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


CONCLUSIONS
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.
Department of Anesthesiology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Willem-Jan M
WJ
Schellekens
Hieronymus W H
HW
van Hees
Michiel
M
Vaneker
Marianne
M
Linkels
P N Richard
PN
Dekhuijzen
Gert Jan
GJ
Scheffer
Johannes G
JG
van der Hoeven
Leo M A
LM
Heunks
D000818:Animals; D003964:Diaphragm / Q000378:metabolism* / Q000473:pathology*; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009133:Muscular Atrophy / Q000209:etiology* / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D012122:Ventilators, Mechanical / Q000009:adverse effects*
D051197:Toll-Like Receptor 4