{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T22:42:39Z","timestamp":1785883359078,"version":"3.56.0"},"reference-count":67,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,1,19]],"date-time":"2023-01-19T00:00:00Z","timestamp":1674086400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Science Foundation Ireland Future Research Leaders Award","award":["16-FRL-3845"],"award-info":[{"award-number":["16-FRL-3845"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Pulmonary sepsis is a leading cause of hospital mortality, and sepses arising from antimicrobial-resistant (AMR) bacterial strains are particularly difficult to treat. Here we investigated the potential of mesenchymal stromal cells (MSCs) to combat established Klebsiella pneumoniae pneumosepsis and further evaluated MSC preconditioning and pre-activation methods. Methods: The potential for na\u00efve and preconditioned MSCs to enhance wound healing, reduce inflammation, preserve metabolic activity, and enhance bacterial killing was assessed in vitro. Rats were subjected to intratracheal K. pneumoniae followed by the intravenous administration of MSCs. Physiological indices, blood, bronchoalveolar lavage (BAL), and tissues were obtained 72 h later. Results: In vitro assays confirmed that preconditioning enhances MSC function, accelerating pulmonary epithelial wound closure, reducing inflammation, attenuating cell death, and increasing bacterial killing. Cytomix-pre-activated MSCs are superior to na\u00efve and hypoxia-exposed MSCs in attenuating Klebsiella pneumosepsis, improving lung compliance and oxygenation, reducing bacteria, and attenuating histologic injuries in lungs. BAL inflammatory cytokines were reduced, correlating with decreases in polymorphonuclear (PMN) cells. MSCs increased PMN apoptosis and the CD4:CD8 ratio in BAL. Systemically, granulocytes, classical monocytes, and the CD4:CD8 ratio were reduced, and nonclassical monocytes were increased. Conclusions: Preconditioning with cytokines, but not hypoxia, enhances the therapeutic potential of MSCs in clinically relevant models of K. pneumoniae-induced pneumosepsis.<\/jats:p>","DOI":"10.3390\/ph16020149","type":"journal-article","created":{"date-parts":[[2023,1,19]],"date-time":"2023-01-19T06:22:10Z","timestamp":1674109330000},"page":"149","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Differential Effects of Cytokine Versus Hypoxic Preconditioning of Human Mesenchymal Stromal Cells in Pulmonary Sepsis Induced by Antimicrobial-Resistant Klebsiella pneumoniae"],"prefix":"10.3390","volume":"16","author":[{"given":"Declan","family":"Byrnes","sequence":"first","affiliation":[{"name":"Anaesthesia, School of Medicine, University of Galway, H91 TK33 Galway, Ireland"},{"name":"Regenerative Medicine Institute (REMEDI) at C\u00daRAM Centre for Research in Medical Devices, Biomedical Sciences Building, University of Galway, H91 TK33 Galway, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire H.","family":"Masterson","sequence":"additional","affiliation":[{"name":"Anaesthesia, School of Medicine, University of Galway, H91 TK33 Galway, Ireland"},{"name":"Regenerative Medicine Institute (REMEDI) at C\u00daRAM Centre for Research in Medical Devices, Biomedical Sciences Building, University of Galway, H91 TK33 Galway, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack","family":"Brady","sequence":"additional","affiliation":[{"name":"Anaesthesia, School of Medicine, University of Galway, H91 TK33 Galway, Ireland"},{"name":"Regenerative Medicine Institute (REMEDI) at C\u00daRAM Centre for Research in Medical Devices, Biomedical Sciences Building, University of Galway, H91 TK33 Galway, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8302-1282","authenticated-orcid":false,"given":"Senthilkumar","family":"Alagesan","sequence":"additional","affiliation":[{"name":"Anaesthesia, School of Medicine, University of Galway, H91 TK33 Galway, Ireland"},{"name":"Regenerative Medicine Institute (REMEDI) at C\u00daRAM Centre for Research in Medical Devices, Biomedical Sciences Building, University of Galway, H91 TK33 Galway, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hector E.","family":"Gonzalez","sequence":"additional","affiliation":[{"name":"Anaesthesia, School of Medicine, University of Galway, H91 TK33 Galway, Ireland"},{"name":"Regenerative Medicine Institute (REMEDI) at C\u00daRAM Centre for Research in Medical Devices, Biomedical Sciences Building, University of Galway, H91 TK33 Galway, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5474-5388","authenticated-orcid":false,"given":"Sean D.","family":"McCarthy","sequence":"additional","affiliation":[{"name":"Anaesthesia, School of Medicine, University of Galway, H91 TK33 Galway, Ireland"},{"name":"Regenerative Medicine Institute (REMEDI) at C\u00daRAM Centre for Research in Medical Devices, Biomedical Sciences Building, University of Galway, H91 TK33 Galway, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Fandi\u00f1o","sequence":"additional","affiliation":[{"name":"Anaesthesia, School of Medicine, University of Galway, H91 TK33 Galway, Ireland"},{"name":"Regenerative Medicine Institute (REMEDI) at C\u00daRAM Centre for Research in Medical Devices, Biomedical Sciences Building, University of Galway, H91 TK33 Galway, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel P.","family":"O\u2019Toole","sequence":"additional","affiliation":[{"name":"Anaesthesia, School of Medicine, University of Galway, H91 TK33 Galway, Ireland"},{"name":"Regenerative Medicine Institute (REMEDI) at C\u00daRAM Centre for Research in Medical Devices, Biomedical Sciences Building, University of Galway, H91 TK33 Galway, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1246-9573","authenticated-orcid":false,"given":"John G.","family":"Laffey","sequence":"additional","affiliation":[{"name":"Anaesthesia, School of Medicine, University of Galway, H91 TK33 Galway, Ireland"},{"name":"Regenerative Medicine Institute (REMEDI) at C\u00daRAM Centre for Research in Medical Devices, Biomedical Sciences Building, University of Galway, H91 TK33 Galway, Ireland"},{"name":"Department of Anaesthesia, Galway University Hospitals, SAOLTA University Health Group, H91 YR71 Galway, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,19]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2016). 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