Abstract

Background: Chronic obstructive pulmonary disease (COPD) is one of the leading causes of mortality worldwide and currently there are no efficient treatments. Liver X receptor (LXR) plays a role not in lipid metabolism and inflammation. Objectives: To investigate the effects of CS on LXR activation and target gene regulation in vivo and in vitro and to study potential protective effects of LXR activation against CS-induced emphysema. Methods: Sprague Dawley rats were exposed to second hand CS for two months. The lung tissue and bronchoalveolar lavage (BAL) cells were examined for LXR target gene expression and emphysema development was measured by MLI. Rat AM and EC treated with CS extract, LPS or DMHCA, a steroidal LXR agonist were examined for LXR target gene and protein expression and migratory capacity. LXR localization before and after CS exposure was determined by immunofluorescence. Results: Whereas expression of ATP binding cassette transporter A1, a known LXR target gene, was not changed in the lung, but significantly downregulated in the BAL cells from CS-exposed rat lungs and in CS extract-treated AM. Immunofluorescence showed reduced nuclear localization of the anti-inflammatory LXRβ isoform in AM and pulmonary EC. Activation of LXR attenuated LPS-induced genes such as COX2, CCL5 and IL18, but upregulated IL18 binding protein (IL-18BP), an endogeneous IL-18 inhibitor. It increased the migratory capacities of rat alveolar macrophages towards CCL5. Conclusions: Activation of LXR attenuated the pro-inflammatory cytokine production by AM suggesting that LXR agonist treatment might be beneficial to prevent and treat CS-emphysema. Funded by AHA 0735388N, FAMRI CIA 072053, and Bixler Family Foundation.

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