Phosphatidylinositol‐4,5‐bisphosphate 3‐kinase <b>(PI3K)</b> inhibitors reduce vascular inflammation <i>in vitro</i> and <i>in vivo</i>

Abstract

Background and Purpose: 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.

Experimental Approach: 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.

Key Results: 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 <i>in vitro</i>. <i>In vivo>/i>, 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.

Conclusions and Implications: 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.