title: Differential and opposing effects of imatinib on LPS- and ventilator-induced lung injury.
abstract: Endothelial dysfunction underlies the pathophysiology of vascular disorders such as acute lung injury (ALI) syndromes. Recent work has identified the Abl family kinases (c-Abl and Arg) as important regulators of endothelial cell (EC) barrier function and suggests that their inhibition by currently available pharmaceutical agents such as imatinib may be EC protective. Here we describe novel and differential effects of imatinib in regulating lung pathophysiology in two clinically relevant experimental models of ALI. Imatinib attenuates endotoxin (LPS)-induced vascular leak and lung inflammation in mice but exacerbates these features in a mouse model of ventilator-induced lung injury (VILI). We next explored these discrepant observations in vitro through investigation of the roles for Abl kinases in cultured lung EC. Imatinib attenuates LPS-induced lung EC permeability, restores VE-cadherin junctions, and reduces inflammation by suppressing VCAM-1 expression and inflammatory cytokine (IL-8 and IL-6) secretion. Conversely, in EC exposed to pathological 18% cyclic stretch (CS) (in vitro model of VILI), imatinib decreases VE-cadherin expression, disrupts cell-cell junctions, and increases IL-8 levels. Downregulation of c-Abl expression with siRNA attenuates LPS-induced VCAM-1 expression, whereas specific reduction of Arg reduces VE-cadherin expression in 18% CS-challenged ECs to mimic the imatinib effects. In summary, imatinib exhibits pulmonary barrier-protective and anti-inflammatory effects in LPS-injured mice and lung EC; however, imatinib exacerbates VILI as well as dysfunction in 18% CS-EC. These findings identify the Abl family kinases as important modulators of EC function and potential therapeutic targets in lung injury syndromes.
authors.affiliation: University of Illinois at Chicago, Division of Pulmonary, Critical Care, Sleep, and Allergy, Illinois; and.
authors.forename: E
authors.initials: E
authors.lastname: Letsiou
authors.affiliation: University of Illinois at Chicago, Division of Pulmonary, Critical Care, Sleep, and Allergy, Illinois; and.
authors.forename: A N
authors.initials: AN
authors.lastname: Rizzo
authors.affiliation: University of Illinois at Chicago, Division of Pulmonary, Critical Care, Sleep, and Allergy, Illinois; and.
authors.forename: S
authors.initials: S
authors.lastname: Sammani
authors.affiliation: University of Illinois at Chicago, Division of Pulmonary, Critical Care, Sleep, and Allergy, Illinois; and.
authors.forename: P
authors.initials: P
authors.lastname: Naureckas
authors.affiliation: University of Illinois at Chicago, Division of Pulmonary, Critical Care, Sleep, and Allergy, Illinois; and.
authors.forename: J R
authors.initials: JR
authors.lastname: Jacobson
authors.affiliation: Arizona Health Sciences Center, University of Arizona, Arizona.
authors.forename: J G N
authors.initials: JG
authors.lastname: Garcia
authors.affiliation: University of Illinois at Chicago, Division of Pulmonary, Critical Care, Sleep, and Allergy, Illinois; and sdudek@uic.edu.
authors.forename: S M
authors.initials: SM
authors.lastname: Dudek
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001549:Benzamides / Q000494:pharmacology* / Q000627:therapeutic use; D001696:Biomechanical Phenomena; D002199:Capillary Permeability / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D004353:Drug Evaluation, Preclinical; D004730:Endothelium, Vascular / Q000187:drug effects / Q000276:immunology / Q000503:physiopathology; D006801:Humans; D000068877:Imatinib Mesylate; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000276:immunology; D008297:Male; D008810:Mice, Inbred C57BL; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D013312:Stress, Physiological; D055397:Ventilator-Induced Lung Injury / Q000188:drug therapy* / Q000276:immunology; D000509:alpha-Fetoproteins / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D001549:Benzamides; D016207:Cytokines; D008070:Lipopolysaccharides; D010879:Piperazines; D011743:Pyrimidines; D000509:alpha-Fetoproteins; C545206:alpha-fetoprotein related protein, mouse; D000068877:Imatinib Mesylate; D016315:Proto-Oncogene Proteins c-abl
keywords: ARDS; Arg; LPS; VILI; c-Abl; endothelium; imatinib; permeability; stretch