Inhibition of the Mineralocorticoid Receptor Improves Resolution of Burn Scars
Fuat Baris Bengur, MD; Shawn J. Loder, MD; David Guerrero, BS; Thomas Mitts, MD; Aleksander Hinek, PhD; Lauren Kokai, PhD; J Peter Rubin, MD
University of Pittsburgh, Department of Plastic Surgery, Pittsburgh, PA
PURPOSE: Preventing hypertrophic or dystrophic scars is a balance between achieving the minimum necessary fibroproliferative activity and not exceeding the threshold for extracellular matrix deposition (ECM). Most anti-fibrotic agents, such as glucocorticoids, should be carefully applied to minimize their deleterious effects against wound healing. The mineralocorticoid receptor (MR) is a cell-specific mediator of the wound healing cascade. We previously evaluated the efficacy of MR-inhibition with or without mineralocorticoid stimulation in an immunocompromised model, noting that MR-inhibition was sufficient to enhance gross and histologic evidence of scar resolution with diminished collagen content in mature scars. Given the strong overlap between MR-signaling and leukocyte activity in organ fibrosis, we sought to determine the efficacy of our approach in an immunocompetent model and identify if the inhibition of MR receptor could similarly help modulate the effects of glucocorticoids on wound healing.
METHODS: Female C57Bl/6 mice sustained bilateral 1 cm full-thickness thermal injury and were stratified into either a) vehicle, b) spironolactone, c) dexamethasone, or d) spironolactone and dexamethasone (combined). Spironolactone and/or dexamethasone delivered intraperitoneally thrice weekly. Mice were followed photographically for 6 weeks to longitudinally measure time to re-epithelialization and ultimate scar area. After the sacrifice wound biopsies were collected for gross analysis with H&E and Movat’s Pentachrome to assess collagen, fibrin, and elastic fibers.
RESULTS: By day-10, initial burn eschars had completely detached in the spironolactone-only group and the underlying granulation tissue was revealed. Eschars remained present through day 14 in the control mice and through day 21 in the dexamethasone only-group. Open wound area was smaller in the spironolactone-only group vs. control and dexamethasone-only by day-7 (p<0.05) – this relationship remained significant through day-14. At day-21 open wounds were noted in 50% of the dexamethasone-only mice whereas, 17% of the mice receiving the combined treatment. Scar area was noted to be significantly diminished in both the spironolactone-only and combined groups vs. both control and dexamethasone-only groups (p<0.05). Histologic evaluation confirmed evidence of rapid scar resolution in the spironolactone group.
CONCLUSION: These results corroborate our prior findings of the efficacy of MR-inhibition in improving scar resolution in immunocompromised animal. In the immunocompetent animals, rapid eschar detachment, wound closure and epithelialization were noted with spironolactone therapy. Our results progressed the idea that MR manipulation is a useful novel therapeutic approach in the treatment of burn scars with a possible ECM-modifying mechanism involving immunologic mediators.
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