Toll-like receptor 4 signaling in ventilator-induced diaphragm atrophy

Willem Jan M. Schellekens, Hieronymus W.H. Van Hees, Michiel Vaneker, Marianne Linkels, P. N.Richard Dekhuijzen, Gert Jan Scheffer, Johannes G. Van Der Hoeven, Leo M.A. Heunks*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

BACKGROUND: Mechanical ventilation induces diaphragm muscle atrophy, which plays a key role in difficult weaning from mechanical ventilation. The signaling pathways involved in ventilator-induced diaphragm atrophy are poorly understood. The current study investigated the role of Toll-like receptor 4 signaling in the development of ventilator-induced diaphragm atrophy. METHODS: Unventilated animals were selected for control: wild-type (n = 6) and Toll-like receptor 4 deficient mice (n = 6). Mechanical ventilation (8 h): wild-type (n = 8) and Toll-like receptor 4 deficient (n = 7) mice.Myosin heavy chain content, proinflammatory cytokines, proteolytic activity of the ubiquitin-proteasome pathway, caspase-3 activity, and autophagy were measured in the diaphragm. RESULTS: Mechanical ventilation reduced myosin content by approximately 50% in diaphragms of wild-type mice (P less than 0.05). In contrast, ventilation of Toll-like receptor 4 deficient mice did not significantly affect diaphragm myosin content. Likewise, mechanical ventilation significantly increased interleukin-6 and keratinocyte-derived chemokine in the diaphragm of wild-type mice, but not in ventilated Toll-like receptor 4 deficient mice. Mechanical ventilation increased diaphragmatic muscle atrophy factor box transcription in both wild-type and Toll-like receptor 4 deficient mice. Other components of the ubiquitin-proteasome pathway and caspase-3 activity were not affected by ventilation of either wild-type mice or Toll-like receptor 4 deficient mice. Mechanical ventilation induced autophagy in diaphragms of ventilated wild-type mice, but not Toll-like receptor 4 deficient mice. CONCLUSION: Toll-like receptor 4 signaling plays an important role in the development of ventilator-induced diaphragm atrophy, most likely through increased expression of cytokines and activation of lysosomal autophagy.

Original languageEnglish
Pages (from-to)329-338
Number of pages10
JournalAnesthesiology
Volume117
Issue number2
DOIs
Publication statusPublished - 1 Aug 2012

Cite this

Schellekens, W. J. M., Van Hees, H. W. H., Vaneker, M., Linkels, M., Dekhuijzen, P. N. R., Scheffer, G. J., ... Heunks, L. M. A. (2012). Toll-like receptor 4 signaling in ventilator-induced diaphragm atrophy. Anesthesiology, 117(2), 329-338. https://doi.org/10.1097/ALN.0b013e3182608cc0