IS-741 attenuates local migration of monocytes and subsequent pancreatic fibrosis in experimental chronic pancreatitis induced by dibutyltin dichloride in rats.
OBJECTIVE
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.
Kaku
Toyoma
T
Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Oono
Takamasa
T
Zhao
Haifeng
H
Gibo
Junya
J
Kawabe
Ken
K
Ito
Tetsuhide
T
Takayanagi
Ryoichi
R
D000199:Actins / Q000235:genetics; D000681:Amylases / Q000378:metabolism; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D017931:DNA Primers; D004261:DNA Replication; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005355:Fibrosis / Q000517:prevention & control; D008297:Male; D009000:Monocytes / Q000187:drug effects / Q000502:physiology*; D009947:Organotin Compounds; D010179:Pancreas / Q000187:drug effects / Q000473:pathology*; D050500:Pancreatitis, Chronic / Q000139:chemically induced* / Q000188:drug therapy* / Q000201:enzymology; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D016133:Polymerase Chain Reaction; D011725:Pyridines / Q000627:therapeutic use*; D051381:Rats; D011917:Rats, Inbred Lew
D000199:Actins; D000681:Amylases; D017931:DNA Primers; D004791:Enzyme Inhibitors; D009947:Organotin Compounds; D010741:Phospholipases A; D011725:Pyridines; C498862:Acta2 protein, rat; C097462:IS 741; C020735:dibutyldichlorotin