Fentanyl alleviates intestinal mucosal barrier damage in rats with severe acute pancreatitis by inhibiting the MMP-9/FasL/Fas pathway

Abstract

Background

Fentanyl is an analgesic used against pancreatitis-related pain, while whether it ameliorates severe acute pancreatitis (SAP) has yet to be checked. This study aims to determine fentanyl-delivered effect on SAP and the mechanism underlying this effect.

Methods

Rat SAP models were established, following fentanyl treatment. The serum activity of amylase (AMY), lipase (LIP), and diamine oxidase (DAO) was detected by enzyme-linked immunosorbent assay (ELISA). Histological examination was performed in the pancreatic and intestinal tissues with hematoxylin-eosin staining. After transfection with matrix metalloproteinase (MMP) 9 overexpression plasmids, Caco-2 monolayers were treated with fentanyl and subsequently exposed to lipopolysaccharide (LPS). The transepithelial electrical resistance (TEER) value was determined in rat intestinal mucosa through an Ussing chamber assisted by Analyze & Acquire, and in Caco-2 cell monolayers through a voltohmmeter. Intestinal mucosa and paracellular permeabilities were determined by fluorescein isothiocyanate (FITC)-labeled dextran assay. The expressions of ZO-1, Occludin, MMP9, Fas and Fas ligand (FasL) in rat intestinal mucosa and/or Caco-2 monolayers were analyzed by qRT-PCR or/and western blot.

Results

Fentanyl alleviated SAP-related histological alterations in the pancreas and intestines, reduced the elevated levels of SAP-related AMY, LIP, and DAO, but promoted the levels of ZO-1 and Occludin. In SAP rats and Caco-2 monolayers, SAP-related or LPS-induced TEER value decreases, permeability increases, and increases in the expressions of MMP9, Fas, and FasL were reversed partly by fentanyl. Notably, MMP9 overexpression could reverse the above fentanyl-delivered in vitro effects.

Conclusions

Fentanyl alleviates intestinal mucosal barrier damage in rats with SAP by inhibiting the MMP9/FasL/Fas pathway.

Keywords:

• Fentanyl
• intestinal mucosal barrier damage
• severe acute pancreatitis
• MMP9
• the FasL/Fas pathway

Author contributions

Substantial contributions to conception and design: Yunchao Mo, Xiangdong Zhang

Data acquisition, data analysis and interpretation: Yongguang Lao, Bizhu Wang, Xinmei Li, Yuhong Zheng, Weihua Ding

Drafting the article or critically revising it for important intellectual content: Yunchao Mo, Xiangdong Zhang

Final approval of the version to be published: Yunchao Mo, Xiangdong Zhang, Yongguang Lao, Bizhu Wang, Xinmei Li, Yuhong Zheng, Weihua Ding

Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of the work are appropriately investigated and resolved: Yunchao Mo, Xiangdong Zhang, Yongguang Lao, Bizhu Wang, Xinmei Li, Yuhong Zheng, Weihua Ding.

Disclosure statement

No potential conflict of interest was reported by the author(s).