Abstract
BackgroundHigh-tidal-volume mechanical ventilation and hyperoxia used in patients with acute lung injury (ALI) can induce the release of cytokines, including high-mobility group box-1 (HMGB1), oxygen radicals, neutrophil infiltration, and the disruption of epithelial and endothelial barriers. Hyperoxia has been shown to increase ventilator-induced lung injury, but the mechanisms regulating interaction between high tidal volume and hyperoxia are unclear. We hypothesized that subcutaneous injections of enoxaparin would decrease the effects of hyperoxia on high-tidal-volume ventilation-induced HMGB1 production and neutrophil infiltration via the serine/threonine kinase/protein kinase B (Akt) pathway.MethodsMale C57BL/6, either wild type or Akt+/-, aged between 6 and 8 weeks, weighing between 20 and 25 g, were exposed to high-tidal-volume (30 ml/kg) mechanical ventilation with room air or hyperoxia for 2 to 8 hours with or without 4 mg/kg enoxaparin administration. Nonventilated mice served as a control group. Evan blue dye, lung wet-to-dry weight ratio, free radicals, myeloperoxidase, Western blot of Akt, and gene expression of HMGB1 were measured. The expression of HMGB1 was studied by immunohistochemistry.ResultsHigh-tidal-volume ventilation using hyperoxia induced microvascular permeability, Akt activation, HMGB1 mRNA expression, neutrophil infiltration, oxygen radicals, HMGB1 production, and positive staining of Akt in bronchial epithelium. Hyperoxia-induced augmentation of ventilator-induced lung injury was attenuated with Akt deficient mice and pharmacological inhibition of Akt activity by enoxaparin.ConclusionThese data suggest that enoxaparin attenuates hyperoxia-augmented high-tidal-volume ventilation-induced neutrophil influx and HMGB1 production through inhibition of the Akt pathway. Understanding the protective mechanism of enoxaparin related with the reduction of HMGB1 may help further knowledge of the effects of mechanical forces in the lung and development of possible therapeutic strategies involved in acute lung injury.
Highlights
Acute respiratory distress syndrome (ARDS)/acute lung injury (ALI) is characterized by noncardiogenic pulmonary edema, the release of cytokines, and the influx of neutrophils [1]
Inhibition of the effects of hyperoxia on lung stretchinduced microvascular leak, oxygen radicals, neutrophil sequestration, and high-mobility group box-1 (HMGB1) production with enoxaparin To determine the effects of hyperoxia on changes of microvascular permeability and lung water in ventilator-induced lung injury (VILI), we measured lung Evans blue dye (EBD) and wet-to-dry weight ratio
The MPO levels and HMGB1 protein production in mice ventilated with hyperoxia at VT 30 ml/kg were significantly elevated compared with those of control, nonventilated mice and mice ventilated with room air at a VT of 30 ml/kg (Figures 3)
Summary
Acute respiratory distress syndrome (ARDS)/acute lung injury (ALI) is characterized by noncardiogenic pulmonary edema, the release of cytokines, and the influx of neutrophils [1]. During endotoxemia HMGB1 rises in the circulation starting at 8 hours, increasing until 16 hours, and thereafter remains at a high level until 36 h [12] It is a late mediator of lung injury, HMGB1 might express its toxicity in a short period of time in VILI [10], even in patients without previous lung injury [13]. High-tidal-volume mechanical ventilation can lead to increase of HMGB1 production, recruitment of neutrophils, and the development of acute lung injury involving activation of phosphoinositide 3-OH kinase (PI 3-K) and serine/threonine kinase/protein kinase B (Akt) in an isolated mouse model of endotoxemia [14]. High-tidal-volume mechanical ventilation and hyperoxia used in patients with acute lung injury (ALI) can induce the release of cytokines, including high-mobility group box-1 (HMGB1), oxygen radicals, neutrophil infiltration, and the disruption of epithelial and endothelial barriers.
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