Nitric oxide synthases\u27 role in cutaneous wound healing

Nitric Oxide (NO) has a role in wound healing, but the relative contribution and importance of the various isozymes of Nitric Oxide Synthase (NOS) is controversial. Effects of NO are concentration dependent. At low concentrations (picomolar) produced by constitutive isoforms, Endothelial NOS (ENOS) and Neuronal NOS (NNOS), NO serves as an important physiologic messenger. Elevated, potentially cytotoxic concentrations of NO (nanomolar to micromolar) produced by Inducible NOS (INOS) under inflammatory conditions is pathogenic in many inflammatory diseases. Selective inhibition of INOS is a potential anti-inflammatory therapeutic target. Early wound healing is an inflammatory process. Macrophages, a major source of INOS, are the “director cell” of wound healing. A current hypothesis is that NO from INOS is critical for wound healing, and much published research attempts to prove this theory. ENOS has also been shown to be important for wound healing. This work looked for microanatomic expression of NOS isozymes over time, tested whether selective inhibition of INOS affects wound healing in normal rats, and looked for detrimental effects on wound healing of elevated INOS in systemic inflammatory disease. Adjuvant-induced arthritis (AIA) was the model of inflammatory disease. In normal rat wounds, INOS-selective inhibitors did not delay or alter the pattern of wound healing. INOS staining was limited to pockets of infection and foreign body reactions, and the incidence of delayed healing due to inadequately resolved surface bacterial infection was increased. It was concluded that INOS is not critical for normal noninfected healing, and that INOS\u27 role is to combat infection or other contaminants. ENOS was expressed throughout the wound bed in granulation tissue capillaries and hyperproliferative epidermis. AIA did not affect time to healing but qualitative endpoints were affected. AIA healing was abnormal grossly and histologically, primarily due to altered migration of the epidermal tongue. INOS expression was markedly increased in AIA wounds, including abnormally migrating hyperproliferative epidermis and foreign bodies. Therapeutic inhibition of INOS in AIA wounds did not return healing to normal. It was concluded that INOS is elevated in inflamed AIA wounds and associated with abnormal wound healing and response to foreign bodies