Abstract 5456: Potential role of nitric oxide in chromium-induced lung carcinogenesis

Abstract

Abstract Certain hexavalent chromium [Cr(VI)] compounds are well established human respiratory toxins and carcinogens of occupational and environmental relevance. Our recent studies have shown that intranasal (IN) exposure of Balb/c mice to particulate zinc Cr(VI) compounds leads to pronounced innate inflammation in the lung, which we postulate plays a significant role in pulmonary tumorigenesis. Nitric oxide (NO) has been shown to be induced via inflammatory response mediators, and has been implicated in the progression of different cancers, including lung. Moreover, NO-induced tumor invasiveness has been correlated with enhanced matrix metalloproteinase (MMP) expression in lung tumor cell lines. Of particular relevance to the present study is the finding that in vitro exposure of human lung cells to Cr(VI) in culture led to increased NO production. The aim of the present study was to explore the role of NO in chromium-induced lung tumorigenesis. BALB/c mice received weekly IN delivery of either saline or 10 ug particulate basic zinc chromate, which is an intermediately water soluble chromate typically encountered in mining/chromate production facilities and which is also present as an environmental atmospheric contaminant in urban areas surrounding ferrochrome production facilities. After 9 weeks, immune cells, cytokines, NO, MMPs and pathologic features of lung injury and inflammation were measured in airway lavage fluid and lung tissue, at both 24h after the final Cr(VI) dose, as well as 1 week later. As previously shown, repetitive Cr(VI) exposure induced a neutrophilic inflammatory airway response 24h after treatment. Neutrophils were subsequently replaced by increasing numbers of macrophages 1 week after treatment. Peribronchiolar inflammation was observed in chromate-exposed mice, and was accompanied by a 100-fold increase in pro-MMP9 release into the airways. Notably, airway NO was significantly increased ∼ 1.9 fold in Cr(VI)-exposed mice as compared to their saline-treated counterparts at both time points following final exposure. Moreover, immunoreactivity of induced nitric oxide synthase (iNOS) was markedly increased in airways exposed to Cr(VI), with staining localized to infiltrating immune cells. In conclusion, repetitive exposure to particulate chromate induces an inflammatory environment in the lung, accompanied by enhanced NO production, which we postulate may promote Cr(VI) carcinogenesis. Supported by NIH grants CA107972 and ES017334 to SC and ES017307 to SRP. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5456. doi:1538-7445.AM2012-5456