title: Kynurenine Modulates MMP-1 and Type-I Collagen Expression Via Aryl Hydrocarbon Receptor Activation in Dermal Fibroblasts.
abstract: Dermal fibrosis is characterized by a high deposition of extracellular matrix (ECM) and tissue cellularity. Unfortunately all means of treating this condition are unsatisfactory. We have previously reported the anti-fibrotic effects of Kynurenine (Kyn), a tryptophan metabolite, in fibrotic rabbit ear model. Here, we report the mechanism by which Kyn modulates the expression of key ECM components in dermal fibroblasts. The results showed that Kyn activates aryl hydrocarbon receptor (AHR) nuclear translocation and up-regulates cytochrome-P450 (CYP1A-1) expression, the AHR target gene. A specific AHR antagonist, 6,2',4'-trimethoxyflavone, inhibited the Kyn-dependent modulation of CYP1A-1, MMP-1, and type-I collagen expression. Establishing the anti-fibrogenic effect of Kyn and its mechanism of action, we then developed nano-fibrous Kyn slow-releasing dressings and examined their anti-fibrotic efficacy in vitro and in a rat model. Our results showed the feasibility of incorporating Kyn into PVA/PLGA nanofibers, prolonging the Kyn release up to 4 days tested. Application of medicated-dressings significantly improved the dermal fibrosis indicated by MMP-1 induction, alpha-smooth muscle actin and type-I collagen suppression, and reduced tissue cellularity, T-cells and myofibroblasts. This study clarifies the mechanism by which Kyn modulates ECM expression and reports the development of a new slow-releasing anti-fibrogenic dressing. J. Cell. Physiol. 231: 2749-2760, 2016. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Malihe-Sadat
authors.initials: MS
authors.lastname: Poormasjedi-Meibod
authors.affiliation: Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Sanam
authors.initials: S
authors.lastname: Salimi Elizei
authors.affiliation: Department of Materials Engineering, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Victor
authors.initials: V
authors.lastname: Leung
authors.affiliation: Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Reza
authors.initials: R
authors.lastname: Baradar Jalili
authors.affiliation: Department of Materials Engineering, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Frank
authors.initials: F
authors.lastname: Ko
authors.affiliation: Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Aziz
authors.initials: A
authors.lastname: Ghahary
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001458:Bandages; D001672:Biocompatible Materials / Q000494:pharmacology; D024042:Collagen Type I / Q000378:metabolism*; D020405:Dermis / Q000166:cytology*; D065546:Drug Liberation; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D047309:Flavones / Q000494:pharmacology; D006801:Humans; D007737:Kynurenine / Q000494:pharmacology*; D019344:Lactic Acid / Q000737:chemistry; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D058628:Myofibroblasts / Q000187:drug effects / Q000473:pathology; D057139:Nanofibers / Q000648:ultrastructure; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011142:Polyvinyl Alcohol / Q000737:chemistry; D020318:Rats, Long-Evans; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D014945:Wound Healing / Q000187:drug effects
chemical_list: C546607:6,2',4'-trimethoxyflavone; C541116:ACTA2 protein, human; D000199:Actins; D001672:Biocompatible Materials; D024042:Collagen Type I; D047309:Flavones; D018336:Receptors, Aryl Hydrocarbon; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D007737:Kynurenine; D011142:Polyvinyl Alcohol; D020781:Matrix Metalloproteinase 1