Acute lung injury (ALI) is a devastating illness with very high morbidity and mortality and limited therapeutic options. The recognition of the deleterious effects of mechanical ventilation (MV), the mainstay supportive therapy for ALI, has led to increasing interest in the pathways involved in pulmonary vascular permeability observed in ventilator-associated lung injury (VALI). Low tidal volume lung strategies remain the only supportive treatment of ALI/VALI with proven efficacy. Therefore, novel therapies that will specifically target mechanisms involved in barrier disruption in ALIA/ALI are needed. Endothelial cell apoptosis has been recently implicated as a necessary event in the early pathogenesis of VALI. Additionally, the p38 mitogen activated protein (MAP) kinase, a known mediator of endothelial cell apoptosis is activated in response to injurious modes of MV. However, the downstream effectors of p38 MAP kinase involved in mediating the development and severity of VALI remain unknown. Activation of p38 MAP kinase and its downstream effector MAPK-activated protein kinase MK2 (MK2) leads to phosphorylation of the small heat shock protein 27 (HSP27), a known regulator of apoptosis. In addition, phosphorylation of HSP25 (HSP27's murine homologue) correlates with HVT MV mediated apoptosis and pulmonary edema. However, the specific mechanism(s) by which MK2 or HSP25 contribute to the development of VALI are unknown. This proposal will test the hypothesis that MK2-mediated phosphorylation of HSP27 is critical for promoting HVT MV mediated apoptosis and resultant pulmonary edema using an in vitro mechanical stress model and an established murine model of VALI in wild type and MK2-/- mice.
The specific aims of this application are to: 1) Define the role of MK2 in promoting mechanical stress-induced apoptosis in vitro;2) Define the role of HSP25/27 phosphorylation in mechanical stress-induced apoptosis in vitro;and 3) Determine the role for HSP25/27 phosphorylation in HVT MV mediated apoptosis and resultant pulmonary vascular permeability in vivo.
Mechanical ventilation, although the cornerstone of treatment for many disorders, has the potential to exacerbate and cause de novo lung injury. We have identified a pathway and a potential mechanism that is relevant in mediating injury due to mechanical ventilation. We hope that further insight will help identify novel therapeutic targets.
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