Adenosine Kinase Inhibition Prevents Severe Acute Pancreatitis via Suppressing Inflammation and Acinar Cell Necroptosis.

Shukun Sun,Yu Han,Shujian Wei,Bailu Wang,Chuanxin Zhang,Shengchuan Cao,Yuguo Chen,Han Liu,Qiuhuan Yuan

doi:10.3389/fcell.2022.827714

Abstract

Background: Inflammatory disorder and acinar cell death contribute to the initiation and progression of severe acute pancreatitis (SAP). Adenosine kinase (ADK) has potential effects on both inflammation and cell death. However, the role of ADK in SAP remains to be explored. Methods: To establish an experimental SAP model, male C57BL/6 mice were intraperitoneally injected with cerulein (50 μg/kg, seven doses at hourly intervals) and LPS (10 mg/kg, at the last cerulein injection). For ADK inhibition, ABT702 (1.5 mg/kg) was intraperitoneally injected 1 h before cerulein treatment. The pancreas and serum were collected and analyzed to determine the severity of pancreatic injury and explore the potential pathophysiological mechanisms. Pancreatic acinar cells (AR42J) were used to explore the in vitro effects of ADK inhibition on cerulein–induced inflammation and necroptotic cell death. Results: ADK inhibition notably attenuated the severity of SAP, as indicated by the decreased serum amylase (7,416.76 ± 1,457.76 vs. 4,581.89 ± 1,175.04 U/L) and lipase (46.51 ± 11.50 vs. 32.94 ± 11.46 U/L) levels and fewer pancreatic histopathological alterations (histological scores: 6.433 ± 0.60 vs. 3.77 ± 0.70). MOMA-2 and CD11b staining confirmed that ADK inhibition prevented the infiltration of neutrophils and macrophages. The phosphorylation of nuclear factor-κB (NF-κB) was also reduced by ADK inhibition. ADK inhibition markedly limited the necrotic area of the pancreas and prevented the activation of the necroptotic signaling pathway. Endoplasmic reticulum (ER) stress was activated in the pancreas using the SAP model and cerulein–treated AR42J cells whereas ADK inhibition reversed the activation of ER stress both in vivo and in vitro. Moreover, the alleviating effects of ADK inhibition on ER stress, inflammation, and cell necroptosis were eliminated by the adenosine A2A receptor antagonist. Conclusion: ADK inhibition reduced inflammation and necroptotic acinar cell death in SAP via the adenosine A2A receptor/ER stress pathway, suggesting that ADK might be a potential therapeutic target for SAP.

Highlights

Acute pancreatitis (AP) is the leading cause of gastrointestinal disease-related hospital admission and causes considerable morbidity and mortality (Lee and Papachristou, 2019; Mayerle et al, 2019)
We investigated the effects of Adenosine kinase (ADK) on acute pancreatitis and found that ADK inhibition attenuates the severity of AP by limiting the infiltration of neutrophils and macrophages, suppressing the production of proinflammatory molecules and preventing acinar cell necroptosis
ADK inhibition significantly prevented the increase in serum amylase (7,416.76 ± 1,457.76 vs. 4,581.89 ± 1,175.04 U/L) and lipase (46.51 ± 11.50 vs. 32.94 ± 11.46 U/L) in severe acute pancreatitis (SAP) mice (Figures 1C,D)

Summary

Introduction

Acute pancreatitis (AP) is the leading cause of gastrointestinal disease-related hospital admission and causes considerable morbidity and mortality (Lee and Papachristou, 2019; Mayerle et al, 2019). Inflammatory disorder and acinar cell death are the major hallmarks of AP (Bhatia, 2004b; Habtezion, 2015). Acinar cells undergo two major modes of death during AP: necrosis and apoptosis (Wang et al, 2016). Necrosis has long been considered unregulated and passive cell death; necroptosis is a new regulated form of necrosis, and its emerging role in SAP has attracted increasing attention (Wang et al, 2016). Inflammatory disorder and acinar cell death contribute to the initiation and progression of severe acute pancreatitis (SAP). The role of ADK in SAP remains to be explored

Methods

Results

Conclusion