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Interferon signaling, systemic inflammation, and atherosclerosis following welding fume inhalation exposure: from the lung to the blood to the vasculature.

Erdely-A; Hulderman-T; Liston-AL; Salmen-Muniz-R; Stone-S; Chen-BT; Frazer-DG; Li-S; Kashon-ML; Antonini-JM; Simeonova-PP; Zeidler-Erdely-PC
Toxicologist 2011 Mar; 120(Suppl 2):39
Inhalation of particulates can result in measurable systemic markers related to adverse cardiovascular outcomes. Our aim was the determination of a systemic signature and atherosclerosis progression following gas metal arc-stainless steel (GMASS) welding fume exposure. C57BL/6 mice were exposed for 10d to GMA-SS by inhalation (40mg/m3 for 3hr/day) and harvested 4hr, 14d and 28d post-exposure. Systemic responses were measured by serum protein profiling and microarray (Ingenuity pathway analysis and real-time RT-PCR confirmation) for whole blood cells, aorta and lung. Atherosclerotic susceptible apolipoprotein E knockout (apoE- /-) mice were exposed (40mg/m3 for 3hr/day) during week 6 and 7 of two months of Western (high fat) diet feeding. Exposed C57BL/6 mice exhibited a specific network of type I interferon signaling in blood cells and aorta from 4hr to 28d post-exposure The central component of the network was the transcription factor interferon regulatory factor 7 (Irf7), the master regulator of the type I interferon response. Increases in related genes (Oasl2 and Ifitm3) were also validated. Type I interferon signaling was also a top network in the lung supporting the concept of a systemic signature reflecting the ongoing pulmonary response. Serum levels of primary inflammatory mediators were not elevated although oncostatin M, an IL-6 family cytokine and type I interferon enhancer, was increased. In apoE-/- mice, pulmonary inflammation, serum levels of IL-1 and MAC-3 and blood cell expression of Irf7 were increased post-GMA-SS exposure. Atherosclerosis severity, determined by plaque area and intensity in the aorta (en face), was increased. The data suggest an immunomodulatory and mild systemic inflammatory effect with increased progression of atherosclerosis due to GMA-SS exposure. Most notably, a pulmonary and corresponding systemic signature of type I interferon signaling was consistently evident across tissue and time.
Laboratory-animals; Animal-studies; Animals; Welding; Fumes; Respiratory-system-disorders; Respiratory-irritants; Pulmonary-system-disorders; Pulmonary-disorders; Pulmonary-function; Pulmonary-system; Lung; Lung-disorders; Lung-function; Cardiovascular-system-disorders; Cardiovascular-function; Cardiopulmonary-system-disorders; Cardiopulmonary-system; Cardiopulmonary-function
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The Toxicologist. Society of Toxicology 50th Annual Meeting and ToxExpo, March 6-10, 2011, Washington, DC