Abstract

Acute pancreatitis (AP) is a common inflammatory disease mediated by damage to acinar cells and subsequent pancreatic inflammation with infiltration of leukocytes. The neuronal guidance protein, netrin-1, has been shown to control leukocyte trafficking and modulate inflammatory responses in several inflammation-based diseases. The present study was aimed toward investigating the effects of netrin-1 in an in vivo model of AP in mice. AP was induced in C57BL/6 mice by administration of two intraperitoneal injections of L-Arginine (4 g/kg). Mice were treated with recombinant mouse netrin-1 at a dose of 1 µg/mouse or vehicle (0.1% BSA) intravenously through the tail vein immediately after the second injection of L-Arginine, and every 24 h thereafter. Mice were sacrificed at several time intervals from 0 to 96 h after the induction of pancreatitis. Blood and tissue samples of pancreas and lung were collected and processed to determine the severity of pancreatitis biochemically and histologically. Immunohistochemical staining demonstrated that netrin-1 was mainly expressed in the islet cells of the normal pancreas and the AP model pancreas, and the pancreatic expression of netrin-1 was down-regulated at both the mRNA and protein levels during the course of AP. Exogenous netrin-1 administration significantly reduced plasma amylase levels, myeloperoxidase activity, pro-inflammatory cytokine production, and pancreas and lung tissue damages. Furthermore, netrin-1 administration did not cause significant inhibition of nuclear factor-kappa B activation in the pancreas of L-Arginine-induced AP. In conclusion, our novel data suggest that netrin-1 is capable of improving damage of pancreas and lung, and exerting anti-inflammatory effects in mice with severe acute pancreatitis. Thus, our results indicate that netrin-1 may constitute a novel target in the management of AP.

Highlights

  • Acute pancreatitis (AP) is an inflammatory condition with a clinical course that varies from mild to severe [1]

  • The exact mechanisms are for the most part unknown, there is some evidence that the severity and outcome of AP might be determined by the acinar cell response to activation of trypsinogen, as well as the events that occur subsequent to acinar cell injury, including activation of transcription factors such as nuclear factor-kappa B (NF-kB), recruitment of inflammatory cells, and generation of inflammatory mediators [1,5]

  • The results showed that both netrin-1 mRNA and protein were expressed in the pancreas of the normal group, and both significantly decreased at 24, 48, 72, and 96 h after the AP model was induced compared to the normal group (P,0.05, Figure 1A, 1B)

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Summary

Introduction

Acute pancreatitis (AP) is an inflammatory condition with a clinical course that varies from mild to severe [1]. The exact mechanisms are for the most part unknown, there is some evidence that the severity and outcome of AP might be determined by the acinar cell response to activation of trypsinogen, as well as the events that occur subsequent to acinar cell injury, including activation of transcription factors such as nuclear factor-kappa B (NF-kB), recruitment of inflammatory cells, and generation of inflammatory mediators [1,5]. In light of this knowledge, inhibition of the inflammatory pathway seems to be the most promising approach for preventing the development of the disease

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