Pretreatment of Rho Kinase Inhibitor Inhibits Systemic Inflammation and Prevents Endotoxin-Induced Acute Lung Injury in Mice

Background. Systemic inflammatory mediators play an important role in the development of sepsis. In this study, we analyzed the role of Rho kinase in the activation of immune response and acute lung injury in a mouse model of sepsis. Methods. C57BL/6J mice were randomly divided into three groups: control, LPS, and LPS+fasudil. We used a mouse model of endotoxemia that consists of intraperitoneal injection of a high dose of LPS (30 mg/kg); a Rho kinase inhibitor, fasudil (10 mg/kg), dissolved in sterile saline (1 mu L/g body weight) was applied by intraperitoneal injection at 18 and 1 h before injection of LPS (LPS+fasudil group). The control mice received vehicle sterile saline only. Blood was collected and lungs were harvested at 3 and/or 6 h for analysis. Results. At 3 and 6 h, the increased TNF-alpha and IL-1 beta levels in plasma and MPO activity in lung tissue by LPS could be significantly inhibited by fasudil. In addition, LPS-induced histologic changes in the lungs at 6 h could be effectively reversed by fasudil pretreatment. Furthermore, pretreatment of mice with fasudil inhibited LPS-induced increasing of TNF-alpha, IL-1 beta mRNA expression (3 and 6 h) and AP-1/DNA binding activity (3 h) in blood cells. In survival studies, fasudil (10 mg/kg), which was administered 18 and 1 h before the application of LPS, conferred a protection against lethality induced by LPS (30 mg/kg). Conclusion. These results suggest that Rho kinase may play a role in the pathology of systemic inflammation during early phase of sepsis, and the potential mechanism of action may be partly through the adjustment of AP-1 pathway. (c) 2011 Elsevier Inc. All rights reserved.