title: Cerulein-induced pancreatic fibrosis is modulated by Smad7, the major negative regulator of transforming growth factor-β signaling.
abstract: Chronic pancreatitis is the most common disease of the exocrine pancreas, characterized by progressive inflammation, acinar atrophy and fibrosis. Transforming growth factor-β signaling (TGFβ) is the most potent fibrogenic cytokine known, and its increased expression is a common denominator for fibrosis in chronic pancreatitis. Smad7 is induced by the TGFβ superfamily members as an intracellular inhibitory feedback antagonizing TGFβ signaling. To investigate the functional role of Smad7 in vivo, we induced chronic pancreatitis by repeated administration of cerulein in mice that are deficient in exon-I of Smad7. The response to chronic pancreatitis induction was significantly more severe in Smad7 mutant mice as indicated by a stronger accumulation of extracellular matrix, increased levels of inflammatory cells and an elevated number of mesenchymal cells/myofibroblasts in Smad7 mutant pancreata. Taken together, we conclude that lack of a functional Smad7 gene results in more severe damage in chronic pancreatitis. Therefore, Smad7 could be envisaged as a promising target in antifibrotic therapy of the pancreas.
authors.affiliation: Center for Digestive Diseases, Karolinska University Hospital, Stockholm, Sweden; Division of Surgery, CLINTEC, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Xuan
authors.initials: X
authors.lastname: Li
authors.affiliation: Center for Digestive Diseases, Karolinska University Hospital, Stockholm, Sweden; Division of Surgery, CLINTEC, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Nania
authors.affiliation: Center for Digestive Diseases, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Nino
authors.initials: N
authors.lastname: Fejzibegovic
authors.affiliation: Department of Laboratory Medicine (LABMED), Division of Pathology, Karolinska Universitetssjukhuset, Stockholm, Sweden.
authors.forename: Carlos Fernández
authors.initials: CF
authors.lastname: Moro
authors.affiliation: Division of Surgery, CLINTEC, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Lena
authors.initials: L
authors.lastname: Klopp-Schulze
authors.affiliation: Department of Pathology, Institute of Clinical Medicine, University of Oslo, 0316 Oslo, Norway.
authors.forename: Caroline
authors.initials: C
authors.lastname: Verbeke
authors.affiliation: Center for Digestive Diseases, Karolinska University Hospital, Stockholm, Sweden; Division of Surgery, CLINTEC, Karolinska Institutet, Stockholm, Sweden.
authors.forename: J-Matthias
authors.initials: JM
authors.lastname: Löhr
authors.affiliation: Center for Digestive Diseases, Karolinska University Hospital, Stockholm, Sweden; Division of Surgery, CLINTEC, Karolinska Institutet, Stockholm, Sweden. Electronic address: rainer.heuchel@ki.se.
authors.forename: Rainer L
authors.initials: RL
authors.lastname: Heuchel
mesh_terms: D000818:Animals; D002108:Ceruletide / Q000633:toxicity*; D005091:Exons; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D005260:Female; D005355:Fibrosis; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D058628:Myofibroblasts / Q000473:pathology; D010179:Pancreas / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D050500:Pancreatitis, Chronic / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D051906:Smad7 Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D016212:Transforming Growth Factor beta; D002108:Ceruletide
keywords: Chronic pancreatitis; Fibrosis; Smad7; TGFβ