{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T12:11:59Z","timestamp":1789647119321,"version":"4.0.0"},"reference-count":46,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,6,16]],"date-time":"2025-06-16T00:00:00Z","timestamp":1750032000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the 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>Patients with sepsis often receive mechanical ventilation (MV). Continued use of MV may increase overdistention in the lungs, inflammatory mediator production, and inflammatory cell recruitment, eventually causing ventilator-induced lung injury (VILI). Endoplasmic reticulum (ER) stress caused by MV, oxidative stress, and sepsis results in dissociation of GRP78 from transmembrane proteins (PERK, IRE1\u03b1, and ATF6) and generates abundant incorrect protein structures. Phosphoinositide 3-kinase-\u03b3 (PI3K-\u03b3) has been demonstrated to modulate ER stress associated with sepsis and acute lung injury (ALI). However, the regulatory mechanisms by which ER stress is involved in VILI remain unclear. In this study, MV was hypothesized to augment lung injury and induce ER stress through the PI3K-\u03b3 pathway, regardless of endotoxemia. Wild-type or PI3K-\u03b3-deficient C57BL\/6 mice were exposed to 30 mL\/kg tidal volume of MV with or without endotoxemia for 5 h. The control group comprised nonventilated mice. MV with endotoxemia increased microvascular permeability, lung edema, interleukin-6 and metalloproteinase-9 production, oxidative loads, ER stress biomarkers (GRP78, IRE-1\u03b1, PERK), morphological rearrangement, PI3K-\u03b3 expression, and bronchial epithelial apoptosis in rodent lungs. The increase in lung injury was substantially reduced in PI3K-\u03b3-deficient mice and in mice administered 4-phenylbutyric acid. In conclusion, MV-augmented ALI after endotoxemia partially depends on the PI3K-\u03b3 pathway.<\/jats:p>","DOI":"10.3390\/ijms26125761","type":"journal-article","created":{"date-parts":[[2025,6,16]],"date-time":"2025-06-16T10:47:22Z","timestamp":1750070842000},"page":"5761","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Attenuation of Ventilation-Induced Endoplasmic Reticulum Stress Associated with Lung Injury Through Phosphoinositide 3-Kinase-Gamma in a Murine Endotoxemia Model"],"prefix":"10.3390","volume":"26","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":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1396-5648","authenticated-orcid":false,"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":[{"vocabulary":"crossref","role":"author"}]},{"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":[{"vocabulary":"crossref","role":"author"}]},{"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":[{"vocabulary":"crossref","role":"author"}]},{"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":[{"vocabulary":"crossref","role":"author"}]},{"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":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5082-0152","authenticated-orcid":false,"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":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1007\/s00134-021-06506-y","article-title":"Surviving sepsis campaign: International guidelines for management of sepsis and septic shock 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