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Updated: Jul 16, 2026
Inducing Acute Lung Injury in Mice by Direct Intratracheal Lipopolysaccharide Instillation
Published on: July 6, 2019
Blocking p21-activated kinase reduces lipopolysaccharide-induced acute lung injury by preventing polymorphonuclear
Jörg Reutershan1, Rebecca Stockton, Alexander Zarbock
1Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908-1394, USA.
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.
Insights
Neutrophil p21-activated kinase (PAK) is crucial for polymorphonuclear leukocyte (PMN) migration in acute lung injury (ALI). Inhibiting PAK reduces PMN infiltration into the lungs, suggesting PAK as a potential therapeutic target for ALI.
Area of Science:
- Cell Biology
- Immunology
- Pulmonary Medicine
Background:
- Excessive polymorphonuclear leukocyte (PMN) recruitment to the lungs drives acute lung injury (ALI).
- While leukocyte-endothelial interactions are initiated by chemokine receptors and adhesion molecules, the mediators of PMN transmigration across the alveolo-capillary barrier are not fully understood.
- p21-activated kinase (PAK) is a known effector of small GTPases involved in cell migration.
Purpose of the Study:
- To investigate the role of p21-activated kinase (PAK) in the pathogenesis of acute lung injury (ALI).
Main Methods:
- Utilized an inhibitory PAK peptide to assess PAK's function in cytoskeletal actin polymerization, cell adhesion, and oxidative burst.
- Examined PMN migration in vitro and in a murine model of lipopolysaccharide-induced lung injury.
Main Results:
- An inhibitory PAK peptide significantly suppressed PMN migration into the lung interstitium and alveolar space.
- Neutrophils treated with the inhibitory PAK peptide demonstrated impaired ability to enter the alveolar space.
- Blocking PAK function inhibited PMN chemotaxis, chemokine-induced cytoskeletal actin polymerization, and adhesion-induced oxidative burst, with PAK phosphorylation induced by the chemoattractant CXCL2/3.
Conclusions:
- Neutrophil PAK is a critical mediator of PMN migration in the context of ALI.
- PAK represents a potential therapeutic target for mitigating acute lung injury.
