Phosphatidylinositol‐4,5‐bisphosphate 3‐kinase (PI3K) inhibitors reduce vascular inflammation in vitro and in vivo

Endothelial cells play central roles in increasing vascular permeability and leukocyte recruitment. Therapeutic approaches for treating endothelial cell barrier dysfunction to reduce unwanted fluid accumulation in tissues are limited. Phosphatidylinositol-4,5-bisphosphate 3-kinase (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. 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 in vivo. The effects of inflammatory mediators that induce vascular leakage and neutrophil accumulation (TNFα, IL-1β and C5a) were examined, with the neuropeptides substance P and α-CGRP used as controls. The ability of PI3K inhibitors to modulate inflammatory responses was studied. A broad spectrum PI3K inhibitor (PI-103) and a selective inhibitor of the class 1A p110α catalytic subunit (BYL-719/alpelisib) inhibited endothelial morphological changes and permeability induced by TNFα and IL-1β in vitro. In vivo, oedema and neutrophil accumulation induced by TNFα and IL-1β, but not by the complement fragment C5a, is inhibited by BYL-719, whereas PI-103 blocks effects of all three mediators. Neither influences the acute oedema formation induced by neuropeptides. Selective p110α inhibition of vascular inflammation may provide a novel therapeutic pathway for limiting adverse tissue swelling. Moreover, the limited effect of BYL-719 on C5a-mediated responses implies that this innate component of the immune response will continue to provide essential defence activity during p110α blockade.