title: Low-molecular-weight heparin reduces hyperoxia-augmented ventilator-induced lung injury via serine/threonine kinase-protein kinase B.
abstract: BACKGROUND
  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. 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.
  
  
  METHODS
  Male 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.
  
  
  RESULTS
  High-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.
  
  
  CONCLUSIONS
  These 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.
authors: Department of Medicine, Chang Gung Memorial Hospital, Kweishan, Taoyuan, Taiwan. lfp3434@adm.cgmh.org.tw
authors: Li-Fu
authors: LF
authors: Li
authors: Cheng-Ta
authors: CT
authors: Yang
authors: Chung-Chi
authors: CC
authors: Huang
authors: Yung-Yang
authors: YY
authors: Liu
authors: Kuo-Chin
authors: KC
authors: Kao
authors: Horng-Chyuan
authors: HC
authors: Lin
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002199:Capillary Permeability / Q000187:drug effects; D004195:Disease Models, Animal; D017984:Enoxaparin / Q000008:administration & dosage / Q000494:pharmacology*; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism; D018496:Hyperoxia / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D007150:Immunohistochemistry; D007279:Injections, Subcutaneous; D008168:Lung / Q000098:blood supply / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000187:drug effects; D009195:Peroxidase / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012121:Respiration, Artificial / Q000009:adverse effects*; D015398:Signal Transduction / Q000187:drug effects; D013990:Tidal Volume; D013997:Time Factors; D055397:Ventilator-Induced Lung Injury / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*
chemical_list: D017984:Enoxaparin; D024243:HMGB1 Protein; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D009195:Peroxidase; D051057:Proto-Oncogene Proteins c-akt