IS-741 attenuates local migration of monocytes and subsequent pancreatic fibrosis in experimental chronic pancreatitis induced by dibutyltin dichloride in rats.

Abstract

OBJECTIVES:

Chronic pancreatitis consists of excessive leukocyte infiltration and fibrosis. IS-741 has been reported to be an antiinflammatory drug through an inhibitory action on cell adhesion. In this study, we investigated whether IS-741 could inhibit the progression of pancreatic fibrosis through monocyte infiltration. Moreover, we investigated the effect of IS-741 on rat pancreatic stellate cells (PSCs).

METHODS:

Chronic pancreatitis was induced by dibutyltin dichloride in rats. From days 7 to 28 after dibutyltin dichloride application, IS-741 or distilled water was administered. At days 14 and 28, histological [hematoxylin-eosin stain and immunostain for ED1 and [alpha] smooth muscle actin (alpha-SMA)] and biochemical evaluations (intrapancreatic amylase, protein, cytokines, chemokines, and alpha-SMA) were performed. In vitro, rat PSCs were incubated with cytokine, chemokine, and growth factor simultaneously with IS-741, and their proliferation and activation were examined.

RESULTS:

Histologically, IS-741 inhibited pancreatic fibrosis and decreased the number of ED1- and [alpha]-SMA-positive cells. The intrapancreatic expression of cytokines, chemokine, and [alpha]-SMA were also decreased. In vitro, IS-741 has no direct effect on the proliferation, alpha-SMA expression, and collagen synthesis of PSCs.

CONCLUSIONS:

These results suggest that IS-741 suppressed macrophage infiltration and subsequent pancreatic fibrosis and that the infiltration of monocytes into pancreas is essential for pancreatic fibrosis.

• Authors: Toyoma Kaku, Takamasa Oono, Haifeng Zhao, Junya Gibo, Ken Kawabe, Tetsuhide Ito, Ryoichi Takayanagi
• Journal: Pancreas (Pancreas) Vol. 34 Issue 3 Pg. 299-309 (Apr 2007) ISSN: 1536-4828 [Electronic] United States
• PMID: 17414052 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Actins
• DNA Primers
• Enzyme Inhibitors
• Organotin Compounds
• Pyridines
• smooth muscle actin, rat
• IS 741
• Phospholipases A
• Amylases
• dibutyldichlorotin

Topics

• Actins (genetics)
• Amylases (metabolism)
• Animals
• Cell Movement (drug effects)
• DNA Primers
• DNA Replication
• Disease Models, Animal
• Enzyme Inhibitors (therapeutic use)
• Fibrosis (prevention & control)
• Male
• Monocytes (drug effects, physiology)
• Organotin Compounds
• Pancreas (drug effects, pathology)
• Pancreatitis, Chronic (chemically induced, drug therapy, enzymology)
• Phospholipases A (antagonists & inhibitors)
• Polymerase Chain Reaction
• Pyridines (therapeutic use)
• Rats
• Rats, Inbred Lew