{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T17:58:00Z","timestamp":1790272680463,"version":"4.1.0"},"reference-count":0,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Anesthesiology"],"published-print":{"date-parts":[[2012,8,1]]},"abstract":"\n Background<\/jats:title>\n 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.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n 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.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n 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.<\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n 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.<\/jats:p>\n <\/jats:sec>","DOI":"10.1097\/aln.0b013e3182608cc0","type":"journal-article","created":{"date-parts":[[2012,6,20]],"date-time":"2012-06-20T15:42:17Z","timestamp":1340206937000},"page":"329-338","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":43,"title":["Toll-like Receptor 4 Signaling in Ventilator-induced Diaphragm Atrophy"],"prefix":"10.1097","volume":"117","author":[{"given":"Willem-Jan\u00a0M.","family":"Schellekens","sequence":"first","affiliation":[{"name":"Resident, Department of Anesthesiology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hieronymus W.\u00a0H.","family":"van Hees","sequence":"additional","affiliation":[{"name":"Staff Pulmonary Diseases, Department of Pulmonary Diseases, Radboud University Nijmegen Medical Centre."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michiel","family":"Vaneker","sequence":"additional","affiliation":[{"name":"Staff Anesthesiologist, Department of Anesthesiology, Radboud University Nijmegen Medical Centre."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianne","family":"Linkels","sequence":"additional","affiliation":[{"name":"Researcher Pulmonary Diseases, Department of Pulmonary Diseases, Radboud University Nijmegen Medical Centre."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P. N.\u00a0Richard","family":"Dekhuijzen","sequence":"additional","affiliation":[{"name":"Professor and Chairman, Department of Pulmonary Diseases, Radboud University Nijmegen Medical Centre."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gert\u00a0Jan","family":"Scheffer","sequence":"additional","affiliation":[{"name":"Professor and Chairman, Department of Anesthesiology, Radboud University Nijmegen Medical Centre."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes\u00a0G.","family":"van der Hoeven","sequence":"additional","affiliation":[{"name":"Professor and Chairman, Department of Intensive Care Medicine, Radboud University Nijmegen Medical Centre."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leo M.\u00a0A.","family":"Heunks","sequence":"additional","affiliation":[{"name":"Staff, Intensive Care Medicine, Department of Intensive Care Medicine, Radboud University Nijmegen Medical Centre."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","container-title":["Anesthesiology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/pubs.asahq.org\/anesthesiology\/article-pdf\/117\/2\/329\/258065\/0000542-201208000-00023.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.lww.com\/00000542-201208000-00020","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T20:09:30Z","timestamp":1760386170000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/00000542-201208000-00020"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,8,1]]},"references-count":0,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2012]]}},"URL":"https:\/\/doi.org\/10.1097\/aln.0b013e3182608cc0","relation":{},"ISSN":["0003-3022"],"issn-type":[{"value":"0003-3022","type":"print"}],"subject":[],"published":{"date-parts":[[2012,8,1]]}}}