Oxidized phospholipids reduce ventilator-induced vascular leak and inflammation in vivo

Rats received a single intravenous injection of OxPAPC (1.5 mg/kg) followed by mechanical ventilation at low tidal volume (LTV) (7 mL/kg) or HTV (20 mL/kg). Bronchoalveolar lavage was performed and lung tissue was stained for histological analysis. In vitro, the effects of OxPAPC on endothelial barrier dysfunction and GTPase activation were assessed in cells exposed to thrombin and pathologic (18%) cyclic stretch.HTV induced profound increases in bronchoalveolar lavage and tissue neutrophils and in lavage protein. Intravenous OxPAPC markedly attenuated HTV-induced protein and inflammatory cell accumulation in bronchoalveolar lavage fluid and lung tissue. In vitro, high-magnitude stretch enhanced thrombin-induced endothelial paracellular gap formation associated with Rho activation. These effects were dramatically attenuated by OxPAPC and were associated with OxPAPC-induced activation of Rac.OxPAPC exhibits protective effects in these models of ventilator-induced lung injury.Acute lung injury (ALI) is a devastating clinical syndrome characterized by acute lung inflammation and vascular barrier disruption that affects more than 200,000 patients per year in the US and is associated with a mortality rate of 30% to 50% [1,2]. Mechanical ventilation, particularly with high tidal volumes (HTVs), can worsen or even cause de novo lung injury [3-5]. The landmark ARDSnet trial demonstrated a 22% decrease in mortality in acute respiratory distress syndrome (ARDS) with the use of low tidal volume (LTV) mechanical ventilation [6]. However, despite recent advances in LTV ventilatory strategies and a better understanding of the underlying inflammatory pathophysiology of ALI, there remain few effective treatments for this devastating illness. Meta-analyses of large-scale human trials have failed to show a mortality benefit from early high-dose corticosteroids, N-acetylcysteine, surfactant, or prostaglandin E1 despite promising preclinical studies [7]. Thus, ALI and ventilator-induce