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
Experimental

Abstract

Purpose

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.

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.

Keywords

JNK Diaphragm Akt Mechanical ventilation Foxo4 

Abbreviations

ALI

Acute lung injury

Akt

Serine/threonine kinase/protein kinase B

ARDS

Acute respiratory distress syndrome

DAB

Diaminobenzidine

Foxo4

Class O of forkhead box transcription factor 4

H&E

Hematoxylin and eosin

IFN-γ

Interferon-γ

JNK

c-Jun NH2-terminal kinase

MDA

Malondialdehyde

PaCO2

Arterial carbon dioxide pressure

PaO2

Arterial oxygen pressure

PI3-K

Phosphoinositide 3-OH kinase

ROS

Reactive oxygen species

TNF-α

Tumor necrosis factor-alpha

VIDD

Ventilator-induced diaphragmatic damage

VILI

Ventilator-induced lung injury

VT

Tidal volume

Notes

Acknowledgments

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)

References

  1. 1.
    Dreyfuss D, Saumon G (1998) Ventilator-induced lung injury: lessons from experimental studies. Am J Respir Crit Care Med 157:294–323PubMedGoogle Scholar
  2. 2.
    Jubran A (2006) Critical illness and mechanical ventilation: effects on the diaphragm. Respir Care 51:1054–1061PubMedGoogle Scholar
  3. 3.
    Petrof BJ, Jaber S, Matecki S (2010) Ventilator-induced diaphragmatic dysfunction. Curr Opin Crit Care 16:19–25PubMedCrossRefGoogle Scholar
  4. 4.
    Zergeroglu MA, McKenzie MJ, Shanely RA, Van Gammeren D, DeRuisseau KC, Powers SK (2003) Mechanical ventilation-induced oxidative stress in the diaphragm. J Appl Physiol 95:1116–1124PubMedGoogle Scholar
  5. 5.
    McClung JM, Van Gammeren D, Whidden MA, Falk DJ, Kavazis AN, Hudson MB, Gayan-Ramirez G, Decramer M, DeRuisseau KC, Powers SK (2009) Apocynin attenuates diaphragm oxidative stress and protease activation during prolonged mechanical ventilation. Crit Care Med 37:1373–1379PubMedCrossRefGoogle Scholar
  6. 6.
    Vassilakopoulos T (2008) Ventilator-induced diaphragm dysfunction: the clinical relevance of animal models. Intensive Care Med 34:7–16PubMedCrossRefGoogle Scholar
  7. 7.
    Li LF, Yu L, Quinn DA (2004) Ventilation-induced neutrophil infiltration depends on c-Jun N-terminal kinase. Am J Respir Crit Care Med 169:518–524PubMedCrossRefGoogle Scholar
  8. 8.
    Li LF, Yang CT, Huang CC, Liu YY, Lin HC, Kao KC (2011) Low-molecular-weight heparin reduces hyperoxia-augmented ventilator-induced lung injury via serine/threonine kinase-protein kinase B. Respir Res 12:90PubMedCrossRefGoogle Scholar
  9. 9.
    Pardo PS, Lopez MA, Boriek AM (2008) FOXO transcription factors are mechanosensitive and their regulation is altered with aging in the respiratory pump. Am J Physiol Cell Physiol 294:C1056–C1066PubMedCrossRefGoogle Scholar
  10. 10.
    Stitt TN, Drujan D, Clarke BA, Panaro F, Timofeyva Y, Kline WO, Gonzalez M, Yancopoulos GD, Glass DJ (2004) The IGF-1/PI3 K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors. Mol Cell 14:395–403PubMedCrossRefGoogle Scholar
  11. 11.
    Lüpertz R, Chovolou Y, Unfried K, Kampkotter A, Watjen W, Kahl R (2008) The forkhead transcription factor FOXO4 sensitizes cancer cells to doxorubicin-mediated cytotoxicity. Carcinogenesis 29:2045–2052PubMedCrossRefGoogle Scholar
  12. 12.
    Levine S, Biswas C, Dierov J, Barsotti R, Shrager JB, Nguyen T, Sonnad S, Kucharchzuk JC, Kaiser LR, Singhal S (2011) Increased proteolysis, myosin depletion, and atrophic AKT-FOXO signaling in human disuse diaphragm fibers in mechanically ventilated humans. Am J Respir Crit Care Med 183:483–490PubMedCrossRefGoogle Scholar
  13. 13.
    Hussain SNA, Mofarrahi M, Sigala I, Kim HC, Vassilakopoulos T, Maltais F, Bellenis I, Chaturvedi R, Gottfried SB, Metrakos P, Danialou G, Matecki S, Jaber S, Petrof BJ, Goldberg P (2010) Mechanical ventilation-induced diaphragm disuse in humans triggers autophagy. Am J Respir Crit Care Med 182:1377–1386PubMedCrossRefGoogle Scholar
  14. 14.
    Cho H, Thorvaldsen JL, Chu Q, Feng F, Birnbaum MJ (2001) Akt1/PKBalpha is required for normal growth but dispensable for maintenance of glucose homeostasis in mice. J Biol Chem 276:38349–38352PubMedCrossRefGoogle Scholar
  15. 15.
