Abstract
Sepsis, during which the intestinal epithelial barrier is frequently disrupted, remains a challenging and life-threatening problem in clinical practice. The P2X7 receptor (P2X7R) is a non-selective adenosine triphosphate-gated cation channel present in macrophages that is involved in inflammatory responses. However, little is known about the role of P2X7R in macrophages during sepsis-induced intestinal barrier disruption. In this study, mice were treated with the P2X7R antagonist A740003 or the agonist BzATP by intra-peritoneal injection after the induction of gut-origin sepsis. The survival rates, inflammatory responses, intestinal barrier integrity, macrophage marker expression, and ERK and NF-κB activities were evaluated. Intestinal macrophages were also isolated and studied after exposure to Brilliant Blue G or BzATP. We found that a systemic P2X7R blockade downregulated sepsis-induced inflammatory responses and attenuated intestinal barrier dysfunction based on the evidence that mice in the A740003-treated group exhibited alleviated pro-inflammatory cytokine synthesis, intestinal hyperpermeability, epithelial apoptosis rates and tight junction damage compared with the septic mice. These changes were partly mediated by the inhibition of M1 macrophages activation via ERK/NF-κB pathways. Our data presented herein show that a P2X7R blockade could be a potential therapeutic target for the treatment of sepsis-induced intestinal barrier dysfunction.
Highlights
Sepsis remains a challenging and often life-threatening problem in clinical practice that is associated with unacceptable morbidity and mortality rates
Western blot (WB) analysis showed that there were no significant differences in P2X7 receptor (P2X7R) levels between the agonist/antagonist-treated mice and the normal mice before cecal ligation and puncture (CLP) intervention (p > 0.05)
We tested the therapeutic effects of P2X7R antagonists in polymicrobial sepsis, and we especially focused on their effects on the intestinal barrier
Summary
Sepsis remains a challenging and often life-threatening problem in clinical practice that is associated with unacceptable morbidity and mortality rates. Some pro-inflammatory cytokines, such as IL-6 and TNF-α, have been found to contribute to the disruption of intestinal epithelial barrier function[4]. The P2X7 receptor (P2X7R) is an extracellular ATP-gated cation channel expressed in epithelial cells and immune effector cells and is involved in the regulation of pro-inflammatory cytokine production[11], apoptosis and autophagy induction[12], and host defenses against infectious pathogens[13]. In the absence of this receptor, septic mice exhibited improved survival, decreased levels of NO and pro-inflammatory cytokines, reduced peritoneal cell apoptosis, and produced less pronounced morphological changes[14, 15]. Despite the importance of P2X7R during inflammatory responses to pathogens, it is not established whether this receptor plays a role in sepsis-induced intestinal barrier dysfunction
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