Blocking p21-activated kinase reduces lipopolysaccharide-induced acute lung injury by preventing polymorphonuclear leukocyte infiltration.
BACKGROUND
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.


OBJECTIVE
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.


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.
Reutershan
Jörg
J
Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908-1394, USA.
Stockton
Rebecca
R
Zarbock
Alexander
A
Sullivan
Gail W
GW
Chang
Daniel
D
Scott
David
D
Schwartz
Martin A
MA
Ley
Klaus
K
D000199:Actins / Q000737:chemistry; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D019743:Chemokines, CXC / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology* / Q000648:ultrastructure; D010455:Peptides / Q000494:pharmacology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D023063:Receptors, Interleukin-8B / Q000378:metabolism; D016897:Respiratory Burst; D012128:Respiratory Distress Syndrome / Q000276:immunology*; D054462:p21-Activated Kinases
D000199:Actins; C499707:CXCL3 protein, human; D019743:Chemokines, CXC; D008070:Lipopolysaccharides; D010455:Peptides; D023063:Receptors, Interleukin-8B; C515903:PAK1 protein, human; C515905:Pak1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases