Intensive Care Medicine

, Volume 37, Issue 12, pp 2015–2022 | Cite as

High tidal volume mechanical ventilation elicits increased activity in protein kinase B and c-Jun NH2-terminal kinase pathways in mouse diaphragm

  • Li-Fu Li
  • Mei-Ling Tien
  • Sum-Yee Leung
  • Meng-Chih Lin



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 NH2-terminal kinase (JNK) pathways.


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.


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.


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.


JNK Diaphragm Akt Mechanical ventilation Foxo4 



Acute lung injury


Serine/threonine kinase/protein kinase B


Acute respiratory distress syndrome




Class O of forkhead box transcription factor 4


Hematoxylin and eosin




c-Jun NH2-terminal kinase




Arterial carbon dioxide pressure


Arterial oxygen pressure


Phosphoinositide 3-OH kinase


Reactive oxygen species


Tumor necrosis factor-alpha


Ventilator-induced diaphragmatic damage


Ventilator-induced lung injury


Tidal volume



We thank Wi–Wi Li for her help with the experiments. This study was supported by the National Science Council (98-2314-B-182A-084-MY3).

Supplementary material

134_2011_2350_MOESM1_ESM.doc (11.6 mb)
Supplementary material 1 (DOC 11834 kb)


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Copyright information

© Copyright jointly held by Springer and ESICM 2011

Authors and Affiliations

  • Li-Fu Li
    • 1
    • 2
    • 3
  • Mei-Ling Tien
    • 4
  • Sum-Yee Leung
    • 4
    • 5
  • Meng-Chih Lin
    • 4
    • 5
  1. 1.Division of Pulmonary and Critical Care MedicineChang Gung Memorial HospitalTaoyuanTaiwan
  2. 2.Chang Gung UniversityTaoyuanTaiwan
  3. 3.Department of Respiratory TherapyChang Gung Memorial HospitalTaoyuanTaiwan
  4. 4.Department of Respiratory CareGraduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung UniversityKaohsiungTaiwan
  5. 5.Division of Pulmonary and Critical Care MedicineKaohsiung Chang Gung Memorial HospitalKaohsiungTaiwan

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