Targeting P2X Receptors-Current Progress in Sepsis

Abstract

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Inflammation, as the main pathophysiological mechanism, runs through the whole course of sepsis. Notably, P2X receptors have the capacity to mediate inflammation, nerve signaling, and thrombosis, which underscores their pivotal role in the progression of sepsis. The goal of this study is to review the specific role of the P2X family in the pathogenesis of sepsis in various organs in light of currently available evidence.

Keywords: P2X receptors; multiple organ dysfunction; purinergic receptor; sepsis.

Figure 1

Overview of liver injury in sepsis. The liver can be divided into hepatic lobules. P2X1 significantly inhibits the secretion of growth-promoting factor interleukin-22 (IL-22) in vitro in immune cells; P2X7 mainly promotes inflammation through the P2X7-NLRP3-Caspase-1 pathway; P2X on the apical membrane is activated by ATP and mediates intracellular Ca²⁺ influx, affecting cell metabolism and proliferation.

Figure 2

Overview of sepsis-associated encephalopathy. Astrocytes release inflammatory mediators in response to systemic inflammation, leading to neuronal and endothelial cell damage. This process results in the release of large amounts of ATP, activating P2X receptors and causing ion flow disruption. Consequently, tight junctions between cells are compromised, and the blood–brain barrier becomes dysfunctional.

Figure 3

Overview of lung injury in sepsis. The opening of P2X1 channels increases Ca²⁺ entry into bronchial mucosal epithelial cells causing bronchial contraction. P2X1, P2X3 and P2X4 on the surface of vascular endothelial cells were associated with pulmonary artery vasoconstriction. P2X7 is located on the surface of lamellar bodies (LBs) in alveolar epithelial cells (AT cells) and assists in the secretion of surface-active substances. The ion concentration gradient caused by P2X caused mitochondrial damage. Activation of P2X7 receptors on pulmonary interstitial cell membranes upregulates the secretion of inflammatory cytokines through the classic pathways.