title: Inhibition of transforming growth factor beta decreases pancreatic fibrosis and protects the pancreas against chronic injury in mice.
abstract: Transforming growth factor-beta (TGF-beta) is an important cytokine in the fibrogenesis in many organs, including the pancreas. Using an adenoviral vector expressing the entire extracellular domain of type II human TGF-beta receptor (AdTbeta-ExR), we investigated whether inhibition of TGF-beta action is effective against persistent pancreatic fibrosis, and whether it exerts a beneficial effect on the pancreas in the process of chronic injury. To induce chronic pancreatic injury and pancreatic fibrosis, mice were subjected to three episodes of acute pancreatitis induced by six intraperitoneal injections of 50 microg/kg body weight cerulein at hourly intervals, per week for 3 consecutive weeks. Mice were infected once with AdTbeta-ExR, or with a control adenoviral vector expressing bacterial beta-galactosidase (AdLacZ). Pancreatic fibrosis was evaluated by histology and hydroxyproline content. Activation of pancreatic stellate cells (PSCs) was assessed by immunostaining for alpha-smooth muscle actin. Apoptosis and proliferation of acinar cells were assessed by immunostaining of ssDNA and Ki-67, respectively. Three-week cerulein injection induced pancreatic fibrosis and pancreatic atrophy with proliferation of activated PSCs. In AdTbeta-ExR-injected mice, but not AdLacZ-injected mice, pancreatic fibrosis was significantly attenuated. This finding was accompanied by a reduction of activated PSCs. AdTbeta-ExR, but not AdLacZ, significantly increased pancreas weight after chronic pancreatic injury. AdTbeta-ExR did not change the proportion of proliferating acinar cells, whereas it reduced the number of apoptotic acinar cells. Our results demonstrate that inhibition of TGF-beta action not only decreases pancreatic fibrosis but also protects the pancreas against chronic injury by preventing acinar cell apoptosis.
authors.affiliation: Third Department of Internal Medicine, University of Occupational and Environmental Health, Japan, School of Medicine, Kitakyushu, Japan.
authors.forename: Yoshikuni
authors.initials: Y
authors.lastname: Nagashio
authors.forename: Hikaru
authors.initials: H
authors.lastname: Ueno
authors.forename: Michio
authors.initials: M
authors.lastname: Imamura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Asaumi
authors.forename: Shiro
authors.initials: S
authors.lastname: Watanabe
authors.forename: Taizo
authors.initials: T
authors.lastname: Yamaguchi
authors.forename: Masashi
authors.initials: M
authors.lastname: Taguchi
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Tashiro
authors.forename: Makoto
authors.initials: M
authors.lastname: Otsuki
mesh_terms: D000818:Animals; D002108:Ceruletide; D002908:Chronic Disease; D004195:Disease Models, Animal; D005355:Fibrosis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D010182:Pancreatic Diseases / Q000139:chemically induced / Q000517:prevention & control*; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors*
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D002108:Ceruletide