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1 Chemistry Department, Shippensburg University, Shippensburg, PA, USA
2 Department of Environmental Medicine, Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
3 Department of Medicine and Therapeutics, The Conway Institute, University College Dublin, Dublin, Ireland
4 Department of Environmental Medicine, Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA; Division of Pulmonary and Critical Care Medicine, 4University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
* To whom correspondence should be addressed. E-mail: patricia_sime{at}urmc.rochester.edu.
Cigarette smoking can lead to many human pathologies including cardiovascular and respiratory disease. Recent studies have defined a role for fibroblasts in the development of colon cancer. Moreover, fibroblasts are now thought of as key "sentinel" cells that initiate inflammation by releasing pro-inflammatory mediators including prostaglandins (PGs). Pathological overexpression of cyclo-oxygenase 2 (COX-2) and excess eicosanoid production is found in the early stages of carcinogenesis. By promoting chronic inflammation, COX-2 and eicosanoid production may actually predispose to malignancy. Furthermore, the associated inflammation induced by production of these mediators is central to the pathogenesis of chronic obstructive pulmonary disease (COPD). Little is known of the responses of normal lung fibroblasts to cigarette smoke, despite their abundance. We report herein that normal human lung fibroblasts, when exposed to cigarette smoke extract, induce COX-2 with concurrent synthesis of prostaglandin E2 (PGE2). The mechanisms by which cigarette-derived toxicants lead to increased COX-2 levels and PGE2 synthesis, include increases in steady-state COX-2 mRNA levels (~ 4-5 fold), phosphorylation of the extracellular signal-regulated kinases 1 and 2 (ERK 1/2), and nuclear translocation of the p50 and p65 subunits of the transcription factor NF-kB, which are important elements in COX-2 expression. Furthermore, there was a dramatic 25-fold increase in microsomal prostaglandin E synthase (mPGES), the key enzyme involved in the production of PGE2. We propose that normal human lung fibroblasts, when exposed to cigarette smoke constituents, elicit COX-2 expression with consequent prostaglandin synthesis, thus creating a proinflammatory environment. This chronic inflammatory state may act as one of the first steps towards epithelial transformation.
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