A) Representative micrographs of Hematoxylin- and Eosin-stained lung sections from mice 42 h after infection. Note that the high statin fed mice exhibit reduced cellularity and vascular hemorrhage. Original magnification, 10X. B) Vascular integrity was determined by assessing the amount of albumin present in the BAL fluid by ELISA prior to and following infection (n = 3/group for uninfected and n = 6/group for infected mice). Data are presented as the mean ± SEM. Statistics were determined by a two-tailed student’s t-test. P < 0.05 was considered significant in comparison to Control fed mice. We subsequently

examined the impact of oral simvastatin therapy selleck products on development of bacteremia. Following intratracheal challenge at 24 hpi, bacterial titers in the blood were not Fedratinib concentration significantly different among all three groups tested; although mice receiving HSD had lower median titers compared to mice on the control diet (P = 0.12) (Figure 3). Between 24 and 36 h, pneumococcal titers in the blood increased at a similar rate for all Sirolimus clinical trial mice, nonetheless mice on HSD had significantly fewer pneumococci in their blood compared to control mice (P = 0.007). After

36 h, mice receiving the control diet continued to experience bacterial replication whereas those on a simvastatin diet maintained or began to clear bacteria from the blood. At 42 hpi, mice on the HSD continued to have significantly less bacterial titers in the blood compared to control fed mice (P = 0.03). Figure 3 Mice on simvastatin prophylaxis show enhanced protection from bacteremia. Bacterial titers in the blood of challenged mice 24, 36 and 42 h after infection. Mice on Control (n = 11), Low (n = 11) or High (n = 12) diet were challenged intratracheally with 1 X 105 cfu. Mice receiving statins

had significantly fewer bacteria in the blood. Data are presented as the mean ± SEM. Statistics were determined by a two-tailed student’s t-test. P < 0.05 was considered significant. High-dose simvastatin reduces chemokine production in the lungs Statins have been reported to reduce cytokine second production following LPS stimulation of monocytes and decrease lung inflammation following instillation of LPS in healthy human volunteers [18, 19]. Thus we investigated the effect of simvastatin therapy on the local and systemic production of cytokines and chemokines during pneumococcal pneumonia. At 24 hpi, before bacterial titers in the lungs were significantly different, no differences were observed for TNFα, IL-6, IL-10, IL-12, MCP-1, KC and IFNγ in the BAL fluid or serum of mice on LSD versus controls (Figure 4A, B). In contrast, mice on HSD had significant reductions in MCP-1 (P = 0.03) and KC (P = 0.02) in the BAL fluid but not serum. No differences were observed for all other cytokines or chemokines in the BALF or in the serum of HSD mice.