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Characterization of LPS‐Induced Inflammation in Mice Expressing Human Cholestyl Ester Transfer Protein
Author(s) -
Murphy Beth Ann,
Metzger Daniel,
Gollapudi Anantha,
Cumiskey Anne Marie,
Johns Douglas G
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.lb678
Subject(s) - cholesterylester transfer protein , lipopolysaccharide , in vivo , genetically modified mouse , inflammation , transgene , pharmacology , medicine , endocrinology , cholesterol , acute phase protein , toxicity , cytokine , chemistry , tumor necrosis factor alpha , lipoprotein , biology , biochemistry , microbiology and biotechnology , gene
Cholesteryl ester transfer protein (CETP) inhibitors increase plasma HDL and reduce LDL cholesterol in humans. In animal models, exogenous HDL ameliorates lipopolysaccharide (LPS) associated toxicities. In contrast, the ILLUMINATE trial showed that pharmacologically increasing HDL with the CETP inhibitor, torceptrapib, tended to increase infection in patients. Thus, the effect that elevating HDL has on the response to infection is unclear. To probe how HDL levels influence the toxic and inflammatory response to LPS, we injected human CETP transgenic mice and wild‐type littermates with LPS (5, 25 mg/kg). 100% of mice of both phenotypes succumbed to LPS‐induced toxicity at both doses. Despite this similarity, ex vivo LPS‐invoked TNFα release is significantly greater (p=0.005) in CETP‐tg mouse blood vs. WT controls. In addition, we showed in vivo that both circulating TNFα and endotoxin levels of CETP‐tg mice were significantly greater compared to that of WT mice injected with the same amount of LPS (5 mg/kg). Taken together these data suggest that less efficient endotoxin clearance could account for the enhanced cytokine response of CETP‐tg mice. Therefore, we hypothesize that increasing HDL via pharmacological CETP inhibition should not result in an increased incidence of infection. However, the effect of CETP inhibitors on human morbidity and mortality/outcomes, is being tested in phase III clinical trials.