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Blocking p21-activated Kinase Reduces Lipopolysaccharide-induced Acute Lung Injury by Preventing Polymorphonuclear Leukocyte Infiltration

¹ Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia; ² Department of Anesthesiology and Intensive Care Medicine, University of Tübingen, Tübingen, Germany; ³ Department of Anesthesiology and Critical Care Medicine, University of Münster, Münster, Germany; Departments of ⁴ Biomedical Engineering, ⁵ Microbiology, and ⁶ Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia

Correspondence and requests for reprints should be addressed to Klaus Ley, M.D., University of Virginia Health System, Robert M. Berne Cardiovascular Research Center, P.O. Box 801394, Charlottesville, VA 22908-1394. E-mail: klausley{at}virginia.edu

Rationale: Excessive recruitment of polymorphonuclear leukocytes (PMNs) to the lung promotes acute lung injury (ALI). Chemokine receptors and adhesion molecules initiate leukocyte–endothelial interactions, but mediators of PMN migration through the alveolo-capillary membrane remain to be identified. p21-Activated kinase (PAK) is an effector of small GTPases and has been implicated in cell migration.

Objectives: To test the role of PAK in ALI.

Methods: An inhibitory PAK peptide was used to determine the role of PAK in cytoskeletal actin polymerization, cell adhesion, and oxidative burst. PMN migration was investigated in vitro and in a murine model of lipopolysaccharide-induced lung injury.

Measurements and Main Results: PMN migration into lung interstitium and alveolar space was suppressed by an inhibitory PAK peptide. Neutrophils that had taken up the inhibitory PAK peptide were unable to enter the alveolar space. CXCL2/3, an important PMN chemoattractant in murine lung injury, induced PAK phosphorylation in PMNs. Blocking PAK function inhibited chemotaxis, chemokine-induced cytoskeletal actin polymerization, and adhesion-induced oxidative burst.

Conclusions: We conclude that neutrophil PAK is a critical mediator of PMN migration and may be an attractive target in ALI.

Key Words: acute respiratory distress syndrome • polymorphonuclear leukocytes • inflammation • migration

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Chemokine receptors and adhesion molecules initiate leukocyte–endothelial interactions, but mediators of polymorphonuclear leukocyte migration through the alveolo-capillary membrane remain to be identified. What This Study Adds to the Field p21-Activated kinase is a critical mediator in acute lung injury.

 

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