Abstract
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 HVT 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.
Highlights
Acute lung injury (ALI) is a devastating illness with an annual incidence of 200,000 in the United States and a mortality rate of 40% [1]
High tidal volume mechanical ventilation causes pulmonary vascular permeability In order to determine the role of Mechanical ventilation (MV) with varying tidal volume on lung injury, adult male wild type (WT) C57BL/6J mice were allowed to breathe spontaneously or exposed to MV at 7 ml/kg (LVT) and 20 ml/kg (HVT) for 4 hours
As our laboratory has demonstrated increased stress fiber formation with MK2 activation and heat shock protein 27 (HSP27) phosphorylation in vitro [9], we explored the potential effect of activation of the p38 Mitogen activated protein (MAP) kinase-MK2-HSP25 signaling pathway on actin polymerization in response to HVT MV
Summary
Acute lung injury (ALI) is a devastating illness with an annual incidence of 200,000 in the United States and a mortality rate of 40% [1]. Mechanical ventilation (MV), a mainstay treatment for ALI, potentially contributes to and worsens permeability by exacting mechanical stress on various components of the respiratory system causing ventilator-associated lung injury (VALI) [3,4]. When phosphorylated, HSP27 loses its monomeric actin binding function leading to polymerized F-actin and stress fiber formation [10]. It is well recognized that actin cytoskeletal reorganization plays a pivotal role in mediating endothelial cell barrier function and permeability such that actin polymerization and actin stress fiber formation result in increased vascular permeability by inducing paracellular gaps [11,12,13,14,15]
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