Targeting Abl kinases to regulate vascular leak during sepsis and acute respiratory distress syndrome

Abstract

The vascular endothelium separates circulating fluid and inflammatory cells from the surrounding tissues. Vascular leak occurs in response to wide-spread inflammatory processes, such as sepsis and acute respiratory distress syndrome, because of the formation of gaps between endothelial cells. Although these disorders are leading causes of mortality in the intensive care unit, no medical therapies exist to restore endothelial cell barrier function. Recent evidence highlights a key role for the Abl family of nonreceptor tyrosine kinases in regulating vascular barrier integrity. These kinases have well-described roles in cancer progression and neuronal morphogenesis, but their functions in the vasculature have remained enigmatic until recently. The Abl family kinases, c-Abl (Abl1) and Abl related gene (Arg, Abl2), phosphorylate several cytoskeletal effectors that mediate vascular permeability, including nonmuscle myosin light chain kinase, cortactin, vinculin, and β-catenin. They also regulate cell-cell and cell-matrix junction dynamics, and the formation of actin-based cellular protrusions in multiple cell types. In addition, both c-Abl and Arg are activated by hyperoxia and contribute to oxidant-induced endothelial cell injury. These numerous roles of Abl kinases in endothelial cells and the current clinical usage of imatinib and other Abl kinase inhibitors have spurred recent interest in repurposing these drugs for the treatment of vascular barrier dysfunction. This review will describe the structure and function of Abl kinases with an emphasis on their roles in mediating vascular barrier integrity. We will also provide a critical evaluation of the potential for exploiting Abl kinase inhibition as a novel therapy for inflammatory vascular leak syndromes.

Keywords: acute lung injury; c-abl gene; cytoskeleton; endothelium; imatinib; respiratory distress syndrome, adult; sepsis.

Figure 1. Abl Family Kinase Domain Organization

The Abl Kinase Family is composed of c-Abl and Arg. SH3 - Src Homology 3, SH2 – Src Homology 2, Pro – Proline BD – binding domain, MT – microtubule. Triangles indicate major regulatory phosphorylation sites. Similar figures are availble in comprehensive reviews of Abl family kinase regulation.

Figure 2. Barrier Disruptive and Barrier Protective Pathways of Abl Family Kinases in Endothelial Cytoskeletal Dynamics

Published data indicated that Abl family kinases play both barrier disruptive (A) and barrier protective (B) roles in cellular signaling pathways that mediate endothelial permeability (details described in text). For the sake of clarity this figure is not drawn to size. S1P – Sphingosine 1-Phosphate, S1PR1 – S1P Receptor 1, MLCK – Myosin Light Chain Kinase, CTTN – Cortactin, VEGF – Vascular Endothelial Growth Factor, VEGFR2 – VEGF Receptor 2, VE-Cad – Vascular Endothelial Cadherin, Vascular Endothelial Cellular Adhesion Molecule 1 – VCAM-1, Protease Activated Receptor 1 – PAR-1, Histamine Receptor 1 (H1), Inositol 3-Phosphate – IP3, IP3 Receptor – IP3R, PLCγ – Phospholipase C Gamma - Reactive Oxygen Species – ROS, Glutathione peroxidase 1 – GPx1, LPS – Lipopolysaccharide, Toll Like Receptor 4 – TLR, H₂O₂ – Hydrogen Peroxide, Ca²⁺ - Calcium, NFκB – Nuclear Factor Kappa B, GPCR – G Protein Coupled Receptor, FA – Focal Adhesion.