{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,24]],"date-time":"2025-12-24T03:15:20Z","timestamp":1766546120932,"version":"3.41.2"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,1,7]],"date-time":"2025-01-07T00:00:00Z","timestamp":1736208000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background and aim<\/jats:title><jats:p>NK cells and NK-cell-derived cytokines were shown to regulate neutrophil activation in acute lung injury (ALI). However, the extent to which ALI regulates lung tissue-resident NK (trNK) activity and their molecular phenotypic alterations are not well defined. We aimed to assess the impact of 1,25-hydroxy-vitamin-D3 [1,125(OH)<jats:sub>2<\/jats:sub>D] on ALI clinical outcome in a mouse model and effects on lung trNK cell activations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Oleic acid (OA)-induced ALI in C57BL\/6J mice and 1,25(OH)<jats:sub>2<\/jats:sub>D treatment 2\u00d7\/2 weeks were performed. Lung tissue was harvested to assess alveolar I\/II cell apoptosis and lung injury marker of Surfactant-Protein-D (SP-D). Pulmonary edema markers of epithelial sodium channel, cystic fibrosis transmembrane conductance regulator, and aquaporin 5 were assessed by RT-PCR. Lung trNK cells were assessed for activation markers of CD107a and NKp46, vitamin D receptor (VDR), and programmed cell death protein-1 (PD-1) via flow cytometry. The bronchoalveolar lavage fluid (BALF) obtained was investigated for soluble receptor for advanced glycation end products (sRAGE), inflammatory cytokines, soluble 1,25(OH)<jats:sub>2<\/jats:sub>D, and PDL-1. Na\u00efve mice treated with DMSO (vehicle) were used as a control.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Flow cytometry analysis displayed a high apoptotic rate in alveolar I\/II cells of threefold in ALI mice as compared to na\u00efve mice. These findings were accompanied by elevated markers of pulmonary edema as well as lung injury markers of SP-D. Isolated lung trNK cells of the ALI mice exhibited reduced CD107a and NKp46 markers and cytotoxicity potentials and were correlated through significantly 2.1-fold higher levels of PD-1 and diminished VDR expressions as compared to na\u00efve mice. BALF samples of ALI mice displayed high soluble PDL-1 and reduced soluble 1,25(OH)<jats:sub>2<\/jats:sub>D levels compared to na\u00efve mice. 1,25(OH)<jats:sub>2<\/jats:sub>D treatment alongside OA led to a significant fourfold increase in the CD107a and NKp46 expressions to levels higher than the mice treated with the vehicle. Furthermore, 1,25(OH)<jats:sub>2<\/jats:sub>D ameliorates free radical scavengers of GSH, GPX, CAT, and GPx-1; decreased pro-inflammatory cytokines and soluble PDL-1; and increased soluble 1,25(OH)<jats:sub>2<\/jats:sub>D with amelioration in pulmonary edema markers and alveolar I\/II apoptosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our results indicate 1,25(OH)<jats:sub>2<\/jats:sub>D\u2019s potential therapeutic effect in preventing clinical outcomes associated with ALI via regulating NK cells through inhibiting inflammatory cytokines and alleviating levels of PDL-1 and 1,25(OH)<jats:sub>2<\/jats:sub>D released by lung tissue.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2024.1466802","type":"journal-article","created":{"date-parts":[[2025,1,7]],"date-time":"2025-01-07T05:35:35Z","timestamp":1736228135000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Restoring natural killer cell activity in lung injury with 1,25-hydroxy vitamin D3: a promising therapeutic approach"],"prefix":"10.3389","volume":"15","author":[{"given":"Johnny","family":"Amer","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ahmad","family":"Salhab","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohammad","family":"Abuawad","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,1,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1007\/s12033-024-01141-6","article-title":"Integrative analyses of bulk and single-cell RNA seq identified the shared genes in acute respiratory distress syndrome and rheumatoid arthritis","author":"Shi","year":"2024","journal-title":"Mol Biotechnol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"100777","DOI":"10.1016\/j.cpsurg.2020.100777","article-title":"Acute lung injury","volume":"57","author":"Mowery","year":"2020","journal-title":"Curr Probl Surg"},{"key":"B3","doi-asserted-by":"publisher","first-page":"548","DOI":"10.3390\/antiox12030548","article-title":"Oxidative stress and inflammation in acute and chronic lung injuries","volume":"12","author":"Bezerra","year":"2023","journal-title":"Antioxidants (Basel)"},{"key":"B4","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1007\/s10753-022-01726-w","article-title":"The role of macrophages and alveolar epithelial cells in the development of ARDS","volume":"46","author":"Tao","year":"2023","journal-title":"Inflammation"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.2147\/JIR.S334043","article-title":"Acute respiratory distress syndrome and COVID-19: A literature review","volume":"14","author":"Hussain","year":"2021","journal-title":"J Inflammation Res"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1080\/10408363.2022.2070595","article-title":"Vitamin D: sources, physiological role, biokinetics, deficiency, therapeutic use, toxicity, and overview of analytical methods for detection of vitamin D and its metabolites","volume":"59","author":"Anou\u0161ek","year":"2022","journal-title":"Crit Rev Clin Lab Sci"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.5603\/ARM.a2018.0029","article-title":"Pleiotropic effect of vitamin D in cystic fibrosis","author":"Grzelak","year":"2018","journal-title":"Adv Respir Med"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1136\/bmjresp-2022-001525","article-title":"Acute respiratory distress syndrome: potential of therapeutic interventions effective in treating progression from COVID-19 to treat progression from other illnesses-a systematic review","volume":"10","author":"Ragel","year":"2023","journal-title":"BMJ Open Respir Res"},{"key":"B9","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1186\/s12931-020-01405-0","article-title":"Local expression profiles of vitamin D-related genes in airways of COPD patients","volume":"21","author":"Mathyssen","year":"2020","journal-title":"Respir Res"},{"key":"B10","doi-asserted-by":"publisher","first-page":"767","DOI":"10.3390\/nu15030767","article-title":"Genomic or non-genomic? 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