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Bacterial sepsis results in high mortality rates, and new therapeutics to control infection are urgently needed. Here, we investigate the therapeutic potential of fibrates in the treatment of bacterial sepsis and examine their effects on innate immunity. Fibrates significantly improved the survival from sepsis in mice infected with Salmonella typhimurium, which was paralleled by markedly increased neutrophil influx to the site of infection resulting in rapid clearance of invading bacteria. As a consequence of fibrate-mediated early control of infection, the systemic inflammatory response was repressed in fibrate-treated mice. Mechanistically, we found that fibrates preserve chemotaxis of murine neutrophils by blocking LPS-induced phosphorylation of ERK. This results in a decrease of G protein-coupled receptor kinase-2 expression, thereby inhibiting the LPS-mediated downregulation of CXCR2, a chemokine receptor critical for neutrophil recruitment. Accordingly, application of a synthetic CXCR2 inhibitor completely abrogated the protective effects of fibrates in septicemia in vivo. Our results unravel a novel function of fibrates in innate immunity and host response to infection and suggest fibrates as a promising adjunct therapy in bacterial sepsis. [ABSTRACT FROM AUTHOR]

Eur J Clin Invest 2010; 40 (7): 616–622 Background The impact of cholesteryl ester transfer protein (CETP) in the development of atherosclerosis is a matter for ongoing debate. In this study, we analyse associations of CETP with cardiovascular endpoints in a cohort of patients with stable coronary artery disease (CAD). Design KAROLA is a prospective observational study of patients with CAD and a median follow-up of 8 years ( n = 1132). CETP levels were measured using an enzyme-linked immunosorbent assay. Results Cholesteryl ester transfer protein levels were lower in men ( P = 0·0016), positively correlated to low-density lipoprotein cholesterol, and inversely correlated to triglyceride levels ( P < 0·0001 and P = 0·011 respectively). There was no significant difference in mortality between patients in different CETP quartiles; the hazard ratio of lowest vs. highest quartile was 1·33 (95% confidence interval (CI): 0·77–2·30) for mortality and 1·24 (95% CI: 0·75–2·03) for secondary events. In post hoc analyses, comparing nondiabetic subjects with CETP below vs. above median, the adjusted hazard ratio for death in patients with low CETP levels was 1·84 (95% CI: 1·10–3·09). Conclusion Although statistically significant associations were found only in post hoc analyses, the effect sizes in this study were in line with previous findings in the Framingham and LURIC population. In combination, the emerging evidence challenges the concept of pharmacological CETP inhibition. [ABSTRACT FROM AUTHOR]