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Pulmonary Prostacyclin Synthase Overexpression Chemoprevents Tobacco Smoke Lung Carcinogenesis in Mice

¹ Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, Denver VA Medical Center, Denver, Colorado; ² Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, ³ Department of Pathology, and ⁴ Departments of Medicine and Pharmacology, University of Colorado Health Sciences Center, Denver, Colorado; ⁵ Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas; and ⁶ Inhalation Toxicology Laboratory, Lovelace Respiratory Research Institute, Albuquerque, New Mexico

Increased pulmonary production of prostaglandin I₂ (prostacyclin) by lung-specific overexpression of prostacyclin synthase decreases lung tumor incidence and multiplicity in chemically induced murine lung cancer models. We hypothesized that pulmonary prostacyclin synthase overexpression would prevent lung carcinogenesis in tobacco-smoke exposed mice. Murine exposure to tobacco smoke is an established model of inducing pulmonary adenocarcinomas and allows for the testing of potential chemopreventive strategies. Transgenic FVB/N mice with lung-specific prostacyclin synthase overexpression were exposed to mainstream cigarette smoke for 22 weeks and then held unexposed for an additional 20 weeks. All of the exposed animals developed bronchiolitis analogous to the respiratory bronchiolitis seen in human smokers. The transgenic mice, when compared with smoke-exposed transgene negative littermates, had significant decreases in tumor incidence and multiplicity. Significantly fewer transgenics (6 of 15; 40%) developed tumors compared with the tumor incidence in wild-type littermates (16 of 19; 84%; Fisher’s exact test, P = 0.012). Tumor multiplicity was also significantly decreased in the transgenic animals (tg⁺ = 0.4 ± 0.5 versus wild-type = 1.2 ± 0.86 tumors/mouse; P < 0.001). Targeted prostaglandin levels at the time of sacrifice revealed significantly elevated prostaglandin I₂ levels in the transgenic animals, coupled with significantly decreased prostaglandin E₂ levels. Gene expression analysis of isolated type II pneumocytes suggests potential explanations for the observed chemoprevention, with Western blot analysis confirming decreased expression of cytochrome p450 2e1. These studies extend our previous studies and demonstrate that manipulation of prostaglandin production distal to cyclooxygenase significantly reduces lung carcinogenesis in a tobacco smoke exposure model, and gene expression studies show critical alterations in antioxidation, immune response, and cytokine pathways.

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