Simvastatin antagonizes CD40L secretion, CXC chemokine formation, and pulmonary infiltration of neutrophils in abdominal sepsis

Abstract

Statins have been reported to exert anti-inflammatory actions and protect against septic organ dysfunction. Herein, we hypothesized that simvastatin may attenuate neutrophil activation and lung damage in abdominal sepsis. Male C57BL/6 mice were pretreated with simvastatin (0.5 or 10 mg/kg) before CLP. In separate groups, mice received an anti-CD40L antibody or a CXCR2 antagonist (SB225002) prior to CLP. BALF and lung tissue were harvested for analysis of neutrophil infiltration, as well as edema and CXC chemokine formation. Blood was collected for analysis of Mac-1 and CD40L expression on neutrophils and platelets, as well as soluble CD40L in plasma. Simvastatin decreased CLP-induced neutrophil infiltration and edema formation in the lung. Moreover, Mac-1 expression increased on septic neutrophils, which was significantly attenuated by simvastatin. Inhibition of CD40L reduced CLP-induced up-regulation of Mac-1 on neutrophils. Simvastatin prevented CD40L shedding from the surface of platelets and reduced circulating levels of CD40L in septic mice. CXC chemokine-induced migration of neutrophils in vitro was decreased greatly by simvastatin. Moreover, simvastatin abolished CLP-evoked formation of CXC chemokines in the lung, and a CXCR2 antagonist attenuated pulmonary accumulation of neutrophils. Our data suggest that the inhibitory effect of simvastatin on pulmonary accumulation of neutrophils may be related to a reduction of CD40L secretion into the circulation, as well as a decrease in CXC chemokine formation in the lung. Thus, these protective mechanisms help to explain the beneficial actions exerted by statins, such as simvastatin, in sepsis.

Geranylgeranyl transferase regulates CXC chemokine formation in alveolar macrophages and neutrophil recruitment in septic lung injury

“…Although this study provides the first direct data indicating a role of geranylgeranyl transferase in infectious lung injury, Chiba et al (11) have reported that GGTI-2133 reduces antigen-induced pulmonary bronchoconstriction in an experimental asthma model supporting the concept that geranylgeranyl transferase exert proinflammatory functions in the lung. Moreover, we have recently reported that simvastatin treatment decreases CLP-provoked lung injury (41). With the knowledge that statins prevent formation of geranylgeranylpyrophosphate and isoprenylation of Rho proteins (44), our present findings might help explain the protective effects of simvastatin against lung damage in abdominal sepsis.…”

“…Neutrophil activation and trafficking in the extravascular space are coordinated by secreted CXC chemokines, such as CXCL1 and CXCL2, being murine homologues of human interleukin-8 (34). A functional role of CXC chemokines has been proposed in abdominal infections (40,41). Herein, it was observed that inhibition of geranylgeranyl transferase markedly reduced pulmonary and plasma levels of CXC chemokines in septic animals.…”

“…We have recently reported that simvastatin effectively inhibits neutrophil recruitment and lung injury in abdominal sepsis (41) and clinical data indicate that statins may reduce mortality in patients with severe infections and sepsis (23,24) although the protective mechanisms of statins remain elusive. Statins regulate cholesterol levels by inhibiting the rate-limiting enzyme, HMG-CoA reductase, in the synthesis of mevalonate (1,32).…”

Targeting CD162 protects against streptococcal M1 protein-evoked neutrophil recruitment and lung injury

“…Excessive accumulation infiltration of neutrophils is a ratelimiting step in septic lung damage (11,17). For example, it has been shown that depletion of neutrophils abolishes M1 protein-induced lung damage (35,41).Extravascular localization of neutrophils is coordinated by secreted CXC chemokines, including KC (CXCL1) and MIP-2 (CXCL2) (45). A recent study demonstrated that M1 proteinprovoked pulmonary accumulation of neutrophils is critically dependent on the synthesis and action of CXC chemokines (44).…”

“…Extravascular localization of neutrophils is coordinated by secreted CXC chemokines, including KC (CXCL1) and MIP-2 (CXCL2) (45). A recent study demonstrated that M1 proteinprovoked pulmonary accumulation of neutrophils is critically dependent on the synthesis and action of CXC chemokines (44).…”