{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T13:09:30Z","timestamp":1777900170181,"version":"3.51.4"},"reference-count":43,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,4,29]],"date-time":"2023-04-29T00:00:00Z","timestamp":1682726400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001602","name":"Science Foundation Ireland","doi-asserted-by":"publisher","award":["16-FRL-3845"],"award-info":[{"award-number":["16-FRL-3845"]}],"id":[{"id":"10.13039\/501100001602","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Antimicrobial-resistant (AMR) bacteria, such as Klebsiella species, are an increasingly common cause of hospital-acquired pneumonia, resulting in high mortality and morbidity. Harnessing the host immune response to AMR bacterial infection using mesenchymal stem cells (MSCs) is a promising approach to bypass bacterial AMR mechanisms. The administration of single doses of na\u00efve MSCs to ARDS clinical trial patient cohorts has been shown to be safe, although efficacy is unclear. The study tested whether repeated MSC dosing and\/or preactivation, would attenuate AMR Klebsiella pneumonia-induced established pneumonia. Rat models of established K. pneumoniae-induced pneumonia were randomised to receive intravenous na\u00efve or cytomix-preactivated umbilical cord MSCs as a single dose at 24 h post pneumonia induction with or without a subsequent dose at 48 h. Physiological indices, bronchoalveolar lavage (BAL), and tissues were obtained at 72 h post pneumonia induction. A single dose of na\u00efve MSCs was largely ineffective, whereas two doses of MSCs were effective in attenuating Klebsiella pneumosepsis, improving lung compliance and oxygenation, while reducing bacteria and injury in the lung. Cytomix-preactivated MSCs were superior to na\u00efve MSCs. BAL neutrophil counts and activation were reduced, and apoptosis increased. MSC therapy reduced cytotoxic BAL T cells, and increased CD4+\/CD8+ ratios. Systemically, granulocytes, classical monocytes, and the CD4+\/CD8+ ratio were reduced, and nonclassical monocytes were increased. Repeated doses of MSCs\u2014particularly preactivated MSCs\u2014enhance their therapeutic potential in a clinically relevant model of established AMR K. pneumoniae-induced pneumosepsis.<\/jats:p>","DOI":"10.3390\/ijms24098055","type":"journal-article","created":{"date-parts":[[2023,5,1]],"date-time":"2023-05-01T13:54:46Z","timestamp":1682949286000},"page":"8055","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Multiple Dosing and Preactivation of Mesenchymal Stromal Cells Enhance Efficacy in Established Pneumonia Induced by Antimicrobial-Resistant Klebsiella pneumoniae in Rodents"],"prefix":"10.3390","volume":"24","author":[{"given":"Declan","family":"Byrnes","sequence":"first","affiliation":[{"name":"Anaesthesia, School of Medicine, University of Galway, H91 TR33 Galway, Ireland"},{"name":"Regenerative Medicine Institute (REMEDI) at C\u00daRAM Centre for Research in Medical Devices, Biomedical Sciences Building, University of Galway, H91 TR33 Galway, Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claire H.","family":"Masterson","sequence":"additional","affiliation":[{"name":"Anaesthesia, School of Medicine, University of Galway, H91 TR33 Galway, Ireland"},{"name":"Regenerative Medicine Institute (REMEDI) at C\u00daRAM Centre for Research in Medical Devices, Biomedical Sciences Building, University of Galway, H91 TR33 Galway, Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hector E.","family":"Gonzales","sequence":"additional","affiliation":[{"name":"Anaesthesia, School of Medicine, University of Galway, H91 TR33 Galway, Ireland"},{"name":"Regenerative Medicine Institute (REMEDI) at C\u00daRAM Centre for Research in Medical Devices, Biomedical Sciences Building, University of Galway, H91 TR33 Galway, Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sean D.","family":"McCarthy","sequence":"additional","affiliation":[{"name":"Anaesthesia, School of Medicine, University of Galway, H91 TR33 Galway, Ireland"},{"name":"Regenerative Medicine Institute (REMEDI) at C\u00daRAM Centre for Research in Medical Devices, Biomedical Sciences Building, University of Galway, H91 TR33 Galway, Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel P.","family":"O\u2019Toole","sequence":"additional","affiliation":[{"name":"Anaesthesia, School of Medicine, University of Galway, H91 TR33 Galway, Ireland"},{"name":"Regenerative Medicine Institute (REMEDI) at C\u00daRAM Centre for Research in Medical Devices, Biomedical Sciences Building, University of Galway, H91 TR33 Galway, Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"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 TR33 Galway, Ireland"},{"name":"Regenerative Medicine Institute (REMEDI) at C\u00daRAM Centre for Research in Medical Devices, Biomedical Sciences Building, University of Galway, H91 TR33 Galway, Ireland"},{"name":"Department of Anaesthesia, Galway University Hospitals, SAOLTA University Health Group, H91 YR71 Galway, Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"742","DOI":"10.4187\/respcare.07754","article-title":"Hospital Readmissions and Mortality Among Intubated and Mechanically Ventilated Adult Subjects with Pneumonia Due to Gram-Negative Bacteria","volume":"66","author":"Lodise","year":"2021","journal-title":"Respir. 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