{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T05:18:35Z","timestamp":1787980715578,"version":"build-2784847793"},"reference-count":53,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T00:00:00Z","timestamp":1787788800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012283","name":"Chiayi Chang Gung Memorial Hospital","doi-asserted-by":"publisher","award":["CMRPG6L0141, CMRPG6N0231 and CMRPG6H0151"],"award-info":[{"award-number":["CMRPG6L0141, CMRPG6N0231 and CMRPG6H0151"]}],"id":[{"id":"10.13039\/501100012283","id-type":"DOI","asserted-by":"publisher"}]},{"award":["CMRPG6L0141, CMRPG6N0231 and CMRPG6H0151"],"award-info":[{"award-number":["CMRPG6L0141, CMRPG6N0231 and CMRPG6H0151"]}],"id":[{"id":"https:\/\/ror.org\/04gy6pv35","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Background: Fat embolism (FE) is a severe complication following long-bone fractures. While the initial mechanical insult primarily affects the pulmonary vasculature, the subsequent systemic hypoxia and inflammatory cascades frequently lead to cerebral fat embolism (CFE). This progression highlights a critical, yet under-explored, pathogenic crosstalk within the lung-brain axis. The Renin\u2013Angiotensin System (RAS), particularly the Angiotensin-Converting Enzyme (ACE)\/Angiotensin II (Ang II) pathway, is a potent driver of inflammation and is highly expressed in both pulmonary and cerebral tissues. This study aimed to investigate whether modulating this axis with captopril, a specific ACE inhibitor, could attenuate the lung-brain inflammatory crosstalk and protect against CFE-induced neuroinflammation. Methods: FE was induced in rats via intravenous injection of fat micelles. Captopril (1, 5, 10, or 20 mg\/kg) was administered immediately post-induction. Brain injury was assessed using Oil Red O and H&amp;E staining, brain water content, and malondialdehyde (MDA) assays. ACE expression and localization were evaluated via Western blot and immunofluorescence. The RAS balance was assessed by quantifying Ang II and Ang-(1\u20137) levels using ELISA. Inflammatory and hypoxic markers, including iNOS, HIF-1\u03b1, and phosphorylated ERK (p-ERK), were analyzed by Western blot. Results: In this study, we observed rapid microvascular occlusion, brain edema, and neuronal damage within 2 h. FE triggered a significant upregulation of ACE, predominantly localized in cortical astrocytes, alongside elevated oxidative stress (MDA) and Ang II levels. Systemic administration of captopril (5 mg\/kg) significantly mitigated these cerebral injuries. Captopril not only suppressed local astrocytic ACE expression and Ang II release but also restored the neuroprotective Angiotensin-(1\u20137) levels. Furthermore, captopril effectively blunted the hypoxia-driven inflammatory cascades, significantly downregulating iNOS expression and the HIF-1\u03b1\/VEGF\/ERK signaling pathway. Conclusions: Our findings suggest that CFE is a consequence of dysregulated lung-brain axis communication, driven by hypoxia and RAS overactivation. By inhibiting ACE, captopril effectively modulates this axis, reducing oxidative stress and neuroinflammation. Targeting the ACE\/Ang II pathway represents a promising therapeutic strategy for managing the neurological complications of FE syndrome.<\/jats:p>","DOI":"10.3390\/cells15171550","type":"journal-article","created":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T16:47:13Z","timestamp":1787849233000},"page":"1550","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting the ACE\/Ang II Axis with Captopril Attenuates Neuroinflammation and Cerebral Injury Following Fat Embolism"],"prefix":"10.3390","volume":"15","author":[{"given":"Shu Cheng","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, National Chung Cheng University, Min-Hsiung, Chia-Yi 621, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chin-Kuo","family":"Lin","sequence":"additional","affiliation":[{"name":"Division of Pulmonary Infection and Critical Care, Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chia-Yi 613, Taiwan"},{"name":"College of Medicine, Chang Gung University, Taoyuan City 333, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng-Huang","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Urology, Ditmanson Medical Foundation Chiayi Christian Hospital, Chia-Yi 600, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1431-322X","authenticated-orcid":false,"given":"Michael W. Y.","family":"Chan","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, National Chung Cheng University, Min-Hsiung, Chia-Yi 621, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng-Wei","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Biochemical Science and Technology, National Chia-Yi University, Chia-Yi 600, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Hao","family":"Lin","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Molecular Biology, National Yang Ming Chiao Tung University, Taipei 112, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5548-7675","authenticated-orcid":false,"given":"Chung-Sheng","family":"Shi","sequence":"additional","affiliation":[{"name":"Graduate Institute of Clinical Medicine Sciences, College of Medicine, Chang Gung University, Taoyuan City 333, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chieh-Mo","family":"Lin","sequence":"additional","affiliation":[{"name":"Division of Pulmonary Infection and Critical Care, Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chia-Yi 613, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tzu Hsiung","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Respiratory Therapy, Chang Gung Memorial Hospital, Chia-Yi 613, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin Ching Hsien","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Henry Ford St. John Hospital, 22101 Moross Rd, Detroit, MI 48236, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4878-5084","authenticated-orcid":false,"given":"Jui-Ming","family":"Sun","sequence":"additional","affiliation":[{"name":"Section of Neurosurgery, Department of Surgery, Ditmanson Medical Foundation, Chia-Yi Christian Hospital, Chia-Yi 613, Taiwan"},{"name":"Department of Nursing, School of Nursing, Fooyin University, Kaohsiung 831, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kwok-Tung","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Life Science, National Taiwan Normal University, Taipei 106, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Ling","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Urology, Ditmanson Medical Foundation Chiayi Christian Hospital, Chia-Yi 600, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"335","DOI":"10.2147\/COPD.S479504","article-title":"Clinical and economic evaluation of fluticasone furoate\/umeclidinium\/vilanterol versus tiotropium\/olodaterol therapy in maintenance treatment-naive patients with COPD in the US","volume":"20","author":"Shaikh","year":"2025","journal-title":"Int. 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