The role of neutral endopeptidase in caerulein-induced acute pancreatitis.

Abstract

Substance P (SP) is well known to promote inflammation in acute pancreatitis (AP) by interacting with neurokinin-1 receptor. However, mechanisms that terminate SP-mediated responses are unclear. Neutral endopeptidase (NEP) is a cell-surface enzyme that degrades SP in the extracellular fluid. In this study, we examined the expression and the role of NEP in caerulein-induced AP. Male BALB/c mice (20-25 g) subjected to 3-10 hourly injections of caerulein (50 μg/kg) exhibited reduced NEP activity and protein expression in the pancreas and lungs. Additionally, caerulein (10(-7) M) also downregulated NEP activity and mRNA expression in isolated pancreatic acinar cells. The role of NEP in AP was examined in two opposite ways: inhibition of NEP (phosphoramidon [5 mg/kg] or thiorphan [10 mg/kg]) followed by 6 hourly caerulein injections) or supplementation with exogenous NEP (10 hourly caerulein injections, treatment of recombinant mouse NEP [1 mg/kg] during second caerulein injection). Inhibition of NEP raised SP levels and exacerbated inflammatory conditions in mice. Meanwhile, the severity of AP, determined by histological examination, tissue water content, myeloperoxidase activity, and plasma amylase activity, was markedly better in mice that received exogenous NEP treatment. Our results suggest that NEP is anti-inflammatory in caerulein-induced AP. Acute inhibition of NEP contributes to increased SP levels in caerulein-induced AP, which leads to augmented inflammatory responses in the pancreas and associated lung injury.

• Authors: Yung-Hua Koh, Shabbir Moochhala, Madhav Bhatia
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 187 Issue 10 Pg. 5429-39 (Nov 15 2011) ISSN: 1550-6606 [Electronic] United States
• PMID: 22013111 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Glycopeptides
• RNA, Messenger
• Recombinant Proteins
• Ceruletide
• Thiorphan
• Neprilysin
• phosphoramidon

Topics

• Acinar Cells (drug effects, enzymology, pathology)
• Animals
• Ceruletide (toxicity)
• Glycopeptides (toxicity)
• Lung (drug effects, enzymology, pathology)
• Male
• Mice
• Mice, Inbred BALB C
• Neprilysin (antagonists & inhibitors, biosynthesis, physiology)
• Pancreatitis, Acute Necrotizing (chemically induced, enzymology, pathology)
• RNA, Messenger (antagonists & inhibitors, biosynthesis)
• Random Allocation
• Recombinant Proteins (administration & dosage, antagonists & inhibitors, biosynthesis)
• Severity of Illness Index
• Thiorphan (toxicity)