The Role of LIMK1 in Endothelial Barrier Function: LIMK1 is a Potential Target for the Drug Therapy of Acute Lung Injury

Abstract

Acute lung injury is a syndrome of acute respiratory failure that results from acute pulmonary edema and inflammation. As enhanced pulmonary vascular permeability is a hallmark of acute lung injury, we examined the lung microcirculation in LIMK1 knockout mice. We found that endothelial permeability in the lungs of LIMK1 −/ − mice was lower than that of wild type mice. Perfusion of the lungs of wild type mice with PAR1 peptide showed significant increase of endothelial permeability. Notably, the endothelial permeability of the lungs of LIMK1 −/ − mice after PAR1 peptide perfusion was significantly lower than that of wild type. Down-regulation of endogenous LIMK1 with siRNA in HUVECs resulted in increased trans-endothelial resistance. The overexpression of w.t. LIMK1 in HUVECs led to the decreased transendothelial resistance and opening of tight junctions as was revealed by confocal microscopy with staining for ZO-1 and VE-cadherin. To study endotoxin-induced acute lung injury, anaesthetized mice received LPS (ip) and the wet to dry ratio of the lungs of wild type mice was compared to that of LIMK1 −/ − mice. We found a decreased edema formation in LIMK1 −/ − mice upon LPS treatment. We suggest that the loss of LIMK1 protein leads to less permeable pulmonary blood vessels. These results favor the possibility that the inhibition of LIMK1 function may eliminate acute lung injury.