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

Stephanie Nonas,Santipongse Chatchavalvanich,Konstantin G Birukov,Norbert Leitinger,Jungjie Xing,Anna A Birukova,Joe Gn Garcia,Panfeng Fu,Valery N Bochkov

doi:10.1186/cc6805

Abstract

BackgroundMechanical ventilation at high tidal volume (HTV) may cause pulmonary capillary leakage and acute lung inflammation resulting in ventilator-induced lung injury. Besides blunting the Toll-like receptor-4-induced inflammatory cascade and lung dysfunction in a model of lipopolysaccharide-induced lung injury, oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (OxPAPC) exerts direct barrier-protective effects on pulmonary endothelial cells in vitro via activation of the small GTPases Rac and Cdc42. To test the hypothesis that OxPAPC may attenuate lung inflammation and barrier disruption caused by pathologic lung distension, we used a rodent model of ventilator-induced lung injury and an in vitro model of pulmonary endothelial cells exposed to pathologic mechanochemical stimulation.MethodsRats 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.ResultsHTV 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.ConclusionOxPAPC exhibits protective effects in these models of ventilator-induced lung injury.

Highlights

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]
Effects of oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3phosphorylcholine (OxPAPC) on ventilator-induced lung inflammation and barrier dysfunction We evaluated the effects of intravenously administered OxPAPC on the parameters of lung inflammation and barrier dysfunction in rats exposed to mechanical ventilation at high tidal volume (HTV) (20 mL/kg) compared with control rats exposed to 'protective' low tidal volume (LTV) mechanical ventilation (7 mL/kg) [35,36,37]
Using an aseptic in vivo model of ventilator-induced lung injury (VILI), we show here for the first time that a single intravenous dose of OxPAPC significantly attenuates the early vascular barrier disruption and acute inflammation induced by mechanical ventilation at HTV

Summary

Introduction

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]. Meta-analyses of large-scale human trials have failed to show a mortality benefit from early high-dose corticosteroids, N-acetylcysteine, ALI = acute lung injury; ARDS = acute respiratory distress syndrome; BAL = bronchoalveolar lavage; CS = cyclic stretch; DMPC = di-myristoyl-snglycero-3-phosphorylcholine; EC = endothelial cell; GEF = guanosine nucleotide exchange factor; HPAEC = human pulmonary artery endothelial cell; HPF = high power microscopic field; HTV = high tidal volume; IL = interleukin; LPS = lipopolysaccharide; LTV = low tidal volume; NF-κB = nuclear factor-kappa-B; OxPAPC = oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine; PAPC = 1-palmitoyl-2-arachidonoyl-sn-glycero-3phosphorylcholine; PBS = phosphate-buffered saline; PEEP = positive end-expiratory pressure; PMN = polymorphonuclear leukocyte; RhoGDI = Rho GDP dissociation inhibitor; TLR = Toll-like receptor; TRAP-6 = thrombin receptor activating peptide-6; VILI = ventilator-induced lung injury. To test the hypothesis that OxPAPC may attenuate lung inflammation and barrier disruption caused by pathologic lung distension, we used a rodent model of ventilator-induced lung injury and an in vitro model of pulmonary endothelial cells exposed to pathologic mechanochemical stimulation

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Conclusion