Background: Acute pancreatitis remains a major clinical challenge, with treatment largely limited to supportive care. Neutrophil-driven inflammation plays a central role in disease progression, contributing to pancreatic injury, systemic complications, and organ failure. Targeting neutrophil recruitment and activation has emerged as a potential therapeutic strategy. Objective: This review synthesizes current evidence on neutrophil extravasation inhibitors in acute pancreatitis, focusing on chemokine-mediated recruitment pathways and neutrophil extracellular trap (NET) formation.
Methods: A structured review of preclinical studies examining neutrophil-targeted therapies in experimental pancreatitis models was conducted, with emphasis on CXCR2 signaling inhibition, NET degradation and prevention, and modulation of alternative chemokine pathways.
Results: Multiple approaches demonstrate protective effects. CXCR2 inhibition shows robust efficacy in acute and chronic models, including post-onset treatment. NET-targeted therapies, such as DNase I and peptidylarginine deiminase inhibitors, significantly reduce pancreatic injury, systemic inflammation, and multi-organ damage. Combination therapy with N-acetylcysteine and DNase I produces synergistic effects by preventing NET formation and degrading existing NETs. Additional strategies, including gasdermin D inhibition, AXL/MERTK antagonism, and selective chemokine blockade, offer complementary benefits. Clinical relevance is supported by elevated NET biomarkers in severe cases. Mechanistic studies indicate that NETs amplify neutrophil recruitment and directly induce trypsin activation in acinar cells, forming a pathological feedback loop.
Conclusions: Targeting neutrophil extravasation and NET formation is a promising therapeutic strategy in acute pancreatitis. Multi-mechanistic approaches may improve outcomes and warrant clinical investigation.
Methods: A structured review of preclinical studies examining neutrophil-targeted therapies in experimental pancreatitis models was conducted, with emphasis on CXCR2 signaling inhibition, NET degradation and prevention, and modulation of alternative chemokine pathways.
Results: Multiple approaches demonstrate protective effects. CXCR2 inhibition shows robust efficacy in acute and chronic models, including post-onset treatment. NET-targeted therapies, such as DNase I and peptidylarginine deiminase inhibitors, significantly reduce pancreatic injury, systemic inflammation, and multi-organ damage. Combination therapy with N-acetylcysteine and DNase I produces synergistic effects by preventing NET formation and degrading existing NETs. Additional strategies, including gasdermin D inhibition, AXL/MERTK antagonism, and selective chemokine blockade, offer complementary benefits. Clinical relevance is supported by elevated NET biomarkers in severe cases. Mechanistic studies indicate that NETs amplify neutrophil recruitment and directly induce trypsin activation in acinar cells, forming a pathological feedback loop.
Conclusions: Targeting neutrophil extravasation and NET formation is a promising therapeutic strategy in acute pancreatitis. Multi-mechanistic approaches may improve outcomes and warrant clinical investigation.