1. Academic Validation
  2. Protectin D1 decreases pancreatitis severity in mice by inhibiting neutrophil extracellular trap formation

Protectin D1 decreases pancreatitis severity in mice by inhibiting neutrophil extracellular trap formation

  • Int Immunopharmacol. 2021 May;94:107486. doi: 10.1016/j.intimp.2021.107486.
Zhiyang Wu 1 Guotao Lu 2 Luyao Zhang 3 Lu Ke 4 Chenchen Yuan 4 Nan Ma 4 Xianqiang Yu 4 Xi Guo 1 Wei Zhao 1 Yingjie Wang 1 Sanyuan Hu 5 Dawei Wu 6 Weiqin Li 7
Affiliations

Affiliations

  • 1 Department of Critical Care Medicine, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, 758 Hefei Road, Qingdao, Shandong 266035, China.
  • 2 Department of Gastroenterology, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu, China.
  • 3 Department of Pathology, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, 210023 Nanjing, China.
  • 4 Department of Critical Care Medicine, PLA Key Laboratory of Emergency and Critical Care Research, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China.
  • 5 Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • 6 Department of Critical Care Medicine, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, 758 Hefei Road, Qingdao, Shandong 266035, China. Electronic address: qiluwdw@163.com.
  • 7 Department of Critical Care Medicine, PLA Key Laboratory of Emergency and Critical Care Research, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China. Electronic address: njzy_pancrea@163.com.
Abstract

Background: Docosahexaenoic acid-derived protectin D1 (PD1) was identified critical in the resolution of inflammation in vivo, where it modulates the innate immune response and stimulates resolution. Acute pancreatitis (AP) is characterized by local pancreatic inflammation with mild forms whereas systemic inflammation with severe forms. Herein we investigate the impact of PD1 in murine models of pancreatitis.

Methods: Three independent AP models, which induced in male mice via intraperitoneal injection of caerulein, L-arginine or pancreatic duct ligation, were used to confirm the protective effect of PD1. Infiltrationsof neutrophils and macrophages in pancreas were detected by flow cytometry and immunohistochemistry. In vitro and in vivo neutrophil extracellular traps formation was detected by immunofluorescence staining. Expression of peptidylarginine deiminase 4 (PAD4) in activated neutrophils was evaluated by western blotting.

Results: Systemic treatment with PD1 reduced serum activities of amylase and Lipase, blunted the concentrations of tumor necrosis factor-α and interleukin-6 in serum and protected against pancreas histologic damage in three AP models. PD1 also prolonged the survival in the pancreatic duct ligation model. Moreover, pancreatic infiltrationofneutrophils and neutrophil CitH3 expression were reduced after PD1 administration. In vitro studies revealed PD1 decreased supernatant cell-free DNA and CitH3 levels and downregulated PAD4 expression in mouse bone-marrow derived neutrophils. However, in the caerulein mice pretreated with GSK484 hydrochloride, an inhibitor of PAD4, PD1 treatment showed no more protective effect.

Conclusions: PD1 ameliorates AP by decreasing early infiltration of neutrophils into the pancreas and neutrophil extracellular traps formation through PAD4. These results supply the foundation to consider PD1 as a therapy for AP.

Keywords

Acute pancreatitis; Neutrophil extracellular traps; Neutrophils; PAD4; Protectin D1.

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