title: High tidal volume mechanical ventilation elicits increased activity in protein kinase B and c-Jun NH2-terminal kinase pathways in mouse diaphragm.
abstract: OBJECTIVE
  Unloading of the diaphragm via mechanical ventilation for more than 5 days leads to weaning difficulties. Mechanical ventilation can induce production of inflammatory cytokines and extracellular matrix proteins. The mechanisms regulating interactions between mechanical ventilation and diaphragmatic injury are unclear. We hypothesized that high tidal volume mechanical stretch augmented diaphragmatic injury via serine/threonine kinase/protein kinase B (Akt) and c-Jun NH(2)-terminal kinase (JNK) pathways.
  
  
  METHODS
  Male C57BL/6, either wild type or Akt deficient, weighing between 20 and 25 g, were exposed to high tidal volume (30 ml/kg) or low tidal volume (6 ml/kg) mechanical ventilation with room air for 2-8 h.
  
  
  RESULTS
  High tidal volume mechanical ventilation induced Akt, JNK, and class O of forkhead box transcription factor 4 (Foxo4) activation in a time-dependent manner. Disruption and atrophy of muscle fibers in the diaphragm, positive staining of phospho-Akt in the myofiber membrane, and increased production of free radicals were also found. Mechanical ventilation of Akt-deficient mice resulted in attenuated diaphragmatic injury, Akt, JNK, and Foxo4 activation, and free radical production.
  
  
  CONCLUSIONS
  Our data suggest that high tidal volume mechanical ventilation produces diaphragmatic muscle damage and free radical production through activation of the Akt and JNK pathways.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Kweishan, Taoyuan, Taiwan.
authors.forename: Li-Fu
authors.initials: LF
authors.lastname: Li
authors.forename: Mei-Ling
authors.initials: ML
authors.lastname: Tien
authors.forename: Sum-Yee
authors.initials: SY
authors.lastname: Leung
authors.forename: Meng-Chih
authors.initials: MC
authors.lastname: Lin
mesh_terms: D000818:Animals; D003964:Diaphragm / Q000201:enzymology / Q000293:injuries*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012121:Respiration, Artificial / Q000009:adverse effects* / Q000379:methods*; D013990:Tidal Volume
chemical_list: D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases