Susceptibility to Libby Amphibole-Induced Pulmonary Disease in the Cardiovascular-Compromised Subpopulation.

摘要

Human exposure to asbestos is known to cause the development of mesothelioma, asbestosis and lung cancer. Asbestos toxicity is thought to be mediated through reactive oxygen species (ROS) production by surface available iron (Fe). Within the lung asbestos can complex endogenous Fe possibly increasing toxicity. We hypothesized that asbsestos-induced inflammation and injury would be greater in rat models of human cardiovascular disease (CVD) with Fe-overload. We characterized the baseline pulmonary disease of normotensive Wistar Kyoto, spontaneously hypertensive (SH), and SH heart failure (SHHF) rats. SH and SHHF were found to exist with pulmonary inflammation, oxidative stress, and Fe-overload (SHHF>SH). Libby amphibole (LA) was used to examine the role of Fe in asbestos-induced toxicity. LA complexed Fe in an acellular system, which enhanced ROS production. In in vitro and in vivo models the inflammatory response to LA decreased with increased cellular and fiber-complexed Fe. The chelation of Fe from fibers and cells exacerbated LA-induced inflammation. To determine the role of increased host Fe in LA-induced inflammation, and lung pathology WKY, SH, and SHHF were intratracheally-instilled with LA (0.0, 0.25, and 1mg/rat). LA-induced neutrophilic inflammation was not exacerbated although persistent through 1-month in CVD models compared to WKY. SH and SHHF failed to increase antioxidants but increased Fe-binding proteins after LA exposure. Progressive pulmonary fibrosis was noted over 3-months in all strains, whereas the accumulation of Fe in fiber-laden macrophages occurred primarily in SHHF. At 3-months, only SHHF exposed to LA demonstrated atypical hyperplastic lesions of bronchiolar epithelial origin. Gene expression profiling at 3-months indicated baseline differences reflective of pulmonary inflammation, and immune dysregulation in CVD models. Changes in genes involved in cell-cycle control and cancer pathways correlated with atypical hyperplasia in SHHF. We concluded LA can bind Fe and produce ROS in an acellular system but this process does not exacerbate the inflammatory response in cells or animals. Furthermore, in Fe-overload conditions, more Fe accumulates at sites of fiber deposition without enhancing the inflammatory response. In the presence of baseline lung pathology, the inability to further induce inflammation in response to LA may predispose those with Fe-overload to proliferative lung pathology.