Elsevier

Life Sciences

Volume 202, 1 June 2018, Pages 167-174
Life Sciences

Adenovirus-mediated overexpression of sST2 attenuates cardiac injury in the rat with severe acute pancreatitis

https://doi.org/10.1016/j.lfs.2018.04.008Get rights and content

Abstract

Aims

Severe acute pancreatitis (SAP) is a serious disease associated with systematic inflammation and multiple organs dysfunction. Soluble ST2 (sST2), a member of the Toll interleukin (IL)-1 receptor (TIR) superfamily, has been demonstrated to exert immune-regulatory and anti-inflammatory properties in several inflammation-related diseases. In this study, we investigated whether transfer of sST2 gene by adenovirus vector could attenuate sodium taurocholate-induced SAP and associated cardiac injury.

Main methods

A rat model of SAP was induced by retrograde injection of 5% sodium taurocholate (1 ml/kg) into the biliopancreatic duct. Rats in the treatment groups were intravenously injected with adenovirus expressing sST2 (Ad-sST2, 1 × 109 particles/rat) or green fluorescent protein (Ad-GFP) via the tail vein 48 h before SAP induction. Histological changes in the pancreatic and heart tissues, and parameters for evaluating SAP and associated cardiac injury were determined at 24 h after SAP.

Key findings

Sodium taurocholate induced obvious pathological changes in pancreas and elevated serum levels of amylase and lipase. Furthermore, SAP animals exhibited significant cardiac impairment, evidenced by decreased cardiac function, increased myocardial apoptosis and cardiac-related enzymes including creatine kinase isoenzyme, lactate dehydrogenase, and Troponin T. Administration of Ad-sST2 markedly improved the structure of pancreas and heart tissues, and reversed the alterations in serum amylase, lipase and cardiac-related enzymes. In addition, Ad-sST2 treatment downregulated pro-inflammatory cytokines production, demonstrating the anti-inflammatory property of sST2.

Significance

Our results suggest that administration of Ad-sST2 significantly attenuated the severity of SAP and associated cardiac damage, and the cardioprotective effect is associated with its anti-inflammatory action.

Introduction

Acute pancreatitis (AP) is a common clinical condition with acute onset and considerable mortality rate [1]. It is an acute inflammatory disease that usually initiates at local pancreatic parenchyma then quickly progresses and trigger to systemic inflammatory response syndrome, which in turn may result in multiple organ dysfunctions syndrome [2]. Prognosis of each patient is dependent on the severity of AP, and the most severe form (SAP) is usually complicated with multiple organ injury with a mortality rate ranging from 15 to 30% [3]. Current studies have shown that pro-inflammatory cytokines play a pivotal role in SAP related complications by driving the subsequently inflammatory response [4,5]. Therefore, a better understanding of regulatory inflammatory pathways in SAP is necessary and helpful for discovery of new therapeutic targets.

ST2 is a member of the IL-1 receptor (IL-1R) family, it primarily has two isoforms: the transmembrane form ST2L and the soluble form sST2, which are regulated by different promoters of the ST2 gene [6,7]. ST2L is a membrane-bound isoform contains three domains including the extracellular domains, an intracellular signal domain and a transmembrane domain [8], whereas the sST2 only contains extracellular domains and a unique nine amino acid C-terminal sequence [9,10], and it acts as a decoy receptor of interleukin (IL)-33. Increasing evidence has shown that sST2 levels are elevated in numerous disease states, such as sepsis and trauma [11], LPS-induced lung acute inflammation, hepatic ischaemia/reperfusion injury [12], and myocardial infarction [13], demonstrating a regulatory role of ST2 in immune and inflammatory disorders. Moreover, researchers have demonstrated that sST2 treatment has an anti-inflammatory effect in several experimental models. For example, Yin et al. showed that administration of recombinant sST2-Fc fusion protein attenuated inflammation induced by hepatic ischaemia/reperfusion [12], and Sweet et al. demonstrated that treatment with sST2 suppressed IL-6, IL-12, and TNF-α production in lipopolysaccharide-induced shock model [14]. More recently, Ouziel et al. [15] also revealed that sST2 was upregulated in the early course of acute pancreatitis (AP), and ST2-deficient mice developed more severe pancreatitis, which suggested that sST2 may participate in the regulation of inflammatory storm during SAP, and then protect against SAP-evoked multiple organ dysfunction. Therefore, the present study aimed to investigate the effect of sST2 overexpression on the severity of SAP and associated cardiac injury. Our results demonstrated that adenovirus (Ad)-mediated sST2 overexpression attenuated the severity of SAP and improved cardiac function and morphology, and the beneficial effect of sST2 is associated with its anti-inflammatory action. Therefore, sST2 may provide a therapeutic potential in severe acute pancreatitis and associated complications.

Section snippets

Animals

Twenty-four Sprague-Dawley rats (male, weighting 200–250 g) were used in our study. Before experiment, animals were acclimatized for 1 week and housed under standard conditions with free access to food and water. All procedures were conducted according to the National Institutes of Health guidelines for the care and use of laboratory animals and approved by the Institutional Animal Care and Use Committee of Dalian Medical University.

Construction of adenovirus vectors

The adenovirus expressing sST2 (Ad-sST2) was constructed by

sST2 protected against sodium taurocholate-induced SAP

We first evaluated the effect of sST2 on sodium taurocholate-induced SAP. A rat model of SAP model was established by retrograde injection of sodium taurocholate into the biliopancreatic duct. Histological changes in pancreatic tissues and alterations in serum lipase and amaylase, as well as pancreatic TNF-α expression were determined by H&E staining and biochemical analyses. As shown in Fig. 1A–B, the sham group exhibited normal intact gland structure of the pancreas. In contrast, pancreatic

Discussion

SAP is a fatal clinical condition, characterized by rapid progression, high mortality, and usually complicated with multiple organ injury [25]. Current studies have shown that inflammatory reaction induced by various inflammatory mediators plays an important role in SAP evoked multiple organ damage [26,27]. Therefore, an attempt to modify the excessive inflammatory response has been considered as one effective therapeutic target. In the present study, we investigated the potential role of sST2

Acknowledgments

This study was supported by a grant from the National Natural Science Foundation of China (No. 81573751).

Conflict of interest

The authors declare that there is no conflict of interest relevant to the publication of this paper.

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