N-acetylcysteine S-nitrosothiol Nanoparticles Prevent Wound Expansion and Accelerate Wound Closure in a Murine Burn Model
July 2015 | Volume 14 | Issue 7 | Journal Article | 726 | Copyright © July 2015
Angelo Landriscina BA,a* Tagai Musaev BA,a* Jamie Rosen BA,a Anjana Ray PhD,b Parimala Nacharaju PhD,c Joshua D. Nosanchuk MD,b and Adam J. Friedman MDa,c
aDepartment of Medicine, Albert Einstein College of Medicine, Bronx, NY
bDepartment of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY
cDepartment of Dermatology, George Washington School of Medicine and Health Sciences, Washington, DC
*These authors contributed equally to the production of this work.
Abstract
BACKGROUND: The treatment of cutaneous wounds in the clinical setting continues to be a clinical challenge and economic burden, with burn wounds being especially formidable. Direct mechanical injury coupled with the transfer of thermal energy leads to tissue necrosis, pro-inflammatory cytokine release and the eventual expansion of an initial wound. Our current therapeutic armamentarium falls short of options to help prevent wound expansion, and therefore new modalities are required. Nitrosating substances such as RSNOs have been proven to be effective in promoting wound closure due to their ability to modulate inflammation, cytokine production and vascular function.
OBJECTIVE: We aim to evaluate the efficacy of n-actetylcysteine s-nitrosothiol nanoparticles (NAC-SNO-np) on thermal burn wounds and associated expansion.
METHODS: A multi-burn model was utilized to induce three burn wounds on the dorsal surface of BALB/c mice, allowing for evaluation of the burn itself and peripheral tissue. Wounds were excised and processed for histology and immunohistochemistry on day 7 following wounding.
RESULTS: Following treatment with NAC-SNO-np, burn wound expansion was attenuated and wound healing was accelerated. Histological analysis revealed increased collagen deposition as well as increased macrophage and decreased neutrophil infiltration into the wound bed.
CONCLUSION: NAC-SNO-np represents a platform that harnesses the nitrosative properties of NAC-SNO in order to accelerate the transition from inflammatory to proliferative wound healing. Further studies are needed in order to translate to the clinical setting.
J Drugs Dermatol. 2015;14(7):726-732.
INTRODUCTION
Burns are a major source of morbidity, mortality and healthcare expenditure in the United States, with 450,000 patients treated for burn injury each year.1 Fire, flame and scald burns account for roughly 77% of burns treated in the US.1 Given the nature of these causes, patients often present with multiple and complex burns. Furthermore, burns are dynamic injuries that undergo expansion within the first 24-72 hours with histological evidence of both apoptosis and necrosis in the surrounding
tissue.2 Though the impact of these injuries is large, our current treatment armament falls short, with gold standard treatments
lacking evidence to support their use.3
Recent investigations have turned to the study of endogenous molecules as treatments for a variety of ailments including burns. One such molecule of interest is nitric oxide (NO), given its complex and necessary role in the wound healing process. However, use of nitric oxide is limited due its exceedingly short half-life. 4 In order to overcome these limitations, investigators have turned toward the use of nitrosating substances, those
that donate NO molecules in order to harness NO’s wound healing potential.4 Nitric oxide (NO) and NO-donating nitrosothiols
(RSNOs) are key orchestrators of all three phases of wound healing, both having a broad and sometimes distinct array of roles.5 Nitrosating substances such as RSNOs have been proven to promote wound closure due to their ability to modulate inflammation, cytokine production and vascular function.6
In this study, we evaluate a previously described S-nitroso-N-acetyl cysteine containing hydrogel-based nanoparticle platform (NAC-SNO-np) on in vivo burn wound closure, expansion
and inflammation in a multi burn model.7 This model is adapted from previous studies, and allows for the evaluation of multiple burns, their expansion, and the impact on surrounding tissue.8 Several previously described properties of the nanotechnology
platform such as increased capacity to generate NO, enhanced vasodilatory effect, and low toxicity9 make it an attractive candidate as a potential therapeutic adjuvant.
