title: Pathobiological mechanisms of peritoneal adhesions: The mesenchymal transition of rat peritoneal mesothelial cells induced by TGF-β1 and IL-6 requires activation of Erk1/2 and Smad2 linker region phosphorylation.
abstract: Peritoneal adhesions, primarily caused by surgical procedures, are the leading cause of pelvic pain, bowel obstruction, and infertility. TGF-β1 and IL-6 have been found to be elevated in the peritoneal fluid of patients during/after abdominal surgery. However, it remains to be determined whether these cytokines interact and facilitate adhesion formation by promoting mesothelial to mesenchymal transition (MMT). In the present study, isolated rat peritoneal mesothelial cells were treated with TGF-β1 and/or IL-6 which elicited MMT as determined by morphologic and biochemical techniques. During this transition, cellular morphology changed from that of cobblestone polygonal cells to elongated/spindle-shaped fibroblast-like cells. There was decreased expression of genes characteristic of mesothelial cells, such as E-cadherin, and increased expression of genes characteristic of the myofibroblast phenotype, including α-smooth muscle actin and the EDA form of fibronectin, both of which appear to mediate the transfer of force to the extracellular matrix. Partial characterization of relevant signaling pathways identified Erk1/2 activation, which was enhanced by combined TGF-β1/IL-6 administration, as a crucial necessary factor in the transition. Erk1/2 activation as well as the phosphorylation of the linker region of Smad2 and MMT could be blocked by the MEK inhibitor, U0126, suggesting that such activation may be a potential pharmaceutical target to prevent MMT. In addition, the phenotypic transition could be prevented by hydrocortisone.
authors.affiliation: Joan and Joel Rosenbloom Research Center for Fibrotic Diseases, United States; Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA 19107, United States.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Jin
authors.affiliation: Joan and Joel Rosenbloom Research Center for Fibrotic Diseases, United States; Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA 19107, United States.
authors.forename: Shumei
authors.initials: S
authors.lastname: Ren
authors.affiliation: Joan and Joel Rosenbloom Research Center for Fibrotic Diseases, United States; Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA 19107, United States.
authors.forename: Edward
authors.initials: E
authors.lastname: Macarak
authors.affiliation: Joan and Joel Rosenbloom Research Center for Fibrotic Diseases, United States; Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA 19107, United States. Electronic address: Joel.Rosenbloom@jefferson.edu.
authors.forename: Joel
authors.initials: J
authors.lastname: Rosenbloom
mesh_terms: D000818:Animals; D001202:Ascitic Fluid / Q000378:metabolism / Q000473:pathology; D002070:Butadienes / Q000008:administration & dosage; D015820:Cadherins / Q000096:biosynthesis; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005353:Fibronectins / Q000096:biosynthesis; D006801:Humans; D015850:Interleukin-6 / Q000008:administration & dosage* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000235:genetics; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology; D009570:Nitriles / Q000008:administration & dosage; D010537:Peritoneum / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D051381:Rats; D051899:Smad2 Protein / Q000096:biosynthesis; D053773:Transforming Growth Factor beta1 / Q000008:administration & dosage* / Q000378:metabolism
chemical_list: D002070:Butadienes; D015820:Cadherins; D005353:Fibronectins; D015850:Interleukin-6; D009570:Nitriles; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D053773:Transforming Growth Factor beta1; C113580:U 0126; C000593306:fibronectinEDA, human
keywords: Erk1/2; IL-6; MEK inhibitor; Mesothelial/mesenchymal transition; Peritoneal adhesions; TGF-β