Mitogen activated protein kinase activated protein kinase 2 regulates actin polymerization and vascular leak in ventilator associated lung injury.
Mechanical ventilation, a fundamental therapy for acute lung injury, worsens pulmonary vascular permeability by exacting mechanical stress on various components of the respiratory system causing ventilator associated lung injury. We postulated that MK2 activation via p38 MAP kinase induced HSP25 phosphorylation, in response to mechanical stress, leading to actin stress fiber formation and endothelial barrier dysfunction. We sought to determine the role of p38 MAP kinase and its downstream effector MK2 on HSP25 phosphorylation and actin stress fiber formation in ventilator associated lung injury. Wild type and MK2(-/-) mice received mechanical ventilation with high (20 ml/kg) or low (7 ml/kg) tidal volumes up to 4 hrs, after which lungs were harvested for immunohistochemistry, immunoblotting and lung permeability assays. High tidal volume mechanical ventilation resulted in significant phosphorylation of p38 MAP kinase, MK2, HSP25, actin polymerization, and an increase in pulmonary vascular permeability in wild type mice as compared to spontaneous breathing or low tidal volume mechanical ventilation. However, pretreatment of wild type mice with specific p38 MAP kinase or MK2 inhibitors abrogated HSP25 phosphorylation and actin polymerization, and protected against increased lung permeability. Finally, MK2(-/-) mice were unable to phosphorylate HSP25 or increase actin polymerization from baseline, and were resistant to increases in lung permeability in response to HV(T) MV. Our results suggest that p38 MAP kinase and its downstream effector MK2 mediate lung permeability in ventilator associated lung injury by regulating HSP25 phosphorylation and actin cytoskeletal remodeling.
Damarla
Mahendra
M
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
Hasan
Emile
E
Boueiz
Adel
A
Le
Anne
A
Pae
Hyun Hae
HH
Montouchet
Calypso
C
Kolb
Todd
T
Simms
Tiffany
T
Myers
Allen
A
Kayyali
Usamah S
US
Gaestel
Matthias
M
Peng
Xinqi
X
Reddy
Sekhar P
SP
Damico
Rachel
R
Hassoun
Paul M
PM
D000199:Actins / Q000378:metabolism*; D000818:Animals; D002199:Capillary Permeability; D006360:Heat-Shock Proteins / Q000502:physiology*; D008168:Lung; D055370:Lung Injury / Q000209:etiology* / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D018832:Molecular Chaperones; D009363:Neoplasm Proteins / Q000502:physiology*; D010766:Phosphorylation; D012121:Respiration, Artificial / Q000009:adverse effects*; D013314:Stress, Mechanical; D012122:Ventilators, Mechanical / Q000009:adverse effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
D000199:Actins; D006360:Heat-Shock Proteins; C486113:Hsbp1 protein, mouse; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D048051:p38 Mitogen-Activated Protein Kinases; D048370:MAP Kinase Kinase 2