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Role of Receptor Tyrosine Kinases and Mitogen-Activated Protein Kinases in Metal-Induced Pulmonary Fibrosis*

James C. Bonner, PhD; Yi-Zhe Wang, PhD; Ping Zhang, MD; Annette Rice; Limin Zhang, PhD; Kenneth Adler, PhD; Nonghoon Choe, PhD; Elliott Kagan, MD
Author and Funding Information

*From the National Institute of Environmental Health Sciences (Drs. Bonner, Wang, P. Zhang, and Ms. Rice), Research Triangle Park, NC; North Carolina State University (Drs. L. Zhang and Adler), Raleigh, NC; and Uniformed Services University of the Health Sciences (Drs. Choe and Kagan), Bethesda, MD.

Correspondence to: James C. Bonner, PhD, Head, Airway Inflammation Group, Laboratory of Pulmonary Pathobiology, NIEHS/NIH, Environmental Health Sciences, PO Box 12233, Research Triangle Park, NC 27709



Chest. 2001;120(1_suppl):S55-S56. doi:10.1378/chest.120.1_suppl.S55
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The proliferation of lung fibroblasts is a key component of pulmonary fibrosis. Several cell-surface receptor tyrosine kinases, including the platelet-derived growth factor receptor (PDGF-R) and epidermal growth factor receptor (EGF-R), mediate fibroblast mitogenesis via the activation of mitogen-activated protein (MAP) kinases. We have developed a model of metal-induced oxidative stress in rats using vanadium pentoxide (V2O5) that is characterized by interstitial and peribronchiolar fibrosis, airway smooth-muscle thickening, and mucous cell metaplasia. In vivo activation of the extracellular signal-regulated kinases (ERKs [ERK-1 and ERK-2]) was demonstrated by immunohistochemistry in fibrotic lesions caused by V2O5 exposure. Moreover, V2O5 injury upregulated platelet-derived growth factor α-receptor messenger RNA (mRNA) and protein in vivo. The mechanism of PDGF-Rα upregulation by V2O5 was elucidated in vitro and involved the release of interleukin-1β by alveolar macrophages, which then activated lung fibroblasts in a paracrine manner to activate p38 MAP kinase, which caused stabilization of PDGF-Rα mRNA. V2O5 also activated ERK-1 and ERK-2 in cultured lung fibroblasts in an oxidant-dependent manner that involved upstream activation of the EGF-R, Raf-1, MAP kinase kinase signaling cascade. In another study, V2O5 exposure of human bronchial epithelial cells in vitro caused the release of mitogenic activity for human lung fibroblasts that was abolished by a neutralizing antibody against heparin-binding epidermal growth factor-like growth factor. Induction of heparin-binding epidermal growth factor-like growth factor mRNA and protein by V2O5in vitro was reduced by the MAP kinase kinase inhibitor PD98059 and the p38 MAP kinase inhibitor SB203580. Finally, the intraperitoneal administration of tyrosine kinase inhibitors specific for either the PDGF-R or the EGF-R (tyrphostins AG1296 and AG1478, respectively) significantly reduced pulmonary fibrosis in rats exposed to V2O5. Collectively, these studies have identified signaling pathways and inducible genes activated by V2O5-stimulated oxidative stress that may offer potential targets for therapeutic intervention of pulmonary fibrosis.

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