Spotlight on the Use of Nitric Oxide in Dermatology: What Is It? What Does It Do? Can It Become an Important Addition to the Therapeutic Armamentarium for Skin Disease?

Over the past several years, there has been a conspicu- ous absence of new therapeutic drug classes and individual compounds developed in dermatology, especially for the topical treatment of skin disorders. Many of the therapeutic advances with topical therapy have primarily involved the development of new vehicles and stabilized com-bination formulations. Boron-based compounds represent one of the newer areas of drug development in dermatology, which has led to therapeutic agents that are applied topically.¹ Another specific area of drug development has focused on the eval- uation of nitric oxide delivery systems, including a variety of topical methodologies.2^,3 The high level of interest in nitric ox- ide as a therapeutic agent has progressively emerged over ap- proximately two decades as researchers have come to increas- ingly understand the many physiologic and homeostatic roles that are carried out by this ubiquitous endogenous compound, including many functions within skin.^4-11 The main objective of this manuscript is to provide the reader with a foundation for understanding of what nitric oxide is, how it functions physiologically, and why it may come to serve as an important therapeutic agent in dermatology. As nitric oxide exhibits a diverse spectrum of biologic effects and physiologic functions within multiple organ systems within the human body, emphasis will be placed on understanding relevant mechanisms of action with a focus on dermatologic applications. What Is Nitric Oxide? Nitric oxide (NO) is a diatomic molecule that is endogenously ^4-6,11 expressed by a wide variety of cell types. When host cells are stimulated to release NO, its activities serve to provide both antimicrobial and immunomodulatory properties that are inte- gral to the host immune system.^2,4-6,10,11 Although much of the more recent literature on NO has emphasized its antimicrobial effects, NO exhibits a variety of diverse physiologic and immu- nologic functions.The production and release of constitutively expressed NO is regulated in order to homeostatically sustain a physiologic balance within multiple individual organ systems, such as those involved in maintaining vascular tone, neuronal transmission, modulation of wound healing, platelet adhesion, and multiple functions in skin, such as the antimicrobial barrier, vascular response (ie, vasodilation), and tissue repair.^5,6,11 Signals produced during microbial invasion are also capable of inducing "on demand" the production and release of high concentrations of NO that are capable of neutralizing a wide variety of bacteria, viruses, fungi, and parasites via several distinct mechanisms that are cytotoxic to most microbes.^4-6,10,11 Hence, controlled NO production and release are vital compo- nents of maintaining a functional physiologic balance within skin and other organ systems, and also provide innate protection against both cutaneous and systemic infections.This latter function is supported by studies that demonstrate that NO