    Levine S, Nguyen T, Taylor N, Friscia ME, Budak MT, Rothenberg P, Zhu J, Sachdeva R, Sonnad S, Kaiser LR, Rubinstein NA, Powers SK, Shrager JB (2008) Rapid disuse atrophy of diaphragm fibers in mechanically ventilated humans. N Engl J Med 358:1327–1335PubMedCrossRefGoogle Scholar
  16. 16.
    Whidden MA, McClung JM, Falk DJ, Hudson MB, Smuder AJ, Nelson WB, Powers SK (2009) Xanthine oxidase contributes to mechanical ventilation-induced diaphragmatic oxidative stress and contractile dysfunction. J Appl Physiol 106:385–394PubMedCrossRefGoogle Scholar
  17. 17.
    Martínez-Caro L, Lorente JA, Marín-Corral J, Sánchez-Rodríguez C, Sánchez-Ferrer A, Nin N, Ferruelo A, de Paula M, Fernández-Segoviano P, Barreiro E, Esteban A (2009) Role of free radicals in vascular dysfunction induced by high tidal volume ventilation. Intensive Care Med 35:1110–1119PubMedCrossRefGoogle Scholar
  18. 18.
    McClung JM, Kavazis AN, DeRuisseau KC, Falk DJ, Deering MA, Lee Y, Sugiura T, Powers SK (2007) Caspase-3 regulation of diaphragm myonuclear domain during mechanical ventilation-induced atrophy. Am J Respir Crit Care Med 175:150–159PubMedCrossRefGoogle Scholar
  19. 19.
    Jaber S, Petrof BJ, Jung B, Chanques G, Berthet JP, Rabuel C, Bouyabrine H, Courouble P, Koechlin-Ramonatxo C, Sebbane M, Similowski T, Scheuermann V, Mebazaa A, Capdevila X, Mornet D, Mercier J, Lacampagne A, Philips A, Matecki S (2011) Rapidly progressive diaphragmatic weakness and injury during mechanical ventilation in humans. Am J Respir Crit Care Med 183:364–371PubMedCrossRefGoogle Scholar
  20. 20.
    Powers SK, Shanely RA, Coombes JS, Koesterer TJ, McKenzie M, Van Gammeren D, Cicale M, Dodd SL (2002) Mechanical ventilation results in progressive contractile dysfunction in the diaphragm. J Appl Physiol 92:1851–1858PubMedGoogle Scholar
  21. 21.
    Whidden MA, Smuder AJ, Wu M, Hudson MB, Nelson WB, Powers SK (2010) Oxidative stress is required for mechanical ventilation-induced protease activation in the diaphragm. J Appl Physiol 108:1376–1382PubMedCrossRefGoogle Scholar
  22. 22.
    Moylan JS, Reid MB (2007) Oxidative stress, chronic disease, and muscle wasting. Muscle Nerve 35:411–429PubMedCrossRefGoogle Scholar
  23. 23.
    Powers SK, Duarte J, Kavazis AN, Talbert EE (2010) Reactive oxygen species are signaling molecules for skeletal muscle adaptation. Exp Physiol 95:1–9PubMedCrossRefGoogle Scholar
  24. 24.
    Sandri M, Sandri C, Gilbert A, Skurk C, Calabria E, Picard A, Walsh K, Schiaffino S, Lecker SH, Goldberg AL (2004) Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Cell 117:399–412PubMedCrossRefGoogle Scholar
  25. 25.
    Crossland H, Constantin-Teodosiu D, Gardiner SM, Constantin D, Greenhaff PL (2008) A potential role for Akt/FOXO signalling in both protein loss and the impairment of muscle carbohydrate oxidation during sepsis in rodent skeletal muscle. J Physiol 586:5589–5600PubMedCrossRefGoogle Scholar
  26. 26.
    Supinski GS, Ji X, Callahan LA (2009) The JNK MAP kinase pathway contributes to the development of endotoxin-induced diaphragm caspase activation. Am J Physiol Regul Integr Comp Physiol 297:R825–R834PubMedCrossRefGoogle Scholar
  27. 27.
    Mohamed JS, Lopez MA, Cox GA, Boriek AM (2010) Anisotropic regulation of Ankrd2 gene expression in skeletal muscle by mechanical stretch. FASEB J 24:3330–3340PubMedCrossRefGoogle Scholar
  28. 28.
    Levine S, Budak MT, Dierov J, Singhal S (2011) Inactivity-induced diaphragm dysfunction and mitochondria-targeted antioxidant: new concepts in critical care medicine. Crit Care Med 39:1844–1845PubMedCrossRefGoogle Scholar
  29. 29.
    Powers SK, Hudson MB, Nelson WB, Talbert EE, Min K, Szeto HH, Kavazis AN, Smuder AJ (2011) Mitochondria-targeted antioxidants protect against mechanical ventilation-induced diaphragm weakness. Crit Care Med 39:1749–1759PubMedCrossRefGoogle Scholar
  30. 30.
    Onders RP, Khansarinia S, Weiser T, Chin C, Hungness E, Soper N, Dehoyos A, Cole T, Ducko C (2010) Multicenter analysis of diaphragm pacing in tetraplegics with cardiac pacemakers: positive implications for ventilator weaning in intensive care units. Surgery 148:893–897PubMedCrossRefGoogle Scholar

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

Personalised recommendations