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-kappaB, 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.

It has been hypothesized that the destruction of lung tissue observed in smokers with chronic obstructive pulmonary disease and emphysema is mediated by neutrophils recruited to the lungs by smoke exposure. This study investigated the role of the chemokine receptor CXCR2 in mediating neutrophilic inflammation in the lungs of mice acutely exposed to cigarette smoke. Exposure to dilute mainstream cigarette smoke for 1 h, twice per day for 3 days, induced acute inflammation in the lungs of C57BL/6 mice, with increased neutrophils and the neutrophil chemotactic CXC chemokines macrophage inflammatory protein (MIP)-2 and KC. Treatment with SCH-N, an orally active small molecule inhibitor of CXCR2, reduced the influx of neutrophils into the bronchoalveolar lavage (BAL) fluid. Histological changes were seen, with drug treatment reducing perivascular inflammation and the number of tissue neutrophils. β-Glucuronidase activity was reduced in the BAL fluid of mice treated with SCH-N, indicating that the reduction in neutrophils was associated with a reduction in tissue damaging enzymes. Interestingly, whereas MIP-2 and KC were significantly elevated in the BAL fluid of smoke exposed mice, they were further elevated in mice exposed to smoke and treated with drug. The increase in MIP-2 and KC with drug treatment may be due to the decrease in lung neutrophils that either are not present to bind these chemokines or fail to provide a feedback signal to other cells producing these chemokines. Overall, these results demonstrate that inhibiting CXCR2 reduces neutrophilic inflammation and associated lung tissue damage due to acute cigarette smoke exposure.

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