Abstract
Both cigarette smoke (CS) and asbestos cause lung inflammation and lung cancer, and at high asbestos exposure levels, populations exposed to both of these carcinogens display a synergistic increase in the development of lung cancer. The mechanisms through which these two toxic agents interact to promote lung tumorigenesis are poorly understood. Here, we begin to dissect the inflammatory signals induced by asbestos in combination with CS using a rodent inhalation model and invitro cell culture. Wild-type C57BL/6 mice were exposed to room air as a control, CS, and/or asbestos (4days per week to CS and 1day per week to asbestos for 5weeks). Bronchoalveolar lavage (BAL) fluid was collected following exposure and analyzed for inflammatory mediators. Asbestos-exposed mice displayed an increased innate immune response consistent with NLRP3 inflammasome activation. Compared to mice exposed only to asbestos, animals coexposed to CS+asbestos displayed attenuated levels of innate immune mediators and altered inflammatory cell recruitment. Histopathological changes in CS+asbestos-exposed mice correlated with attenuated fibroproliferative lesion development relative to their counterparts exposed only to asbestos. In vitro experiments using a human monocyte cell line (THP-1 cells) supported the invivo results in that coexposure to cigarette smoke extract repressed NLRP3 inflammasome markers in cells treated with asbestos. These observations indicate that CS represses central components of the innate immune response to inhaled asbestos.
Highlights
Chronic inflammation underlies the pathogenesis of many lung diseases including lung cancer (Gomperts et al 2011)
Since cigarette smoke (CS) and asbestos exposure can synergize in a dosedependent manner to induce lung carcinogenesis in humans (Erren et al 1999; Henderson et al 2004; Markowitz et al 2013), we anticipated that inhalation of CS by mice would exacerbate asbestos-induced lung injury and inflammation
A preliminary study with mice exposed only to asbestos followed by daily analysis of the Bronchoalveolar lavage (BAL) fluid of the exposed animals showed that induction of IL-1b was observed on day 3 postexposure
Summary
Chronic inflammation underlies the pathogenesis of many lung diseases including lung cancer (Gomperts et al 2011). Combined inhalation exposures to CS and asbestos elicit a synergistic to more than additive increase in human lung cancers depending on the level(s) of exposure (Erren et al 1999; Henderson et al 2004; Markowitz et al 2013; Markowitz 2015). How repeated, sequential inhalation exposures to CS and asbestos affect lung inflammation has not been described. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society
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