title: Blocking p21-activated kinase reduces lipopolysaccharide-induced acute lung injury by preventing polymorphonuclear leukocyte infiltration.
abstract: 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.
authors.affiliation: Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908-1394, USA.
authors.forename: Jörg
authors.initials: J
authors.lastname: Reutershan
authors.forename: Rebecca
authors.initials: R
authors.lastname: Stockton
authors.forename: Alexander
authors.initials: A
authors.lastname: Zarbock
authors.forename: Gail W
authors.initials: GW
authors.lastname: Sullivan
authors.forename: Daniel
authors.initials: D
authors.lastname: Chang
authors.forename: David
authors.initials: D
authors.lastname: Scott
authors.forename: Martin A
authors.initials: MA
authors.lastname: Schwartz
authors.forename: Klaus
authors.initials: K
authors.lastname: Ley
mesh_terms: 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
chemical_list: 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