Topical small molecule granzyme B inhibitor improves remodeling in a murine model of impaired burn wound healing
Files
(Published version)
Date
2018
Authors
Shen, Y.
Zeglinski, M.R.
Turner, C.T.
Raithatha, S.A.
Wu, Z.
Russo, V.
Oram, C.
Hiroyasu, S.
Nabai, L.
Zhao, H.
Editors
Advisors
Journal Title
Journal ISSN
Volume Title
Type:
Journal article
Citation
Experimental and Molecular Medicine, 2018; 50(5)
Statement of Responsibility
Conference Name
Abstract
Granzyme B (GzmB) is a serine protease that has long been thought to function exclusively in lymphocyte-mediated apoptosis. In recent years, this paradigm has been revisited due to the recognition that GzmB accumulates in the extracellular milieu in many autoimmune and chronic inflammatory disorders, and contributes to impaired tissue remodeling due to the cleavage of extracellular matrix proteins. Knockout studies suggest that GzmB-mediated cleavage of decorin (DCN) contributes to impaired collagen fibrillogenesis and remodeling. As DCN is anti-fibrotic and contributes to reduced hypertrophic scarring, GzmB-induced DCN cleavage could play a role in wound healing following burn injury. In the present study, a novel, gel-formulated, first-in-class small-molecule inhibitor of GzmB, VTI-1002, was assessed in a murine model of impaired, diabetic burn wound healing. VTI-1002 exhibited high specificity, potency, and target selectivity. Gel-formulated VTI-1002 was able to penetrate the stratum corneum and was retained in the skin with minimal systemic absorption. Daily topical administration of VTI-1002 gel for 30 days following thermal injury showed significantly accelerated wound closure, increased DCN protein levels, and collagen organization that was translated into significantly increased wound tensile strength compared to controls. Overall, VTI-1002 gel was well-tolerated in vivo and no adverse events were observed. Topical application of VTI-1002 represents a novel therapeutic approach for the treatment of cutaneous burn wounds.
School/Discipline
Dissertation Note
Provenance
Description
Access Status
Rights
Copyright 2018 the Authors. This article is licensed under. Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproductionin any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide. link to the Creative Commons license, and indicate ifchanges were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in. credit line to the material. Ifmaterial is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtainpermission directly from the copyright holder. (http://creativecommons.org/licenses/by/4.0/.)