Extracellular release of ATP promotes systemic inflammation during acute pancreatitis

Abstract

In the current study, we explored the role of extracellular ATP (eATP) in promoting systemic inflammation during development of acute pancreatitis (AP). Release of extracellular (e)ATP was evaluated in plasma and bronchoalveolar lavage fluid (BALF) of mice with experimental acute pancreatitis (AP). Prophylactic intervention using apyrase or suramin was used to understand the role and contribution of eATP in pancreatitis-associated systemic injury. AP of varying severity was induced in C57BL/6 mice using 1-day or 2-day caerulein, caerulein + LPS and l-arginine models. eATP was measured in plasma and BALF. Mice were treated with suramin or apyrase in the caerulein and l-arginine models of AP. Plasma cytokines, lung, and pancreatic myeloperoxidase, and morphometric analysis of pancreatic and lung histology, were used to assess the severity of pancreatitis. Plasma eATP and purinergic 2 (P2) receptors in the pancreas and lungs were significantly elevated in the experimental models of AP. Blocking the effect of eATP by suramin led to reduced levels of plasma IL-6 and TNFα as well as reduced lung, and pancreatic injury. Neutralizing eATP with apyrase reduced systemic injury but did not ameliorate local injury. The results of this study support the role of eATP and P2 receptors in promoting systemic inflammation during AP. Modulating purinergic signaling during AP can be an important therapeutic strategy in controlling systemic inflammation and, thus, systemic inflammatory response syndrome during AP. NEW & NOTEWORTHY Released ATP from injured cells promotes systemic inflammation in acute pancreatitis

P2 Purinergic Signaling in the Distal Lung in Health and Disease

“…P2X 4 receptor has failed to demonstrate a significant contribution to the final outcome in a mouse model of traumatic lung injury [ 210 ]. Dixit et al reported recently that the non-specific P2-antagonist suramin alleviated systemic and lung inflammation as well as lung injury in mouse models of acute pancreatitis [ 211 ]. Further, they observed increased plasma levels of ATP, suggesting that ATP was involved in remote activation of the pulmonary immune system, and indeed i.v.…”

Delicate regulation of IL-1β-mediated inflammation by cyclophilin A

“…Macrophages need two distinct stimuli to activate caspase-1, leading to release of active IL-1b. One stimulus (Toll-like receptor [TLR] ligands) induces transcription, and a second stimulus (ATP) induces IL-1b secretion (Dixit et al, 2019;Ferrari et al, 1997b;Netea et al, 2009;Riteau et al, 2012). During the inflammation-activation phase, stressed and activated cells can release ATP and acute cell injury or death will cause massive ATP release into the extracellular milieu.…”

Electroacupuncture Ameliorates Acute Pancreatitis: A Role for the Vagus Nerve–Mediated Cholinergic Anti-Inflammatory Pathway

“…In AP, the initial inflammatory process leads to migration of monocytes and neutrophils into the pancreas ( Dixit et al, 2019 ). Neutrophils have been proposed to play crucial roles in the early phase of disease development, contributing to activation of trypsinogen and progression to severe AP ( Habtezion, 2015 ).…”

“…Acute pancreatitis (AP) is initiated with inappropriate activation of pancreatic enzymes and subsequent local and systemic inflammatory responses ( Kang et al, 2014 ; Dixit et al, 2019 ). Inflammatory mediators released from injured acinar cells and immune cells mediate pancreatic injury and exacerbation of AP ( Pandol et al, 2007 ; Zhang et al, 2013 ).…”