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Pulmonary Prostacyclin Synthase Overexpression Chemoprevents Tobacco Smoke Lung Carcinogenesis in Mice

Pulmonary Prostacyclin Synthase Overexpression Chemoprevents Tobacco Smoke Lung Carcinogenesis in... Increased pulmonary production of prostaglandin I 2 (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 I 2 levels in the transgenic animals, coupled with significantly decreased prostaglandin E 2 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Cancer Research American Association of Cancer Research

Pulmonary Prostacyclin Synthase Overexpression Chemoprevents Tobacco Smoke Lung Carcinogenesis in Mice

Pulmonary Prostacyclin Synthase Overexpression Chemoprevents Tobacco Smoke Lung Carcinogenesis in Mice

Cancer Research , Volume 64 (16): 5897 – Aug 15, 2004

Abstract

Increased pulmonary production of prostaglandin I 2 (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 I 2 levels in the transgenic animals, coupled with significantly decreased prostaglandin E 2 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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Publisher
American Association of Cancer Research
Copyright
Copyright © 2004 by the American Association for Cancer Research.
ISSN
0008-5472
DOI
10.1158/0008-5472.CAN-04-1070
pmid
15313935
Publisher site
See Article on Publisher Site

Abstract

Increased pulmonary production of prostaglandin I 2 (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 I 2 levels in the transgenic animals, coupled with significantly decreased prostaglandin E 2 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.

Journal

Cancer ResearchAmerican Association of Cancer Research

Published: Aug 15, 2004

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