Dynamic purine signaling and metabolism during neutrophil-endothelial interactions

Abstract

During episodes of hypoxia and inflammation, polymorphonuclear leukocytes (PMN) move into underlying tissues by initially passing between endothelial cells that line the inner surface of blood vessels (transendothelial migration, TEM). TEM creates the potential for disturbances in vascular barrier and concomitant loss of extravascular fluid and resultant edema. Recent studies have demonstrated a crucial role for nucleotide metabolism and nucleoside signaling during inflammation. These studies have implicated multiple adenine nucleotides as endogenous tissue protective mechanisms invivo. Here, we review the functional components of vascular barrier, identify strategies for increasing nucleotide generation and nucleoside signaling, and discuss potential therapeutic targets to regulate the vascular barrier during inflammation.

Figure 1

Neutrophil (PMN) transendothelial migration (TEM). PMN exit the circulation and move into underlying tissue by passing between endothelial cells. During this process, inter-endothelial gaps have the potential to increase vascular permeability, with resultant tissue edema and organ dysfunction. While the endogenous mechanism(s) which regulate these pathways remain poorly understood, work in recent years has revealed new and previously unappreciated targets for potential therapeutic intervention.

Figure 2

Proposed model of coordinated nucleotide metabolism and nucleoside signaling in posthypoxic endothelial cells. In areas of ongoing inflammation, diminished oxygen supply coordinates the induction of CD39, CD73, and AdoRA_2B. At such sites, activated PMN provide a readily available extracellular source of ATP, that through two enzymatic steps results in the liberation of extracellular adenosine. Activation of surface AdoR functions to promote the re-establishment of vascular integrity. Under such circumstances, PMN appear to “close the door after exiting.”