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?

of a topical delivery system that is effective and safe. The pharmacokinetic profile of a given NO-releasing formulation must also avoid adverse cutaneous or systemic sequelae. Sever- al NO delivery platforms have been evaluated, many for topical application and with ongoing development programs, and each with potential advantages and disadvantages, which have been summarized in the literature; these include acidi ed nitrate, diazeniumdiolates (NONOates), nanoparticles, probiotic patch, S-nitrosothiols (RSNOs), and NO-metal complexes.^{2,3,5,11,14,15,17,19,20} Studies completed with some NO-based topical formulations, such as with nanoparticles or with a macromolecule that in- corporates N-diazeniumdiolate donor technology, provide both cogent basic science and clinical research support for the use of NO-based topical therapy for the treatment of acne.^{11,14,15,17,19,38} How Might a Nitric-Oxide Releasing Formulation Therapeutically Modify the Pathophysiology of Acne? Understanding of the pathophysiology of acne has increased substantially over the past one to two decades due to major advancements in basic science technologies, such as immunohistochemistry, gene array analysis, and real-time polymerase chain reaction, with studies supporting the new- er information on relevant pathways thoroughly summarized in the literature.^32-35 Although follicular hyperkeratinization and microcomedone formation are well known to occur during the preclinical development of an acne lesion, sub- clinical in ammation characterized by T-helper (CD4+) cell and macrophage in ltration, follicular production of IL-1, upregulation of vascular adhesion molecules, and a relative absence of neutrophils has also been documented.^32-35 Increased expression of IL-1 has been noted in association with comedone formation and in early in ammatory lesions and appears to play roles in both the initiation and propagation of acne.³⁴ These data collectively support the presence of pre- clinical in ammation prior to both visible in ammatory and comedonal acne lesion emergence. Importantly, persistent in ammation is also present after visible acne lesions prog- ress from being palpable to becoming macular, with scar formation dependent on the capacity for physiologic tissue restoration within the dermal matrix.^32,34