title: 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.
authors: From the Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medicine, College of Medicine (A.N.R., S.M.D.) and Department of Pharmacology (A.N.R., G.P.v.N.A., S.M.D.), University of Illinois at Chicago; Departments of Physiology (J.A., G.P.v.N.A.) and Pulmonary Diseases (J.A.), Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands.
authors: Alicia N
authors: AN
authors: Rizzo
authors: From the Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medicine, College of Medicine (A.N.R., S.M.D.) and Department of Pharmacology (A.N.R., G.P.v.N.A., S.M.D.), University of Illinois at Chicago; Departments of Physiology (J.A., G.P.v.N.A.) and Pulmonary Diseases (J.A.), Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands.
authors: Jurjan
authors: J
authors: Aman
authors: From the Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medicine, College of Medicine (A.N.R., S.M.D.) and Department of Pharmacology (A.N.R., G.P.v.N.A., S.M.D.), University of Illinois at Chicago; Departments of Physiology (J.A., G.P.v.N.A.) and Pulmonary Diseases (J.A.), Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands.
authors: Geerten P
authors: GP
authors: van Nieuw Amerongen
authors: From the Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medicine, College of Medicine (A.N.R., S.M.D.) and Department of Pharmacology (A.N.R., G.P.v.N.A., S.M.D.), University of Illinois at Chicago; Departments of Physiology (J.A., G.P.v.N.A.) and Pulmonary Diseases (J.A.), Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands. sdudek@uic.edu.
authors: Steven M
authors: SM
authors: Dudek
mesh_terms: D001549:Benzamides / Q000008:administration & dosage*; D002199:Capillary Permeability / Q000187:drug effects; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D058990:Molecular Targeted Therapy / Q000379:methods*; D010879:Piperazines / Q000008:administration & dosage*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D016315:Proto-Oncogene Proteins c-abl / Q000187:drug effects* / Q000235:genetics; D011743:Pyrimidines / Q000008:administration & dosage*; D012128:Respiratory Distress Syndrome / Q000188:drug therapy* / Q000503:physiopathology; D018805:Sepsis / Q000188:drug therapy* / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome
chemical_list: D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016315:Proto-Oncogene Proteins c-abl
keywords: acute lung injury; c-abl gene; cytoskeleton; endothelium; imatinib; respiratory distress syndrome, adult; sepsis