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Potential Mechanisms of Action for Exogenous Ketone Enhancement of Ischemic Wound Healing in Young and Aged Fischer Rats
Author(s) -
Kesl Shan L,
Wu Mack,
Gould Lisa J,
D'Agostino Dominic P
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1036.9
Subject(s) - wound healing , ketone bodies , inflammation , medicine , oxidative stress , population , endocrinology , pharmacology , chemistry , immunology , metabolism , environmental health
Chronic wounds represent an under‐acknowledged socioeconomic epidemic, affecting 1.8 million new patients per year and costing the US health care system upwards of $25 billion annually. This substantial cost is rapidly growing due to a disproportionate occurrence in the ever‐aging population. Ketone bodies, including β‐Hydroxybutyrate (βHB), are naturally occurring energy substrates. We previously reported that oral ketone supplementation without dietary restriction enhanced wound closure and increased blood flow in young and aged Fischer 344 rats. We hypothesized that exogenous ketone supplementation promoted wound healing via enhancement of physiological factors such as increasing proliferation, advancing migration, reducing ROS production, and resolving inflammation. Experiments in vitro with young and aged primary human dermal fibroblasts supplemented with 5mM βHB for 72 hours ahead of an oxidative stimulus (100μM tert‐butyl‐hydrogen peroxide) resulted in significantly decreased cellular ROS production, enhanced cell migration, and augmented cellular proliferation (p<0.05). Additionally, peri‐wound tissue lysates were isolated from 1,3 Butanediol (BD), βHB NA+/K+ salt mixed with MCT oil in a 1:1 ratio (BMS+MCT), and standard diet (SD) fed rats on day three and day seven post‐wounding. Ketone administration during wound healing elicited changes in inflammatory cytokines including a significant elevation in epidermal growth factor (EGF) at day 7 of wound healing compared to control (p<0.05). BMS+MCT supplementation in aged rats significantly decreased tumor necrosis factor‐ alpha (TNF‐α) levels on day 7 of wound healing compared to controls (p<0.05). Furthermore, ketone supplementation significantly reduced leptin levels in both young and aged rats. Harvested wound tissue demonstrated a change in immunofluorescence of the pro‐inflammatory (IRF‐5 labeled, M1) to anti‐inflammatory (CD206 labeled, M2) macrophage ratio and immunohistochemistry labeled CD31 blood vessel density markers compared to controls. We conclude that ketone supplementation in vivo and in vitro modifies systemic physiology to enhance wound closure. Support or Funding Information This study was supported by the Office of Naval Research (ONR) Grant N000140610105 (DPD), Scivation Inc, and a Morsani College of Medicine Department of Molecular Pharmacology and Physiology departmental grant.