Published ahead of print on February 22, 2007, doi:10.1164/rccm.200612-1822OC Am. J. Respir. Crit. Care Med., Volume 175, Number 10, May 2007, 1027-1035 A more recent version of this article appeared on May 15, 2007
Submitted on December 16, 2006 Blocking p21-Activated Kinase Reduces LPS-Induced Acute Lung Injury by Preventing PMN InfiltrationJorg Reutershan1,1 Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottsville, VA, USA; Department of Anesthesiology and Intensive Care Medicine, University of Tubingen, Tubingen, Germany, 2 Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottsville, VA, USA, 3 Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottsville, VA, USA; Department of Anesthesiology and Critical Care Medicine, University of Munster, Munster, Germany, 4 Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottsville, VA, USA; Department of Biomedical Engineering, University of Virginia, Charlottsville, VA, USA; Department of Microbiology, University of Virginia, Charlottsville, VA, USA, 5 Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottsville, VA, USA; Department of Biomedical Engineering, University of Virginia, Charlottsville, VA, USA; Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottsville, VA, USA * To whom correspondence should be addressed. E-mail: klausley{at}virginia.edu.
Rationale: Excessive recruitment of polymorphonuclear leukocytes (PMNs) to the lung promotes acute lung injury. 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 acute lung injury. Methods: An inhibitory PAK peptide was used to determine the role of PAK in cytoskeletal polymerization, cell adhesion, and oxidative burst. PMN migration was investigated in vitro and in a murine model of lipopolysaccharide(LPS)-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 acute lung injury. Key words: acute respiratory distress syndrome, polymorphonuclear leukocytes, inflammation, migration
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