Rho-kinase signalling in systemic inflammatory responses

Abstract: Endotoxemic liver injury is characterized by an initial release of pro-inflammatory cytokines and CXC chemokines, which leads to a recruitment of leukocytes to the liver microvasculature. The mechanisms of leukocyte recruitment are well characterized and comprise on the one hand a mechanical trapping of leukocytes in sinusoids, and on the other hand a multi-step process of leukocyte-endothelial cell interactions in postsinusoidal venules. This process is mediated by a balanced interplay of several adhesion molecules, which finally results in a firm adhesion of leukocytes to the endothelial wall and a subsequent leukocyte extravasation and migration into the surrounding tissue. Rho-kinase is an effector enzyme of small Rho-GTPases which are ubiquitously expressed and mediate a variety of intracellular mechanisms. Most importantly, Rho-kinase is involved in the organization of the actin cytoskeleton and cell movement. Further, it is known to be involved in the regulation of innate immunity. Thus, we herein investigated the involvement of Rho-kinase in endotoxemic liver and lung injury in a model of systemic inflammatory reaction. Further, we investigated the potential effects of simvastatin on LPS-induced liver injury, knowing that HMG-CoA reductase substrates are required for Rho-kinase activation. We found that Rho-kinase is centrally involved in the regulation of inflammatory responses in endotoxemic systemic inflammation-induced liver and lung injury. Further, Rho-kinase also mediates local inflammatory reaction in the lung. HMG-CoA reductase inhibition was further shown to effectively prevent endotoxemic liver injury. Thus, we herein propose Rho-kinase as an attractive target for treatment and prevention of endotoxin-induced inflammatory organ injury.