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Nitric Oxide Therapy for Dermatologic Disease

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Nitric Oxide Therapy for Dermatologic Disease SPECIAL FOCUS y Nitric oxide-releasing materials Special Report For reprint orders, please contact [email protected] 0 Special Report2015/05/05 Nitric oxide therapy for dermatologic disease Brandon L Adler1 Future Sci. OA Nitric oxide (NO) plays an important role in the maintenance and regulation of the skin and the integrity of its environment. Derangement of NO production is implicated in & Adam J Friedman*,1,2,3 1 the etiology of a multitude of dermatologic diseases, indicating future therapeutic Department of Medicine (Division of Dermatology), Albert Einstein College of directions. In an era of increasing resistance rates to available antibiotics and subpar Medicine, Bronx, NY, USA development of new agents, NO is promising as a prospective topical broad-spectrum 2Department of Physiology & Biophysics, 1(1), FSO37 antimicrobial agent with small likelihood of resistance development. Because the Albert Einstein College of Medicine, greatest strides have been made in the setting of infectious disease and skin and soft- Bronx, NY, USA 3 tissue infection, this will be a major focus of this article. In addition, we will review George Washington School of Medicine & Health Sciences, Washington, DC, USA NO’s role in skin regulation and dysregulation, immune function, the various topical *Author for correspondence: release systems that have been devised and tested, NO’s relation to UV radiation and [email protected] skin pigmentation, and finally, its potential applications as a cosmeceutical. Nitric oxide (NO) is a molecule that plays many roles in both normal and abnormal skin processes. There is strong evidence that NO-releasing materials may serve as new, unique antimicrobial agents, at a juncture when current antibiotics are confounded by increasingly resistant microorganisms. We review the numerous functions NO serves in skin physiology, focusing on its antimicrobial capabilities, and present evidence for its potential utility as a cosmetic agent. Keywords: cosmeceutical • nitric oxide synthase • NOS • reactive nitrogen oxide species • RNOS • skin and soft-tissue infection • SSTI Nitric oxide & skin NOS (nNOS) and NOS3/endothelial NOS Nearly every member of the skin cell popu- (eNOS), calcium-dependent enzymes that lation expresses nitric oxide synthase (NOS) are regulated by calmodulin. Once activated, 0 and is thereby able to produce NO to they produce small amounts of NO over accomplish essential physiologic processes. brief periods of time. NOS2/inducible NOS This body of cells includes keratinocytes, (iNOS), on the other hand, generates large endothelial cells, fibroblasts, melanocytes, quantities of NO by a noncalcium-depen- 0 adipocytes, Langerhans cells, neutrophils dent mechanism. It is stimulated by bacterial and macrophages. The broad distribution of products, cytokines and neuropeptides [1,2]. skin-situated NO producers enables the mol- ecule’s participation in vital cutaneous phys- Dichotomous role of NO in iologic processes, including formation of a dermatologic physiology & pathology protective barrier and antimicrobial defense, NO is a Janus-faced molecule, playing ben- establishment and maintenance of circula- eficial as well as harmful roles in routine skin tion, and melanogenesis and erythema in physiology and states of dysregulation and response to ultraviolet light exposure [1–3] . disease. Given NO’s crucial role in the basic The production of endogenous NO is integrity and day-to-day functioning of the handled by three isoforms of NOS. Two are skin, it is unsurprising that derangements in constitutively expressed: NOS1/neuronal production, signaling, or both are associated part of 10.4155/FSO.15.37 © Adam J Friedman Future Sci. OA (2015) 1(1), FSO37 eISSN 2056-5623 Special Report Adler & Friedman with disease states. A fine balance must exist in NOS characterized by exaggerated digital vascular spasm in expression and subsequent NO production, as both response to cold exposure or strong emotion, leading excess and dearth are linked to pathology. Addition- to color changes in the overlying skin and ischemic ally, as discussed below, endogenous NO production symptoms that range from achiness and paresthesias has antimicrobial functions and may be augmented by to severe pain and ulceration. A recent multicenter, topical release systems, with attendant consequences double-blind, randomized, placebo-controlled cross- for future management of skin and soft-tissue infection. over study examined a novel topical nitroglycerine gel preparation in Raynaud patients, and found signifi- An overview of NO & dermatologic disease cant improvement in skin blood flow compared with Inappropriate iNOS upregulation is implicated