Arg mediates LPS-induced disruption of the pulmonary endothelial barrier.

Arg mediates LPS-induced disruption of the pulmonary endothelial barrier. Vascul Pharmacol. 2020 Mar 30;:106677 Authors: Rizzo AN, Belvitch P, Demeritte R, Garcia JGN, Letsiou E, Dudek SM Abstract Acute Respiratory Distress Syndrome (ARDS) is a devastating disease process that involves dysregulated inflammation and decreased alveolar-capillary barrier function. Despite increased understanding of the pathophysiology, no effective targeted therapies exist to treat ARDS. Recent preclinical studies suggest that the multi-tyrosine kinase inhibitor, imatinib, which targets the Abl kinases c-Abl and Arg, has the potential to restore endothelial dysfunction caused by inflammatory agonists. Prior work demonstrates that imatinib attenuates LPS (lipopolysaccharide)-induced vascular leak and inflammation; however, the mechanisms underlying these effects remain incompletely understood. In the current study, we demonstrate that imatinib inhibits LPS induced increase in the phosphorylation of CrkL, a specific substrate of Abl kinases, in human pulmonary endothelial cells. Specific silencing of Arg, and not c-Abl, attenuated LPS-induced pulmonary vascular permeability as measured by electrical cellular impedance sensing (ECIS) and gap formation assays. In addition, direct activation of Abl family kinases with the small molecule activator DPH resulted in endothelial barrier disruption that was attenuated by Arg siRNA. In complementary studies to char...
Source: Vascular Pharmacology - Category: Drugs & Pharmacology Authors: Tags: Vascul Pharmacol Source Type: research