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Therapeutic approaches for treating endothelial cell barrier dysfunction to reduce unwanted fluid accumulation in tissues are limited. Phosphatidylinositol\u20104,5\u2010bisphosphate 3\u2010kinase (PI3K) enzymes are implicated in signalling inflammatory endothelial permeability and leukocyte recruitment. We investigated the ability of PI3K inhibitors to influence cutaneous oedema formation and neutrophil accumulation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>\n                      We used cultured endothelial cells to determine the effects of inflammatory mediators on permeability and vascular leakage, and a murine model of vascular inflammation in mouse skin\n                      <jats:italic>in vivo<\/jats:italic>\n                      . The effects of inflammatory mediators that induce vascular leakage and neutrophil accumulation (TNF\u03b1, IL\u20101\u03b2 and C5a) were examined, with the neuropeptides substance P and \u03b1\u2010CGRP used as controls. The ability of PI3K inhibitors to modulate inflammatory responses was studied.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>\n                      A broad spectrum PI3K inhibitor (PI\u2010103) and a selective inhibitor of the class 1A p110\u03b1 catalytic subunit (BYL\u2010719\/alpelisib) inhibited endothelial morphological changes and permeability induced by TNF\u03b1 and IL\u20101\u03b2\n                      <jats:italic>in vitro<\/jats:italic>\n                      .\n                      <jats:italic>In vivo<\/jats:italic>\n                      , oedema and neutrophil accumulation induced by TNF\u03b1 and IL\u20101\u03b2, but not by the complement fragment C5a, is inhibited by BYL\u2010719, whereas PI\u2010103 blocks effects of all three mediators. Neither influences the acute oedema formation induced by neuropeptides.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions and Implications<\/jats:title>\n                    <jats:p>Selective p110\u03b1 inhibition of vascular inflammation may provide a novel therapeutic pathway for limiting adverse tissue swelling. Moreover, the limited effect of BYL\u2010719 on C5a\u2010mediated responses implies that this innate component of the immune response will continue to provide essential defence activity during p110\u03b1 blockade.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.70152","type":"journal-article","created":{"date-parts":[[2025,8,19]],"date-time":"2025-08-19T06:10:53Z","timestamp":1755583853000},"page":"6028-6042","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Phosphatidylinositol\u20104,5\u2010bisphosphate 3\u2010kinase\n                    <b>(<\/b>\n                    PI3K) inhibitors reduce vascular inflammation\n                    <i>in vitro<\/i>\n                    and\n                    <i>in vivo<\/i>"],"prefix":"10.1111","volume":"182","author":[{"given":"Hiba","family":"Chaudhry","sequence":"first","affiliation":[{"name":"School of Cardiovascular and Metabolic Medicine and Sciences (Southbank), BHF Centre of Research Excellence King's College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali A.","family":"Zarban","sequence":"additional","affiliation":[{"name":"School of Cardiovascular and Metabolic Medicine and Sciences (Southbank), BHF Centre of Research Excellence King's College London  London UK"},{"name":"Department of Pharmacology and Toxicology, College of Pharmacy Jazan University  Jazan Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia Cellone","family":"Trevelin","sequence":"additional","affiliation":[{"name":"School of Cardiovascular Medicine and Metabolic Medicine and Sciences, BHF Centre of Research Excellence, James Black Centre King's College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xenia","family":"Kodji","sequence":"additional","affiliation":[{"name":"Skin Research Institute of Singapore (SRIS) Agency for Science, Technology and 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