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

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.Keywords: activator protein-1; asbestos; cigarette smoke; epidermal growth factor receptor; extracellular signal regulated kinases Reactive oxygen species (ROS) and reactive nitrogen species are mediators of cell signaling in airway and pulmonary epithelial cells by a variety of toxic agents, including asbestos and silica, cigarette smoke, airborne particulate matter, diesel exhaust, and ozone. These signaling cascades are under intense investigation by a number of laboratories because of their links to exacerbation of epithelial cell injury and proliferation, cell survival and chemoresistance, altered differentiation, and production of chemokines or cytokines mediating inflammation.The mitogen-activated protein kinase (MAPK) cascades consist of serine threonine kinases that are sequentially phosphorylated by upstream kinases (MAPKKK, MAPKK) and subdivided into three major pathways: extracellular signal-regulated kinases (ERKs), c-Jun-NH 2 -terminal kinases (JNKs 1, 2, and 3) (also referred to as stress-activated protein kinases), and p38 kinases (1-3) (Figure 1). MAPK cascades can be initiated by activation of receptor tyrosine kinases such as the epidermal growth factor receptor (EGFR) or other factors stimulating phosphorylation of upstream MAPKKK and MAPKK. Because the MAPK cascades involve sequential phosphorylation of protein kinases, factors inhibiting the phosphatases that normally check these pathways also cause net increases in the phosphorylation (i.e., activation) of MAPK proteins.Specific MAPKs control the activation of fos and jun family protooncogenes and their protein products (c-Jun, Jun B, Jun D, c-Fos, Fos B, Fra-1, and Fra-2) that are also known as AP-1 family members. The...

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