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Protective Mechanism of MIF Inhibitor ISO-1 on Intrahepatic Bile Duct Cells in Rats with Severe Acute Pancreatitis

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Abstract

Aims

This study aimed to explore the protection mechanism of ISO-1 on severe acute pancreatitis-associated intrahepatic bile duct (IBD) injury in rats.

Methods

Forty-eight specific-pathogen-free male Wistar rats were randomly divided into four groups (N = 12): a sham operation group (SO group), a severe acute pancreatitis model group (SAP group), a ISO-1 treatment group (ISO-1 + SAP group), and a ISO-1 control group (ISO-1 + SO group). All rats were killed after 12 h of being made models. Immunohistochemistry was used to detect the expression of MIF and P38 in IBD cells. MIF mRNA expression in IBD cells was observed using real-time fluorescent quantitative polymerase chain reaction (real-time PCR). In addition, Western blotting was performed to detect the protein expression of P38, phosphorylated P38 (P-P38), nuclear factor-κB (NF-κB p65), and tumor necrosis factor alpha (TNF-α). Enzyme-linked immunosorbent assays were used to analyze the levels of TNF-α, IL-1β, and IL-6 in the IBD of rats.

Results

Compared with SAP, after treatment with ISO-1, the pathological injuries of pancreas, liver, and IBD cells in ISO-1 treatment group remarkably relieved. The expression of MIF in the IBD cells was significantly downregulated both at mRNA and at protein levels in ISO-1 treatment group. Besides, the protein expression levels of P38, P-P38, NF-κBp65, TNF-α, IL-1β, and IL-6 in the IBD in rats were also significantly decreased in ISO-1 treatment group (all P < 0.05).

Conclusion

ISO-1 may protect the IBD cells, reduce pathological injuries, and reduce the inflammatory response in SAP rats. Its mechanisms may be via inhibiting the expression of MIF and then blocking the activation of p38-MAPK and NF-κB signaling pathway.

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Abbreviations

MIF:

Macrophage migration inhibitory factor

ISO-1:

A specific small molecule inhibitor of MIF

SAP:

Severe acute pancreatitis

AP:

Acute pancreatitis

IBD:

Intrahepatic bile duct

SPF:

Specific-pathogen-free

SO:

Sham operation

NF-κB:

Nuclear factor-κB

TNF:

Tumor necrosis factor

ELISA:

Enzyme-linked immunosorbent assays

IL:

Interleukin

MODS:

Multiple organ dysfunction syndrome

MOF:

Multiple organ failure

SIRS:

Systemic inflammatory response syndrome

ARDS:

Acute respiratory distress syndrome

AP:

Acute pancreatitis

MAPK:

Mitogen-activated protein kinase

ICAM:

Intercellular adhesion molecule

VCAM:

Vascular cell adhesion protein

MCP:

Monocyte chemoattractant protein

HRP:

Horseradish peroxidase

H&E:

Hematoxylin and eosin

PBS:

Phosphate-buffered saline

IOD:

Integral optical density

SEM:

Standard error of the mean

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Authors and Affiliations

  1. Hubei Key Laboratory of Digestive System Disease, Department of Hepatobiliary Surgery, Renminbi Hospital of Wuhan University, Wuhan, 430060, Hubei Province, China

    Bin Wang, Kailiang Zhao, Youming Ding & Weixing Wang

  2. Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, China

    Wenjuan Hu

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  1. Bin Wang
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  2. Kailiang Zhao
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  3. Wenjuan Hu
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  4. Youming Ding
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  5. Weixing Wang
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Correspondence to Bin Wang.

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Wang, B., Zhao, K., Hu, W. et al. Protective Mechanism of MIF Inhibitor ISO-1 on Intrahepatic Bile Duct Cells in Rats with Severe Acute Pancreatitis. Dig Dis Sci 66, 3415–3426 (2021). https://doi.org/10.1007/s10620-020-06674-9

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