain gene was shown to be expressed by interstitial macrophages, alveolar epithelial cells, and pleural mesothelial cells. These observations suggest that: (1) PDGF is present in normal and fibrotic lungs, (2) PDGF is specifically associated with macrophages, (3) IPF macrophages and alveolar epithelial cells express PDGF B-chain gene, and (4) PDGF accumulation precedes the fibrotic process. Thus, PDGF may play a role in normal lung mesenchymal cell turnover and in the pathogeny of lung fibrosis.