Activated protein C, an anticoagulant polypeptide, ameliorates severe acute pancreatitis via regulation of mitogen-activated protein kinases.

Abstract

BACKGROUND:

Our aim was to investigate the changes of mitogen-activated protein kinases (MAPKs) by activated protein C (APC) treatment in rats with severe acute pancreatitis (SAP), and relate them to changes in SAP severity, thus providing evidence for developing clinical therapies.

METHODS:

Sprague-Dawley rats were given an intravenous injection of saline (SAP group), APC (50 microg/kg or 10 microg/kg), or CNI1493 just before SAP induction. One group of rats underwent a sham operation (control group). Experimental samples were harvested 16 h after SAP induction. The gene expression of pancreatic MAPKs was evaluated by cDNA microarrays. The mRNA and protein/phosphorylated protein levels of p38 MAPK, extracellular signal-regulated protein kinase (ERK) 1/2, and c-Jun N-terminal kinase (JNK) and the protein levels of tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta were determined in pancreatic tissue. The severity of disease was evaluated by pancreatic histology, the pancreatic wet/dry weight ratio, and the serum amylase level.

RESULTS:

In rats treated with APC (50 microg/kg) or CNI1493, the severity of pancreatitis and expression of pancreatic TNF-alpha and IL-1beta proteins were attenuated by the decreased expression and activity of p38 MAPK and JNK (vs. the SAP group, P < 0.01). The expression and activity of ERK1/2 were increased in APC-treated rats, especially in the group treated with APC 50 microg/kg (vs. the SAP or CNI1493-treated group, P < 0.01, respectively).

CONCLUSIONS:

Inhibition of expression of pancreatic p38 MAPK and JNK and upregulation of ERK1/2 expression by APC treatment may protect against pancreatic injury, thus ameliorating severity of the disease.

• Authors: Ping Chen, Yongping Zhang, Minmin Qiao, Yaozong Yuan
• Journal: Journal of gastroenterology (J Gastroenterol) Vol. 42 Issue 11 Pg. 887-96 (Nov 2007) ISSN: 0944-1174 [Print] Japan
• PMID: 18008033 (Publication Type: Journal Article)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Anticoagulants
• Hydrazones
• Interleukin-1beta
• Protein C
• Proteins
• Tumor Necrosis Factor-alpha
• semapimod
• Mitogen-Activated Protein Kinases

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (administration & dosage, therapeutic use)
• Anticoagulants (administration & dosage, therapeutic use)
• Gene Expression Profiling
• Gene Expression Regulation
• Hydrazones (administration & dosage, therapeutic use)
• Interleukin-1beta (genetics, metabolism)
• Male
• Mitogen-Activated Protein Kinases (genetics, metabolism)
• Oligonucleotide Array Sequence Analysis (methods)
• Pancreas (pathology)
• Pancreatitis, Acute Necrotizing (drug therapy, physiopathology)
• Protein C (administration & dosage, therapeutic use)
• Proteins (genetics, metabolism)
• Rats
• Rats, Sprague-Dawley
• Signal Transduction
• Treatment Outcome
• Tumor Necrosis Factor-alpha (genetics, metabolism)