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Platelet-Derived Growth Factor Receptors Are Essential in the Development of Asbestos-Induced Fibrosis^*

^* From the Tulane University School of Medicine, New Orleans, LA.

Correspondence to: Joseph A. Lasky, MD, FCCP, Associate Professor of Medicine, Section of Pulmonary Diseases and Critical Care Medicine, Tulane University Medical Center, 1430 Tulane Ave SL9, New Orleans, LA 70112-2699

Asbestos exposure results in the formation of fibroproliferative lung abnormalities similar to those encountered in subjects with idiopathic pulmonary fibrosis. Our prior publications demonstrate that platelet-derived growth factor (PDGF) is a potent mitogen and chemoattractant for lung fibroblasts and is elaborated in response to asbestos fibers. Stimulation of alveolar macrophages or lung fibroblasts with asbestos fibers in vitro induces the release of three biologically active PDGF dimers (AA, AB, BB). Likewise, we reported that exposure of rats or mice to chrysotile asbestos results in upregulation of PDGF-A and PDGF-B chain messenger RNA and peptide expression, as well as the PDGF- receptor that binds all three PDGF ligands, at the sites of fiber deposition and subsequent lesion formation. Now, we are employing the PDGF-receptor–selective tyrosine kinase inhibitor to test whether PDGF is essential in the formation of asbestos-induced lesions. We report herein that the development of asbestos-induced scars is blocked by 64% in PDGF-receptor–selective tyrosine kinase inhibitor-treated mice. PDGF ligand or receptor knockout mice are not viable. Thus, in an effort to determine which PDGF ligand-receptor interactions are important to asbestos-induced scar formation, we exposed "Patch" mice, which exhibit a 50% reduction in PDGF-–receptor expression, and ßRH mice with similar reductions in PDGF-ß–receptor expression, along with their wild-type littermates, to a regimen of chrysotile asbestos (15 mg/m³) for 5 h/d on 3 consecutive days. Fibrotic lesions developing at the alveolar duct bifurcations were analyzed 4 weeks following the onset of exposure and were found to be reduced in volume by approximately 50% in two separate experiments in the ßRH mice, but not in Patch mice. Our in vivo findings could not be explained by differences in proliferative responses to PDGF isoforms using lung fibroblast isolates from ßRH mice and their wild-type littermates. Thus, our findings demonstrate that PDGF does play a significant role in asbestos-induced scar formation, and that reduction in expression of PDGF-ß, but not PDGF-, receptor inhibits asbestos-induced fibrogenesis.

Footnotes

Abbreviation: PDGF = platelet-derived growth factor

This Article Full Text (PDF) Free Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Add to My Personal Article Archive Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Lasky, J. A. Articles by Brody, A. Search for Related Content PubMed Articles by Lasky, J. A. Articles by Brody, A.