{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T01:53:30Z","timestamp":1769738010117,"version":"3.49.0"},"reference-count":44,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2024,6,8]],"date-time":"2024-06-08T00:00:00Z","timestamp":1717804800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Chang Gung Medical Research Project","award":["CMRPG2L0302"],"award-info":[{"award-number":["CMRPG2L0302"]}]},{"name":"Chang Gung Medical Research Project","award":["CMRPG2P0101"],"award-info":[{"award-number":["CMRPG2P0101"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Mechanical ventilation (MV), used in patients with acute lung injury (ALI), induces diaphragmatic myofiber atrophy and contractile inactivity, termed ventilator-induced diaphragm dysfunction. Phosphoinositide 3-kinase-\u03b3 (PI3K-\u03b3) is crucial in modulating fibrogenesis during the reparative phase of ALI; however, the mechanisms regulating the interactions among MV, myofiber fibrosis, and PI3K-\u03b3 remain unclear. We hypothesized that MV with or without bleomycin treatment would increase diaphragm muscle fibrosis through the PI3K-\u03b3 pathway. Five days after receiving a single bolus of 0.075 units of bleomycin intratracheally, C57BL\/6 mice were exposed to 6 or 10 mL\/kg of MV for 8 h after receiving 5 mg\/kg of AS605240 intraperitoneally. In wild-type mice, bleomycin exposure followed by MV 10 mL\/kg prompted significant increases in disruptions of diaphragmatic myofibrillar organization, transforming growth factor-\u03b21, oxidative loads, Masson\u2019s trichrome staining, extracellular collagen levels, positive staining of \u03b1-smooth muscle actin, PI3K-\u03b3 expression, and myonuclear apoptosis (p &lt; 0.05). Decreased diaphragm contractility and peroxisome proliferator-activated receptor-\u03b3 coactivator-1\u03b1 levels were also observed (p &lt; 0.05). MV-augmented bleomycin-induced diaphragm fibrosis and myonuclear apoptosis were attenuated in PI3K-\u03b3-deficient mice and through AS605240-induced inhibition of PI3K-\u03b3 activity (p &lt; 0.05). MV-augmented diaphragm fibrosis after bleomycin-induced ALI is partially mediated by PI3K-\u03b3. Therapy targeting PI3K-\u03b3 may ameliorate MV-associated diaphragm fibrosis.<\/jats:p>","DOI":"10.3390\/ijms25126370","type":"journal-article","created":{"date-parts":[[2024,6,10]],"date-time":"2024-06-10T10:08:43Z","timestamp":1718014123000},"page":"6370","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Suppression of Ventilation-Induced Diaphragm Fibrosis through the Phosphoinositide 3-Kinase-\u03b3 in a Murine Bleomycin-Induced Acute Lung Injury Model"],"prefix":"10.3390","volume":"25","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"},{"name":"Department of Respiratory Therapy, Chang Gung Memorial Hospital, Keelung 20401, Taiwan"},{"name":"Community Medicine Research Center, Chang Gung Memorial Hospital, Keelung 20401, 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"},{"name":"Community Medicine Research Center, 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"},{"name":"Department of Respiratory Therapy, Chang Gung Memorial Hospital, Keelung 20401, Taiwan"},{"name":"Community Medicine Research Center, 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"}]},{"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"},{"name":"Community Medicine Research Center, Chang Gung Memorial Hospital, Keelung 20401, 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":[[2024,6,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1038\/labinvest.2014.75","article-title":"Mechanical ventilation augments bleomycin-induced epithelial-mesenchymal transition through the Src pathway","volume":"94","author":"Li","year":"2014","journal-title":"Lab. 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