in such placebo [18]. wide-ranging pathophysiologic conditions as: As experimental data accumulates and our knowl- edge base continues to grow, it is becoming clearer how • Cutaneous lupus erythematosus [3]; disruptions of NO production on even a micro scale • Inflammatory skin disorders: psoriasis,can lead to overt dermatologic disease. Although still atopic dermatitis, irritant and allergic contact in their infancy, targeted therapies could act to restore dermatitis [4–6]; NO homeostasis, thereby alleviating the symptoms of these oftentimes debilitating conditions. At present, • Keloids [7]; much more experimental evidence is available in the infectious disease/microbiology arena, in which the • Morphea/scleroderma [8]; same idea of a necessary fine balance of NO production persists – with even more promising future therapeutic • Pemphigus vulgaris [9]; applications. • Pityriasis lichenoides [10]; NO as an antimicrobial agent • Sjögren’s syndrome [11]; NO exerts antimicrobial activity in a concentration- dependent bimodal fashion. At low concentrations it • Stevens-Johnson syndrome/toxic epidermal stimulates the immune system by enhancing immune necrolysis [12] . cell proliferation, differentiation, and apoptosis, as Regulation of iNOS expression may occur at vari- well as cytokine production, expression of adhesion ous levels, including promoter activity, mRNA and and co-stimulatory factors, and extracellular matrix protein stability, enzyme activity and substrate sup- constituent synthesis and deposition. ply. Glucocorticoids and TGF-β downregulate iNOS, Conversely, iNOS, as a component of the innate and it is thought that a negative feedback loop exists immune system, produces large quantities of NO through which NO itself inhibits iNOS expression when activated by bacterial polysaccharides and endo- and activity. Nevertheless, the lack of clinically effec- toxins as well as proinflammatory cytokines. At con- tive self-regulation of NO in these dysfunctional con- centrations greater than 1 μM, NO’s utility in com- ditions is a pertinent topic for further inquiry. It should bating pathogens derives largely from its ability to stimulate the search for new therapeutic targets to treat react with reactive oxygen intermediates to generate many of these chronic and debilitating conditions. For reactive nitrogen oxide species (RNOS). Peroxynitrite instance, the NOS inhibitor L-NMMA in aqueous (OONO-), the most reactive and cytotoxic RNOS, cream BP was applied to psoriatic lesions and showed forms when NO interacts with superoxide. RNOS 77% inhibition of NO production as well as inhibition possess numerous antimicrobial properties, including: of angiogenesis as compared with control. However, the therapeutic gain of this approach was minimal, • Induction of nitrosative and oxidative stress; with insignificant differences in erythema and skin • Inactivation of essential enzymes; thickness as compared with vehicle [1,9,13–16]. In contrast to the conditions listed above that are • Depletion of intracellular iron stores; characterized by NO overproduction, states of exces- sive vascular tone – although multifactorial – may • Damage to microbial DNA, directly and indirectly relate to NO deficiency [17] . NO was originally termed (via generation of alkylating agents and hydrogen endothelium-derived relaxing factor (EDRF), owing peroxide and inhibition of DNA repair); to its vasodilatory function. Therefore, NO donors have a place in the treatment of vasospastic disease, • Disruption of the microbial cell membrane through notably Raynaud phenomenon. This condition is lipid peroxidation [2,19,20]. 10.4155/FSO.15.37 Future Sci. OA (2015) 1(1), FSO37 future science group Table 1. Antimicrobial activities of nitric oxide-releasing platforms. Platform Advantages Limitations Active against Acidified nitrite creams Easily applied Ingredients must be mixed immediately before Burkholderia cepacia application Skin irritation Mycobacterium ulcerans Propionibacterium acnes Pseudomonas aeruginosa Staphylococcus aureus (inc. MRSA) Tinea pedis Trichophyton spp. Diazeniumdiolates Easily produced Risk of methemoglobin formation and release of Candida albicans (DETA-NO) (NONOates) toxic and carcinogenic byproducts Stable under ambient conditions Escherichia coli (β-Gal-NONOate) Spontaneous release of NO in predictable and dependable fashion gNO Little in vitro toxicity to human skin cells Expensive E. coli Difficult to handle C. albicans Nitric oxide therapy for dermatologic disease Requires gas cylinders for delivery P. aeruginosa Extended duration of treatment requiring S. aureus (inc. MRSA) nonambulation Cannot be exposed to oxygen Group B Streptococcus Potential host toxicity via NO2 production and methemoglobinemia development NO-releasing nanoparticles Ease of synthesis, storage, and administration
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