Simvastatin Blunts Endotoxin-Induced Tissue Factor In Vivo

Abstract

Background-Beyond lipid lowering, various antiinflammatory properties have been ascribed to statins. Moreover, in vitro studies have suggested the presence of anticoagulant effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, as lipopolysaccharide (LPS)-induced monocyte tissue factor (TF) was suppressed. In this study, we examined the role of statins in experimental endotoxemia on inflammatory and procoagulant responses in vivo. Methods and Results-In this double-blind, placebo-controlled, parallel-group study, 20 healthy, male subjects were randomized to receive either simvastatin (80 mg/d) or placebo for 4 days before intravenous administration of LPS (20 IU/kg IV). Plasma high-sensitive C-reactive protein (hsCRP), monocyte chemoattractant protein (MCP-1), sCD40L, sCD40, and prothrombin fragment F1ϩ2 (F1.2) were determined by ELISAs at baseline and at 4 and 8 hours after LPS administration. Monocyte TF expression and monocyte-platelet aggregates were measured by whole-blood flow cytometry over the same time course. The increases in hsCRP and MCP-1, both known inducers of TF, were significantly suppressed by statin treatment after LPS challenge. Statin premedication blunted the increase of monocyte TF expression in response to LPS. In parallel, endotoxin-induced formation of F1.2 was significantly reduced by simvastatin after 4 and 8 hours. LPS infusion affected neither the formation and activation of monocyte-platelet aggregates nor plasma levels of sCD40 and sCD40L. Conclusions-Simvastatin

Pulmonary Infections in the Elderly Lead to Impaired Neutrophil Targeting, Which Is Improved by Simvastatin

“…Simvastatin could attenuate lung damage after inhalational injury in mice, but only at high doses (47). In a doubleblind, placebo-controlled study, the endotoxin-induced systemic inflammatory response was reduced by preemptive simvastatin 80 mg in humans (48). Thus, our data are consistent with animal and human interventional studies of simvastatin.…”

Pravastatin prevents miscarriages in mice: role of tissue factor in placental and fetal injury

“…Statins are postulated to inhibit inflammation and coagulation 31,32 and to reduce TF expression and activity in blood monocytes and neutrophils. 20,33,34 Knowing that TF is a crucial mediator in pregnancy complications observed in CBA/J ϫ DBA/2 mice, we sought to investigate whether pravastatin can prevent pregnancy loss in this model of spontaneous miscarriages. In accordance with our hypothesis, pravastatin prevented fetal loss ( Figure 4A) and IUGR ( Figure 4B) in DBA/2-mated CBA/J mice at day 15 of pregnancy.…”

Statins in patients with sepsis and ARDS: is it over? Yes

“…In addition, simvastatin blunted the increase of monocyte TF expression in response to lipopolysaccharides [2]. Other studies have suggested that statins can inhibit the production of proinflammatory cytokines [3].…”