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Pirfenidone Ointment Modulates the Burn Wound Bed in C57BL/6 Mice by Suppressing Inflammatory Responses

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Abstract

An inflammatory response is the normal response to a burn-induced injury. The burn-associated inflammation can lead to further tissue damage as the tissue tries to repair the damage. Prolonged or excessive inflammation is associated with increased fibrosis of burn wounds and the development of hypertrophic scars. The high incidence of hypertrophic scar formation is one of the many challenges to treating deep partial-thickness burns. Prophylactic treatment to improve burn-induced hypertrophic scarring is lacking. For this reason, we evaluated prophylactic treatment of deep partial-thickness burns with pirfenidone in C57BL/6 mice. Pirfenidone is an FDA-approved anti-fibrotic drug for systemic use in the treatment of idiopathic lung fibrosis and other fibrotic disorders. Additionally, pirfenidone has anti-inflammatory activity. We tested treatment efficacy of pirfenidone using a mouse model of deep partial-thickness burns. Inflammatory cytokines including IL-1β, IL-2, IL-6, IL-13, G-CSF, and MIP-1α, along with neutrophil infiltration, were significantly reduced in wounds when mice were treated during the inflammatory phase of burn wound healing. Additionally, pirfenidone significantly reduced expression of αSMA 12 days after the induction of burns and modestly reduced hydroxyproline in 22-day-old burn wounds. Results show that pirfenidone treatment modulated the inflammatory response of the burn wound. The findings in this study indicate that further examination is required to validate the use of pirfenidone for prophylactic treatment to improve long-term outcomes of scarring and contracture in deep partial-thickness burn wounds.

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Funding

This research was supported in part by an appointment to the Postgraduate Research Participation Program at the US Army Institute of Surgical Research administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and USAMRMC. This work is funded in part through the Congressionally Directed Medical Research Programs, US Army Medical Research and Materiel Command W81XWH-15-2-0083, and the Naval Medical Research Center’s Advanced Medical Development program MIPR N3239815MHX040.

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Authors and Affiliations

  1. Dental and Craniofacial Trauma Research and Tissue Regeneration Directorate, United States Army Institute of Surgical Research, 3650 Chambers Pass, STE B, JBSA Fort Sam Houston, San Antonio, TX, 78234, USA

    Jorge L. Medina, Eliza A. Sebastian, Andrea B. Fourcaudot & Kai P. Leung

  2. Department of Drug Sciences, University of Pavia, V.le Taramelli 12, 27100, Pavia, Italy

    Rossella Dorati

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  1. Jorge L. Medina
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  2. Eliza A. Sebastian
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Correspondence to Kai P. Leung.

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Research was conducted in compliance with the Animal Welfare Act, the implementing Animal Welfare Regulations, and the principles of the Guide for the Care and Use of Laboratory Animals, National Research Council. The facility Institutional Animal Care and Use Committee approved all research conducted in this study. The facility where this research was conducted is fully accredited by AAALAC International.

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The opinions or assertions contained herein are the private views of the author and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense.

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Medina, J.L., Sebastian, E.A., Fourcaudot, A.B. et al. Pirfenidone Ointment Modulates the Burn Wound Bed in C57BL/6 Mice by Suppressing Inflammatory Responses. Inflammation 42, 45–53 (2019). https://doi.org/10.1007/s10753-018-0871-y

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