Animal Health Solution - a Henry Schein Animal Health magazine for veterinary professionals
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8 Covetrus | 855.724.3461 | northamerica.covetrus.com Nitric oxide functions across all phases of wound healing: Inflammatory phase Nitric oxide acts as a signaling molecule that promotes the growth and activity of immune cells and the biochemical reactions which are used to defend against bacteria, fungi, viruses, and parasites. Additionally, nitric oxide induces broad spectrum damage to pathogens caused by nitrosative and oxidative reactions. Nitric oxide further controls immune cell signaling and the biochemical reactions which are used to defend against bacteria, fungi, viruses, and parasites. Further, nitric oxide controls macrophage polarization helping wounds transition from the inflammatory phase. Proliferation phase Nitric oxide drives increased blood flow, angiogenesis, proliferation, and epithelialization resulting in rapid wound closure, reduced proud flesh, and stronger tissue. Nitric oxide upregulates expression of endogenous collagenase, which autolytically debrides the wound, to further promote the healing process. Nitric oxide has been shown to stimulate the proliferation of endothelial cells, protect endothelial cells from apoptosis, and mediate vascular endothelial growth factor (VEGF) production. These effects of nitric oxide on endothelial cells guide angiogenesis, the formation of new capillaries. The resulting increased blood flow boosts the transport of proteins into the wound bed facilitating wound healing. Remodeling Low levels of nitric oxide increase keratinocyte proliferation. Nitric oxide coordinates increased collagen synthesis and deposition in the final phases of wound healing. Treatment with nitric oxide donors has been shown to increase collagen formation from fibroblasts. Antimicrobial effects Antibiotic resistance is increasingly a problem for veterinarians. In addition, the risk of transfer of resistant bacteria to the human population can create issues with the use of antibiotics effective against resistant bacteria. Nitric oxide is a potent antimicrobial which is effective against planktonic and, more importantly, biofilm bacteria, even those with resistance to antibiotics. Its mode of action is via oxidation and nitrosylation of cell proteins and so, unlike other antimicrobials, the development of resistance is extremely unlikely. Early use for wounds and skin infections should reduce reliance on systemic antibiotics. Impact on proud flesh The precise causes of proud flesh are not fully understood but recent literature 5,6,7 points to several factors such as low perfusion (hypoxia) due to poor blood flow, lack of nutrition at the wound site related to the poor blood flow, and infection/biofilm formation. Nitric oxide promotes processes that mitigate each of these symptoms. Nitric oxide delivered therapeutically will promote blood flow to the wound through dilation and angiogenesis, eliminate biofilm/infection, and switch macrophages from pro- to anti-inflammatory polarization states. The latter action will result in the wound moving out of the inflammatory phase when proud flesh characteristically appears, reducing the occurrence of overgranulation and promoting normal healing. 1. Ed. Theoret, C, Schumacher, J. 2016, Equine Wound Management (3), John Wiley & Sons, Ltd, doi: 10.1002/9781118999219 2. Howe LM, Boothe HW Jr. Nitric oxide: a review for veterinary surgeons. Vet Surg. 2001 Jan-Feb;30(1):44-57. doi: 10.1053/jvet.2001.20341. PMID: 11172460. 3. Witte MB, Barbul A. Role of nitric oxide in wound repair. Am J Surg. 2002 Apr;183(4): 406-12. doi: 10.1016/s0002-9610(02)00815-2. PMID: 11975928. 4. Sumner, SM, Wallace, ML, Mulder, AT, Delmotte, SB, Duran, SH, Lindell, H, Annaji, M, Dimick, T, Poudel, I, Babu, JR. Development and evaluation of a novel topically applied sildenafil citrate hydrogel and its influence on wound healing in dogs Am J Vet Res. 2022 Aug; doi: 10.2460/ajvr.21.12.0209 5. Alhajj M, Goyal A. Physiology, Granulation Tissue. [Updated 2022 Oct 24]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK554402/ 6. Deschene, K, et al., Hypoxia regulates expression of extracellular matrix associated proteins in equine dermal fibroblasts via HIF1, Journal of Dermatological Science, 2012, 65 Issue 1, pg 12 – 18 doi: 10.1016/j.jdermsci.2011.09.006 7. Dart AJ, et al. Selected factors that negatively impact healing. Equine Wound Management Oct 18th, 2016. : https://doi.org/10.1002/9781118999219.ch3 Equine wound management is challenging, fortunately there are emerging therapies that provide new strategies to treat the most difficult of wounds, resulting in improved patient outcomes.