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

Am J Respir Crit Care Med. 2007 May 15;175(10):1027-35. doi: 10.1164/rccm.200612-1822OC. Epub 2007 Feb 22.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / chemistry
  • Animals
  • Cell Adhesion / drug effects
  • Chemokines, CXC / metabolism
  • Chemotaxis, Leukocyte* / drug effects
  • Humans
  • Lipopolysaccharides / pharmacology
  • Macrophages / immunology
  • Mice
  • Neutrophils / enzymology
  • Neutrophils / immunology*
  • Neutrophils / ultrastructure
  • Peptides / pharmacology
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / physiology*
  • Receptors, Interleukin-8B / metabolism
  • Respiratory Burst
  • Respiratory Distress Syndrome / immunology*
  • p21-Activated Kinases

Substances

  • Actins
  • CXCL3 protein, human
  • Chemokines, CXC
  • Lipopolysaccharides
  • Peptides
  • Receptors, Interleukin-8B
  • PAK1 protein, human
  • Pak1 protein, mouse
  • Protein-Serine-Threonine Kinases
  • p21-Activated Kinases