title: Thiazolidinedione derivatives as novel therapeutic agents to prevent the development of chronic pancreatitis.
abstract: BACKGROUND
  Thiazolidinedione derivatives are known to be novel insulin-sensitizing agents and ligands of a nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARgamma). Recently, ligands of PPARgamma have been shown to modulate proinflammatory cytokine production and NF-kappaB activation.
  
  
  OBJECTIVE
  To show that thiazolidinedione derivatives interfere with the development of chronic pancreatitis.
  
  
  METHODS
  Rat chow containing 0.2% troglitazone was administered from 1 month to 7 months of age in WBN/Kob rats with spontaneous chronic pancreatitis. Morphologic evaluation of the pancreas was performed at 4 months and 7 months of age. Pancreas weight, protein, amylase, and insulin contents also were determined. Changes of cytokine levels were detected by enzyme-linked immunosorbent assay or semiquantitative reverse transcription-polymerase chain reaction. Localization and expression of PPARgamma in the pancreas and isolated peritoneal macrophages were examined by immunohistochemical study.
  
  
  RESULTS
  Administration of troglitazone reduced the severity of morphologic pancreatic damage including inflammatory cell infiltration, and fibrosis markedly improved by the administration of troglitazone. Further, troglitazone was able to prevent the decrease in amylase content and pancreas atrophy that were observed in WBN/Kob rats. Serum IL-8 levels and TNF-alpha mRNA levels in the pancreas were significantly elevated in WBN/Kob rats, and these were dramatically attenuated by troglitazone. Peritoneal macrophages isolated from normal rats expressed PPARgamma at low levels, whereas those from WBN/Kob rat abundantly expressed PPARgamma.
  
  
  CONCLUSIONS
  Troglitazone prevented the progression of pancreatic inflammatory process in an animal model of chronic pancreatitis. Macrophages may be one of the targets of the PPARgamma ligand to attenuate the severity of chronic pancreatitis, partially mediated by the inhibition of proinflammatory cytokine gene expression.
authors.affiliation: Department of Clinical Laboratory and Gastroenterology, School of Medicine, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan. kyoko-s@ka2.so-net.ne.jp
authors.forename: Kyoko
authors.initials: K
authors.lastname: Shimizu
authors.forename: Keiko
authors.initials: K
authors.lastname: Shiratori
authors.forename: Naoaki
authors.initials: N
authors.lastname: Hayashi
authors.forename: Makio
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Fujiwara
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Horikoshi
mesh_terms: D000681:Amylases / Q000032:analysis; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001786:Blood Glucose; D002839:Chromans / Q000494:pharmacology; D002908:Chronic Disease; D004247:DNA / Q000032:analysis; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000032:analysis / Q000097:blood; D016209:Interleukin-8 / Q000097:blood / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000737:chemistry; D008297:Male; D009929:Organ Size; D010195:Pancreatitis / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control*; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000032:analysis; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000032:analysis; D000077288:Troglitazone; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D001786:Blood Glucose; D002839:Chromans; D007004:Hypoglycemic Agents; D007328:Insulin; D016209:Interleukin-8; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D004247:DNA; C089946:2,4-thiazolidinedione; D000681:Amylases; D000077288:Troglitazone