Ethyl pyruvate reduces ventilation-induced neutrophil infiltration and oxidative stress.
Mechanical ventilation with high tidal volume causes intense inflammatory responses and oxidative stress, including the release of high-mobility group box-1 (HMGB1), plasminogen activator inhibitor-1 (PAI-1) and heme oxygenase-1 (HO-1). The mechanisms regulating ventilator-induced lung injury (VILI) are unclear. We hypothesized that ethyl pyruvate attenuated acute lung injury as adjunctive pharmacological strategy by down-regulating neutrophil infiltration, oxidative stress and HMGB1 mRNA expression. C57BL/6 mice, weighing 20-25 g, were exposed to either low-tidal-volume (6 mL/kg) or high-tidal-volume (30 mL/kg) mechanical ventilation with room air for 2-5 h and subjected to 100 mg/kg ethyl pyruvate administration intraperitoneally. Non-ventilated mice served as the control group. Evans blue dye, lung wet-to-dry weight ratio, lung neutrophil infiltration and myeloperoxidase, free radicals, gene expression of HMGB1, active PAI-1 and HMGB1 production and HO-1 expression were measured. The expression of HO-1 was studied by immunohistochemistry. High-tidal-volume ventilation induced microvascular leak, neutrophil recruitment, oxidative injury, HMGB1 and active PAI-1 protein production, and upregulation of HMGB1 mRNA and stress-inducible protein HO-1. In contrast, administration of ethyl pyruvate before high stretch mechanical ventilation prevented lung edema formation, inflammatory cytokine production, neutrophil accumulation, oxidative stress and HMGB1 and HO-1 expression. High-tidal-volume mechanical ventilation increased microvascular permeability, neutrophil influx and inflammatory cytokines. Ethyl pyruvate is capable of suppressing the VILI related to the reduction of HMGB1 and our findings support the potential use of ethyl pyruvate as a therapeutic agent for the prevention of VILI.
Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Kweishan, Taoyuan 333, Taiwan.
Li-Fu
LF
Li
Kuo-Chin
KC
Kao
Cheng-Ta
CT
Yang
Chung-Chi
CC
Huang
Yung-Yang
YY
Liu
D055371:Acute Lung Injury / Q000209:etiology* / Q000378:metabolism / Q000517:prevention & control*; D000818:Animals; D024243:HMGB1 Protein / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D020556:Neutrophil Infiltration / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011773:Pyruvates / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D012121:Respiration, Artificial / Q000009:adverse effects*; D013990:Tidal Volume / Q000187:drug effects
D024243:HMGB1 Protein; D017395:Plasminogen Activator Inhibitor 1; D011773:Pyruvates; D012333:RNA, Messenger; C046522:ethyl pyruvate; D051547:Heme Oxygenase-1