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Oxidants and Signaling by Mitogen-Activated Protein Kinases in Lung Epithelium

Departments of Pathology and Pharmacology, University of Vermont College of Medicine, Burlington, Vermont; and Department of Environmental Health Sciences and Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University, Baltimore, Maryland

Correspondence and requests for reprints should be addressed to Brooke T. Mossman, Ph.D., Department of Pathology, 218 HSRF Building, University of Vermont College of Medicine, Burlington, VT 05405. E-mail: Brooke.Mossman{at}uvm.edu

Abstract

Oxidants in cigarette smoke and generated from asbestos fibers activate mitogen-activated protein kinase (MAPK) signaling cascades in lung epithelial cells in vitro and in vivo. These signaling pathways lead to the enhanced ability of Jun and Fos family members (i.e., components of the activator protein [AP]-1 transcription factor) to activate transcription of a number of AP-1–dependent target genes involved in cell proliferation or death, differentiation, and inflammation. Research by the Basbaum laboratory has been critical in showing that mucin transcription in response to cigarette smoke and gram-positive bacteria is mediated through activation of the epidermal growth factor receptor and MAPK cascades. Work from our laboratories supports the concept that MAPK signaling and AP-1 transactivation by cigarette smoke and asbestos may synergize in lung epithelial cell injury, compensatory proliferation of lung epithelial cells, and carcinogenesis, supporting a mechanistic framework for the striking increases in lung cancer incidence in asbestos workers who smoke. Targeting of MAPKs and inter-related signaling cascades may be critical to the prevention of lung cancers and control of mucin overproduction in a number of lung diseases including asthma, cystic fibrosis, chronic bronchitis, and chronic obstructive pulmonary disease.

Key Words: activator protein-1 • asbestos • cigarette smoke • epidermal growth factor receptor • extracellular signal regulated kinases

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