{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T19:52:25Z","timestamp":1768420345968,"version":"3.49.0"},"reference-count":54,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,1,19]],"date-time":"2022-01-19T00:00:00Z","timestamp":1642550400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Science and Technology, Chang Gung Medical Research Project","award":["107-2314-B-182A-143-MY3, CMRPG2L301"],"award-info":[{"award-number":["107-2314-B-182A-143-MY3, CMRPG2L301"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Mechanical ventilation (MV) is essential for patients with sepsis-related respiratory failure but can cause ventilator-induced diaphragm dysfunction (VIDD), which involves diaphragmatic myofiber atrophy and contractile inactivity. Mitochondrial DNA, oxidative stress, mitochondrial dynamics, and biogenesis are associated with VIDD. Hypoxia-inducible factor 1\u03b1 (HIF-1\u03b1) is crucial in the modulation of diaphragm immune responses. The mechanism through which HIF-1\u03b1 and mitochondria affect sepsis-related diaphragm injury is unknown. We hypothesized that MV with or without endotoxin administration would aggravate diaphragmatic and mitochondrial injuries through HIF-1\u03b1. C57BL\/6 mice, either wild-type or HIF-1\u03b1-deficient, were exposed to MV with or without endotoxemia for 8 h. MV with endotoxemia augmented VIDD and mitochondrial damage, which presented as increased oxidative loads, dynamin-related protein 1 level, mitochondrial DNA level, and the expressions of HIF-1\u03b1 and light chain 3-II. Furthermore, disarrayed myofibrils; disorganized mitochondria; increased autophagosome numbers; and substantially decreased diaphragm contractility, electron transport chain activities, mitofusin 2, mitochondrial transcription factor A, peroxisome proliferator activated receptor-\u03b3 coactivator-1\u03b1, and prolyl hydroxylase domain 2 were observed (p &lt; 0.05). Endotoxin-stimulated VIDD and mitochondrial injuries were alleviated in HIF-1\u03b1-deficient mice (p &lt; 0.05). Our data revealed that endotoxin aggravated MV-induced diaphragmatic dysfunction and mitochondrial damages, partially through the HIF-1\u03b1 signaling pathway.<\/jats:p>","DOI":"10.3390\/ijms23031083","type":"journal-article","created":{"date-parts":[[2022,1,19]],"date-time":"2022-01-19T21:01:51Z","timestamp":1642626111000},"page":"1083","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Reduction in Ventilation-Induced Diaphragmatic Mitochondrial Injury through Hypoxia-Inducible Factor 1\u03b1 in a Murine Endotoxemia Model"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5819-7238","authenticated-orcid":false,"given":"Li-Fu","family":"Li","sequence":"first","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chang Gung Memorial Hospital, Keelung 20401, Taiwan"},{"name":"Department of Internal Medicine, Chang Gung University, Taoyuan 33302, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chung-Chieh","family":"Yu","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chang Gung Memorial Hospital, Keelung 20401, Taiwan"},{"name":"Department of Internal Medicine, Chang Gung University, Taoyuan 33302, Taiwan"},{"name":"Department of Respiratory Therapy, Chang Gung Memorial Hospital, Keelung 20401, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8906-4566","authenticated-orcid":false,"given":"Huang-Pin","family":"Wu","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chang Gung Memorial Hospital, Keelung 20401, Taiwan"},{"name":"Department of Internal Medicine, Chang Gung University, Taoyuan 33302, Taiwan"},{"name":"Department of Respiratory Therapy, Chang Gung Memorial Hospital, Keelung 20401, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chien-Ming","family":"Chu","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chang Gung Memorial Hospital, Keelung 20401, Taiwan"},{"name":"Department of Internal Medicine, Chang Gung University, Taoyuan 33302, Taiwan"},{"name":"Department of Respiratory Therapy, Chang Gung Memorial Hospital, Keelung 20401, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2169-9952","authenticated-orcid":false,"given":"Chih-Yu","family":"Huang","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chang Gung Memorial Hospital, Keelung 20401, Taiwan"},{"name":"Department of Internal Medicine, Chang Gung University, Taoyuan 33302, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ping-Chi","family":"Liu","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chang Gung Memorial Hospital, Keelung 20401, Taiwan"},{"name":"Department of Internal Medicine, Chang Gung University, Taoyuan 33302, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yung-Yang","family":"Liu","sequence":"additional","affiliation":[{"name":"Chest Department, Taipei Veterans General Hospital, Taipei 112201, Taiwan"},{"name":"School of Medicine, Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan"},{"name":"Institute of Clinical Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1152\/japplphysiol.00189.2019","article-title":"Impaired diaphragm resistance vessel vasodilation with prolonged mechanical ventilation","volume":"127","author":"Horn","year":"2019","journal-title":"J. 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