Journal
JOURNAL OF IMMUNOTOXICOLOGY
Volume 6, Issue 4, Pages 266-275Publisher
TAYLOR & FRANCIS LTD
DOI: 10.3109/15476910903241704
Keywords
Toll-like receptor; kupffer cell; steatohepatitis; fibrosis; IL-6
Categories
Funding
- NIH [KO1ES016588]
- NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES [K01ES016588, R01ES018900] Funding Source: NIH RePORTER
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Owing to increased obesity, non-alcoholic fatty liver disease (NAFLD) is now the most prevalent liver disease in the United States. NAFLD is considered a component of metabolic syndrome, a cluster of disorders that also includes diabetes mellitus, dyslipidemia, arteriosclerosis, and hypertension. Exposure to ambient air particulate matter with aerodynamic diameters < 2.5 mu m (PM2.5) is a risk factor for arteriosclerosis and lung disease, but its effect on NAFLD is unknown. PM2.5 induces pulmonary dysfunction via Toll-like receptor (TLR) activation on alveolar macrophages. TLR activation of Kupffer cells, resident hepatic macrophages, and subsequent pro-inflammatory cytokine production have been shown to play a key role in NAFLD progression. We hypothesized that PM2.5 exposure is a significant risk factor for the progression of NAFLD. Thus, following exposure of male C57BL/6 mice fed high fat chow (HFC) to concentrated air particulate matter (CAPs) or filtered air for 6 weeks, progression of NAFLD was evaluated by standardized histological assessment of hepatic inflammation and fibrosis. In mice fed HFC, the hepatic inflammatory grade (3.00 +/- 0.00 vs. 1.50 +/- 0.71, P < 0.001) and fibrosis stage (1.00 +/- 0.00 vs. 0.60 +/- 0.52, P = 0.023) were both significantly higher in mice exposed to CAPs versus filtered air, respectively. Increased numbers of Kupffer cells contained PM in CAPs-exposed mice scores of (2.00 +/- 0.94 vs. 0.20 +/- 0.42, respectively, P < 0.001). PM exposure increased IL-6 secretion up to sevenfold in a dose-dependent manner by isolated wild-type but not TLR4(-/-) Kupffer cells (P < 0.050). In conclusion, ambient PM2.5 exposure may be a significant risk factor for NAFLD progression.
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