Epigallocatechin-3-gallate reduces neutrophil extracellular trap formation and tissue injury in severe acute pancreatitis

Abstract

Neutrophil extracellular traps (NETs) promote intra‐acinar trypsin activation and tissue damage. Therefore, reducing NET formation can reduce tissue damage in severe acute pancreatitis (SAP). However, NET formation pathways may differ among disease models. In this study, we evaluated the role of the myeloperoxidase–neutrophil elastase (NE) pathway in NET formation in SAP. SAP was induced by intraperitoneal injection of cerulein and LPSs in mice, and NE activity was inhibited by GW311616. Pancreatic tissues were collected for multiplex immunofluorescence, scanning electron microscopy, and western blotting to detect NET formation and the effect of NE on citrullinated histone H3, followed by analyses of serum amylase and cytokine levels. Pretreatment with GW311616 significantly reduced NET formation, pancreatic tissue damage, and systemic inflammatory responses in SAP. Network pharmacology analyses using NE as the target revealed the monomeric compound epigallocatechin‐3‐gallate (EGCG). Binding between EGCG and NE was validated using molecular docking, and the ability of EGCG to inhibit NE activity was verified experimentally. NET formation by PMA‐stimulated neutrophils was significantly reduced in vitro when the cells were pretreated with 40 μM EGCG. Pretreatment with EGCG significantly reduced NET formation, pancreatic tissue damage, and systemic inflammatory responses in vivo. These results reveal that NET formation requires the myeloperoxidase‐NE pathway, and citrullination of histone H3 is affected by NE activity in SAP. EGCG shows therapeutic potential for affecting NE activity, NET formation, and systemic inflammation in SAP.

High expression of P-selectin induces neutrophil extracellular traps via the PSGL-1/Syk/Ca2+/PAD4 pathway to exacerbate acute pancreatitis

“…Clarifying the endogenous mechanisms underlying AP progression could help to clinically treatment and improve prognosis. Besides the classical role of neutrophils, numerous findings suggest that neutrophil-derived NETs play an important role in the pathophysiology of AP (8,(25)(26)(27). Based on the role of Pselectin in neutrophil functions, our study focused on the relationship between the highly expressed P-selectin and NETs in AP and found that in human neutrophils P-selectin is an important stimulus of NETs formation, which is consistent with the findings of Etulain et al in mouse neutrophils (20).…”

Targeting Neutrophil Extracellular Trap Formation: Exploring Promising Pharmacological Strategies for the Treatment of Preeclampsia

“…On the other hand, cyclosporine A uses the calcineurin pathway to reduce NETs [85], while the antioxidants N-acetylcysteine, ethotrexate, trolox, tempol [86], epigallocatechin-3-gallate [87], and diphenyleneiodonium chloride (DPI) [88] decrease NETs by reducing mitochondrial ROS formation [85]. DPI also reduces NET formation through the PKC-βII pathway [89] like metformin.…”

Neutrophil Extracellular Traps and Respiratory Disease

“…Other compounds including those derived from green tea [188] and ginger [189] have been demonstrated to reduce ROS production and NET expression.…”