This previously Axitinib order undescribed effect of simvastatin treatment suggests a so far unknown beneficial effect of HMG-CoA reductase inhibitors, which may be further examined in future studies.In VILI, PMN and Gr-1high monocytes infiltrate the lungs and have been identified as major effector cells for the development of tissue damage [30-32]. Reportedly, simvastatin inhibited tissue leukocyte infiltration in ALI both in animal experiments and in humans [8,9,12]. Leukocyte rolling, adhesion and transmigration were attenuated by simvastatin, at least partly by reduction of adhesion molecules including CEACAM-1, VCAM-1 and PCAM-1 [33-36]. In line, the significant recruitment of PMN and Gr-1high monocytes in murine VILI was diminished by simvastatin in the current study.

Moreover, an MV-induced increase of circulating PMN and Gr-1high monocytes in the blood was even more pronounced in simvastatin-treated mice. This observation may suggest that simvastatin-evoked inhibition of endothelial leukocyte recruitment contributed to reduced pulmonary and concomitantly increased blood counts of PMN and Gr-1high monocytes.Simvastatin reduced production and liberation of various cytokines in animal models of ALI, sepsis and asthma as well as in humans following LPS-inhalation [9,11,12,37-40]. In the current study, VILI-associated pulmonary production of IL-1��, MIP-1�� and IL-12p40 was reduced by simvastatin treatment. Thus, alteration of chemotaxis may have been contributing to the limitation of PMN and Gr-1high monocyte influx into the lungs in this study.

Particularly IL-1�� may be a key mediator in VILI, as IL-1�� blockade as well as IL-1�� deficiency resulted in reduced pulmonary PMN recruitment and hyperpermeability in animal models of VILI [41]. Therefore, dampening of pulmonary IL-1�� production by simvastatin may have been adding to the observed attenuation of microvascular leakage, pulmonary leukocyte recruitment and endothelial cell injury.Although increasing evidence derived from experimental and observational studies suggests beneficial effects of simvastatin in ALI as well as in pneumonia [8-11,14,16,42], a retrospective study analyzing an ALI patient cohort did not find an outcome improvement by conventional statin treatment [43]. Of note, statin doses of 5 mg/kg/d did not improve experimental ALI [8], whereas higher doses of 10 to 20 mg/kg/d evoked protective effects.

Further, previous studies suggested a delay of at least 6 h for the development of barrier-protective effects by simvastatin [24,25]. Brefeldin_A Thus, mice were pretreated with 20 mg/kg/d simvastatin commencing 24 h before the onset of ventilation in the current study. Although mandatory for this experimental approach, simvastatin pre-treatment does not match the clinical scenario. However, animal studies are limited to hours while ARDS patients often are ventilated for days or even weeks.