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Apolipoprotein E deficiency and highfat diet cooperate to trigger lipidosis and inflammation in the lung via the toll-like receptor 4 pathway

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Apolipoprotein E deficiency (ApoE/) combined with a highfat Westerntype diet (WD) is known to activate the tolllike receptor (TLR4) pathway and promote atherosclerosis. However, to date, the pathogenic effects of these conditions on the lung have not been extensively studied. Therefore, the present study examined the effects of ApoE/ and a WD on lung injury and investigated the underlying mechanisms. ApoE/ and wildtype mice were fed a WD or normal chow diet for 4, 12 and 24 weeks. Lung inflammation, lung cholesterol content and cytokines profiles in bronchoalveolar lavage fluid (BALF) were determined. TLR4 and its main downstream molecules were analyzed with western blot analysis. In addition, the role of the TLR4 pathway was further validated using TLR4targeted gene silencing. The results showed that ApoE/ mice developed lung lipidosis following 12 weeks of receiving a WD, as evidenced by an increased lung cholesterol content. Moreover, dependent on the time period of receiving the diet, those mice exhibited pulmonary inflammation, which was manifested by initial leukocyte recruitment (at 4 weeks), by increased alveolar septal thickness and mean linear intercept as well as elevated production of inflammation mediators (at 12 weeks), and by granuloma formation (at 24 weeks). The expression levels of TLR4, myeloid differentiation primary response 88 (MyD88) and nuclear factor kappa B were markedly upregulated in ApoE/ WD mice at week 12. However, these effects were ameliorated by shRNAmediated knockdown of TLR4. By contrast, ApoE/ ND or wildtype WD mice exhibited lowgrade or no inflammation and mild lipidosis. The levels of TLR4 and MyD88 in those mice showed only minor changes. In conclusion, ApoE deficiency acts synergistically with a WD to trigger lung lipidosis and inflammation at least in part via TLR4 signaling.
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Document Type: Research Article

Affiliations: 1: Cardiovascular Department, The Second Affiliated Hospital and Second Clinical Medical College, Fujian Medical University, Quanzhou, Fujian 362000, P.R. China 2: Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Shandong University Qilu Hospital, Jinan, Shandong 250012, P.R. China 3: Rheumatism Department, The Second Affiliated Hospital and Second Clinical Medical College, Fujian Medical University, Quanzhou, Fujian 362000, P.R. China

Publication date: August 1, 2015

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  • Molecular Medicine Reports is a monthly, peer-reviewed journal available in print and online, that includes studies devoted to molecular medicine, underscoring aspects including pharmacology, pathology, genetics, neurosciences, infectious diseases, molecular cardiology and molecular surgery. In vitro and in vivo studies of experimental model systems pertaining to the mechanisms of a variety of diseases offer researchers the necessary tools and knowledge with which to aid the diagnosis and treatment of human diseases.
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