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Cigarette smoke induces cyclooxygenase-2 and microsomal prostaglandin E₂ synthase in human lung fibroblasts: implications for lung inflammation and cancer

¹Chemistry Department, Shippensburg University, Shippensburg, Pennsylvania 17257; ²Department of Environmental Medicine, ³Lung Biology and Disease Program, ⁴Division of Pulmonary and Critical Care Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642; and ⁵Department of Medicine and Therapeutics, The Conway Institute, University College Dublin, Dublin 4, Ireland

Submitted 21 July 2003 ; accepted in final form 25 June 2004

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 proinflammatory mediators including prostaglandins (PGs). Pathological overexpression of cyclooxygenase-2 (COX-2) and excess eicosanoid production are found in the early stages of carcinogenesis. By promoting chronic inflammation, COX-2 and eicosanoid production may actually cause a predisposition to malignancy. Furthermore, the associated inflammation induced by production of these mediators is central to the pathogenesis of chronic obstructive pulmonary disease. 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 (approximately four- to fivefold), phosphorylation of ERK1/2, and nuclear translocation of the p50 and p65 subunits of the transcription factor NF-B, which are important elements in COX-2 expression. Furthermore, there was a dramatic 25-fold increase in microsomal prostaglandin E synthase, 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.

lung disease; mitogen-actived protein kinases; eicosanoids

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