title: Anti-scarring properties of different tryptophan derivatives.
abstract: Hypertrophic scars are associated with prolonged extracellular matrix (ECM) production, aberrant ECM degradation and high tissue cellularity. Routinely used antifibrotic strategies aim to reduce ECM deposition and enhance matrix remodeling. Our previous study investigating the antifibrotic effects of indoleamine2, 3 dioxygenase (IDO) led to the identification of kynurenine (Kyn) as an antiscarring agent. A topical antifibrogenic therapy using Kyn is very attractive; however, it is well established that Kyn passes the blood brain barrier (BBB) which causes complications including excitatory neuronal death. Here we investigated the antiscarring properties of kynurenic acid (KynA), a downstream end product of Kyn that is unlikely to pass the BBB, as an effective and safe replacement for Kyn. Our results indicated that while not having any adverse effect on dermal cell viability, KynA significantly increases the expression of matrix metalloproteinases (MMP1 and MMP3) and suppresses the production of type-I collagen and fibronectin by fibroblasts. Topical application of cream containing KynA in fibrotic rabbit ear significantly decreased scar elevation index (1.13±0.13 vs. 1.61±0.12) and tissue cellularity (221.38±21.7 vs. 314.56±8.66 cells/hpf) in KynA treated wounds compared to controls. KynA treated wounds exhibited lower levels of collagen deposition which is accompanied with a significant decrease in type-I collagen and fibronectin expression, as well as an increase in MMP1 expression compared to untreated wounds or wounds treated with cream only. The results of this study provided evidence for the first time that KynA is promising candidate antifibrogenic agent to improve healing outcome in patients at risk of hypertrophic scarring.
authors.affiliation: Division of plastic surgery, Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Malihe-Sadat
authors.initials: MS
authors.lastname: Poormasjedi-Meibod
authors.affiliation: Division of plastic surgery, Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Ryan
authors.initials: R
authors.lastname: Hartwell
authors.affiliation: Division of plastic surgery, Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Ruhangiz Taghi
authors.initials: RT
authors.lastname: Kilani
authors.affiliation: Division of plastic surgery, Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Aziz
authors.initials: A
authors.lastname: Ghahary
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D017439:Cicatrix, Hypertrophic / Q000188:drug therapy* / Q000235:genetics / Q000517:prevention & control; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007737:Kynurenine / Q000494:pharmacology; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000378:metabolism; D011817:Rabbits; D014364:Tryptophan / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology*; D014945:Wound Healing / Q000187:drug effects
chemical_list: D024042:Collagen Type I; D005353:Fibronectins; D007737:Kynurenine; D014364:Tryptophan; D019278:Matrix Metalloproteinase 3; D020781:Matrix Metalloproteinase 1