{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T08:46:38Z","timestamp":1776501998993,"version":"3.51.2"},"reference-count":51,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2021,10,1]],"date-time":"2021-10-01T00:00:00Z","timestamp":1633046400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100000265","name":"UK Research and Innovation | Medical Research Council","doi-asserted-by":"publisher","award":["MR\/N02995X\/1"],"award-info":[{"award-number":["MR\/N02995X\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012295","name":"NIHR | NIHR Newcastle Biomedical Research Centre","doi-asserted-by":"publisher","award":["IS-BRC-1215-20001"],"award-info":[{"award-number":["IS-BRC-1215-20001"]}],"id":[{"id":"10.13039\/501100012295","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Acquired neutrophil dysfunction frequently develops during critical illness, independently increasing the risk for intensive care unit\u2013acquired infection. PI3K\u03b4 is implicated in driving neutrophil dysfunction and can potentially be targeted pharmacologically. The aims of this study were to determine whether PI3K\u03b4 inhibition reverses dysfunction in neutrophils from critically ill patients and to describe potential mechanisms. Neutrophils were isolated from blood taken from critically ill patients requiring intubation and mechanical ventilation, renal support, or blood pressure support. In separate validation experiments, neutrophil dysfunction was induced pharmacologically in neutrophils from healthy volunteers. Phagocytosis and bacterial killing assays were performed, and activity of RhoA and protein kinase A (PKA) was assessed. Inhibitors of PI3K\u03b4, 3-phosphoinositide-dependent protein kinase-1 (PDK1), and PKA were used to determine mechanisms of neutrophil dysfunction. Sixty-six patients were recruited. In the 27 patients (40.9%) with impaired neutrophil function, PI3K\u03b4 inhibition consistently improved function and significantly increased bacterial killing. These findings were validated in neutrophils from healthy volunteers with salbutamol-induced dysfunction and extended to demonstrate that PI3K\u03b4 inhibition restored killing of clinical isolates of nine pathogens commonly associated with intensive care unit\u2013acquired infection. PI3K\u03b4 activation was associated with PDK1 activation, which in turn phosphorylated PKA, which drove phosphorylation and inhibition of the key regulator of neutrophil phagocytosis, RhoA. These data indicate that, in a significant proportion of critically ill patients, PI3K\u03b4 inhibition can improve neutrophil function through PDK1- and PKA-dependent processes, suggesting that therapeutic use of PI3K\u03b4 inhibitors warrants investigation in this setting.<\/jats:p>","DOI":"10.4049\/jimmunol.2000603","type":"journal-article","created":{"date-parts":[[2021,9,8]],"date-time":"2021-09-08T14:46:28Z","timestamp":1631112388000},"page":"1776-1784","source":"Crossref","is-referenced-by-count":11,"title":["Phosphoinositide 3-Kinase \u03b4 Inhibition Improves Neutrophil Bacterial Killing in Critically Ill Patients at High Risk of Infection"],"prefix":"10.1093","volume":"207","author":[{"given":"Jonathan","family":"Scott","sequence":"first","affiliation":[{"name":"Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University , Newcastle upon Tyne ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marie-H\u00e9l\u00e8ne","family":"Ruchaud-Sparagano","sequence":"additional","affiliation":[{"name":"Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University , Newcastle upon Tyne ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4984-475X","authenticated-orcid":false,"given":"Kathryn","family":"Musgrave","sequence":"additional","affiliation":[{"name":"Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University , Newcastle upon Tyne ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alistair I","family":"Roy","sequence":"additional","affiliation":[{"name":"Integrated Critical Care Unit, Sunderland Royal Hospital , Sunderland ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen E","family":"Wright","sequence":"additional","affiliation":[{"name":"Intensive Care Unit, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust , Newcastle upon Tyne ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7225-7508","authenticated-orcid":false,"given":"John D","family":"Perry","sequence":"additional","affiliation":[{"name":"Microbiology Department, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust , Newcastle upon Tyne ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3211-3216","authenticated-orcid":false,"given":"Andrew","family":"Conway Morris","sequence":"additional","affiliation":[{"name":"Division of Anaesthesia, Department of Medicine, University of Cambridge, Cambridge Biomedical Campus , Cambridge ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9336-1723","authenticated-orcid":false,"given":"Anthony J","family":"Rostron","sequence":"additional","affiliation":[{"name":"Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University , Newcastle upon Tyne ,","place":["United Kingdom"]},{"name":"Integrated Critical Care Unit, Sunderland Royal Hospital , Sunderland ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4731-7294","authenticated-orcid":false,"given":"A John","family":"Simpson","sequence":"additional","affiliation":[{"name":"Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University , Newcastle upon Tyne ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2021,10,1]]},"reference":[{"key":"2025022610321436500_r1","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1097\/00003246-199905000-00020","article-title":"Nosocomial infections in medical intensive care units in the United States","volume":"27","author":"Richards","year":"1999","journal-title":"Crit. 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