title: IS-741 attenuates local migration of monocytes and subsequent pancreatic fibrosis in experimental chronic pancreatitis induced by dibutyltin dichloride in rats.
abstract: 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.
authors.affiliation: Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Toyoma
authors.initials: T
authors.lastname: Kaku
authors.forename: Takamasa
authors.initials: T
authors.lastname: Oono
authors.forename: Haifeng
authors.initials: H
authors.lastname: Zhao
authors.forename: Junya
authors.initials: J
authors.lastname: Gibo
authors.forename: Ken
authors.initials: K
authors.lastname: Kawabe
authors.forename: Tetsuhide
authors.initials: T
authors.lastname: Ito
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Takayanagi
mesh_terms: 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
chemical_list: 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