Abstract 4208: Induction of redox imbalance by Urethane in a murine model of pulmonary adenocarcinoma

Abstract

Abstract The mechanisms involved in in the initiation of lung carcinogenesis are not yet well understood. Literature suggests that the initial events related with inflammation could drive induce an oxidative-prone microenvironment formation and determine the final fate of the organ. Oxidative stress is suggested to play a significant role in the initial phases of the inflammatory process. In the present study our purpose was to investigate the role of redox imbalance induced by urethane exposure, a known lung adenocarcinoma inducer, using resistant and susceptible mice models of lung cancer. C57/B6 and A/J 8-12 weeks-old mice were treated with weekly intra-peritoneal injections of 1mg of Urethane in saline per gram of animal weight for 4 weeks. The control mice were saline-injected under the same weekly regimen. The mice were weekly weighed during the experiment. Total lung tissue was collected at different time periods of both control and urethane-injected mice. Lung tissue was either processed histologically or stored as a homogenate for further biochemical measurements. The susceptible urethane-injected A/J mice presented a delay in weight gain when compared to saline control, whereas C57/B6 mice do not show differences in weight gain in both urethane-injected and saline groups. Measurements performed in resistant C57/B6 mice treated with urethane showed a decrease in catalase activity that correlated to accumulation of carbonylated proteins 2 weeks after the end of the urethane treatment. Such levels are indicative of oxidative stress. However, from the third week on, these levels were back to control levels. The modulation of oxidative state of the C57/B6 lung was not accompanied by histological modifications. Surprisingly, we did not observe the same results in the susceptible A/J mice. In the present study, we have shown that urethane modulates redox components in the lung and this effect seems to be strain dependent. It is known that urethane-treated A/J mice will develop lung adenocarcinoma within 16-20 weeks after the first injection and that only a very small percentage of C57/B6 will develop lung cancer under the same conditions. Our results suggest that the differences in the initial responses observed in the two mice strains collaborate to the formation of a different lung microenvironment. Therefore, we put forward the idea that the ability of resistant mice to upregulate a proper stress response at the initial stage constitutes a protective mechanism against carcinogenesis. On the other hand, the apparent lack of response observed in susceptible mice might mitigate the establishment of a chronic nocive environment that would contribute to the development of lung adenocarcinoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4208. doi:10.1158/1538-7445.AM2011-4208