title: Ghrelin Inhibits Post-Operative Adhesions via Blockage of the TGF-β Signaling Pathway.
abstract: Post-operative adhesions are a critical problem in pelvic and abdominal surgery despite a multitude of studies dedicated to finding modalities to prevent their occurrence. Ghrelin administration promotes an anti-fibrotic response in a surgical mouse model of adhesion-induction, but the mechanisms mediating this effect have not been established. In the current study, the molecular mechanisms that underlie the anti-adhesion effect of ghrelin were investigated. Post-surgical adhesions were experimentally created in C57BL/6 wild-type mice via a combination of ischemic peritoneal buttons and cecal multiple abrasions. Ghrelin or saline intraperitoneal injections were given twice daily from two days before surgery to selected time points post-surgically to assess the phenotypic and molecular effects of treatment (1 day (n = 20), 4 days (n = 20) and 20 days (n = 40) after surgery). Endpoints included the scoring of adhesions and gene and protein expression analysis of pro-fibrogenic factors conducted on peritoneal ischemic tissue by quantitative PCR and Western blot. Ghrelin administration significantly reduced post-surgical adhesions and down-regulated pro-inflammatory gene and protein expression, including Tgfb3 and Tgfbr2. The up-regulation of inhibitory proteins Smad6 and Smad7 confirmed the ghrelin-induced blockage of TGF-β signaling. Ghrelin is a candidate therapeutic drug for post-operative adhesion prevention, inhibiting inflammatory responses via blockage of the TGF-β signaling pathway at the onset of surgery before the occurrence of the granulation-remodeling phase.
authors.affiliation: Division of Urology, Brown University, Providence, Rhode Island, United States of America.|Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island, United States of America.
authors.forename: Enrica
authors.initials: E
authors.lastname: Bianchi
authors.affiliation: Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island, United States of America.
authors.forename: Kim
authors.initials: K
authors.lastname: Boekelheide
authors.affiliation: Division of Urology, Brown University, Providence, Rhode Island, United States of America.|Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island, United States of America.
authors.forename: Mark
authors.initials: M
authors.lastname: Sigman
authors.affiliation: Center for Reproductive Medicine, Scott Department of Urology, Department of Molecular and Cellular Biology Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Dolores J
authors.initials: DJ
authors.lastname: Lamb
authors.affiliation: Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island, United States of America.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Hall
authors.affiliation: Division of Urology, Brown University, Providence, Rhode Island, United States of America.|Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island, United States of America.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Hwang
mesh_terms: D000818:Animals; D001835:Body Weight; D002454:Cell Differentiation; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D054439:Ghrelin / Q000737:chemistry*; D007249:Inflammation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction; D051905:Smad6 Protein / Q000378:metabolism; D051906:Smad7 Protein / Q000378:metabolism; D000267:Tissue Adhesions / Q000517:prevention & control*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D053782:Transforming Growth Factor beta3 / Q000378:metabolism
chemical_list: D054439:Ghrelin; D018125:Receptors, Transforming Growth Factor beta; D051905:Smad6 Protein; C497803:Smad6 protein, mouse; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; C509045:Tgfb3 protein, mouse; D016212:Transforming Growth Factor beta; D053782:Transforming Growth Factor beta3; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II