{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T18:51:02Z","timestamp":1790880662933,"version":"4.1.0"},"reference-count":65,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,2,8]],"date-time":"2021-02-08T00:00:00Z","timestamp":1612742400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Science and Technology","award":["107-2314-B-182A-1431-MY3"],"award-info":[{"award-number":["107-2314-B-182A-1431-MY3"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Mechanical ventilation (MV) is required to maintain life for patients with sepsis-related acute lung injury but can cause diaphragmatic myotrauma with muscle damage and weakness, known as ventilator-induced diaphragm dysfunction (VIDD). Hypoxia-inducible factor 1\u03b1 (HIF-1\u03b1) plays a crucial role in inducing inflammation and apoptosis. Low-molecular-weight heparin (LMWH) was proven to have anti-inflammatory properties. However, HIF-1\u03b1 and LMWH affect sepsis-related diaphragm injury has not been investigated. We hypothesized that LMWH would reduce endotoxin-augmented VIDD through HIF-1\u03b1. C57BL\/6 mice, either wild-type or HIF-1\u03b1\u2013deficient, were exposed to MV with or without endotoxemia for 8 h. Enoxaparin (4 mg\/kg) was administered subcutaneously 30 min before MV. MV with endotoxemia aggravated VIDD, as demonstrated by increased interleukin-6 and macrophage inflammatory protein-2 levels, oxidative loads, and the expression of HIF-1\u03b1, calpain, caspase-3, atrogin-1, muscle ring finger-1, and microtubule-associated protein light chain 3-II. Disorganized myofibrils, disrupted mitochondria, increased numbers of autophagic and apoptotic mediators, substantial apoptosis of diaphragm muscle fibers, and decreased diaphragm function were also observed (p &lt; 0.05). Endotoxin-exacerbated VIDD and myonuclear apoptosis were attenuated by pharmacologic inhibition by LMWH and in HIF-1\u03b1\u2013deficient mice (p &lt; 0.05). Our data indicate that enoxaparin reduces endotoxin-augmented MV-induced diaphragmatic injury, partially through HIF-1\u03b1 pathway inhibition.<\/jats:p>","DOI":"10.3390\/ijms22041702","type":"journal-article","created":{"date-parts":[[2021,2,9]],"date-time":"2021-02-09T23:43:16Z","timestamp":1612914196000},"page":"1702","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Suppression of Hypoxia-Inducible Factor 1\u03b1 by Low-Molecular-Weight Heparin Mitigates Ventilation-Induced Diaphragm Dysfunction in a Murine Endotoxemia Model"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5819-7238","authenticated-orcid":false,"given":"Li-Fu","family":"Li","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Keelung 20401, Taiwan"},{"name":"Department of Internal Medicine, Chang Gung University, Taoyuan 33302, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chung-Chieh","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Pulmonary and Critical Care 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":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hung-Yu","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Keelung 20401, Taiwan"},{"name":"Department of Internal Medicine, Chang Gung University, Taoyuan 33302, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huang-Pin","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Pulmonary and Critical Care 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":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chien-Ming","family":"Chu","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Pulmonary and Critical Care 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":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chih-Yu","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Keelung 20401, Taiwan"},{"name":"Department of Internal Medicine, Chang Gung University, Taoyuan 33302, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping-Chi","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Keelung 20401, Taiwan"},{"name":"Department of Internal Medicine, Chang Gung University, Taoyuan 33302, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yung-Yang","family":"Liu","sequence":"additional","affiliation":[{"name":"Chest Department, Taipei Veterans General Hospital, Taipei 11217, Taiwan"},{"name":"Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei 11217, Taiwan"},{"name":"Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei 11217, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1791","DOI":"10.1016\/j.yexcr.2009.03.019","article-title":"HIF-1 in the inflammatory microenvironment","volume":"315","author":"Dehne","year":"2009","journal-title":"Exp. 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