Lipoxin A4 inhibits UV radiation-induced skin inflammation and oxidative stress in mice

Background: Lipoxin A4 (LXA(4)) is a metabolic product of arachidonic acid. Despite potent anti-inflammatory and pro-resolution activities, it remains to be determined if LXA(4) has effect on ultraviolet (UV) radiation-induced skin inflammation. Objective: To investigate the effects of systemic administration with LXA(4) on UV radiation-induced inflammation and oxidative damage in the skin of mice. Methods: Varied parameters of inflammation and oxidative stress in the skin of mice were evaluated after UV radiation (4.14 J/cm(2)). Results: Pretreatment with LXA(4) significantly inhibited UV radiation-induced skin edema and myeloperoxidase activity. LXA(4) efficacy was enhanced by increasing the time of pre-treatment to up to 72 h. LXA(4) reduced UV radiation-induced skin edema, neutrophil recruitment (myeloperoxidase activity and LysM-eGFP(+) cells), MMP-9 activity, deposition of collagen fibers, epidermal thickness, sunburn cell counts, and production of pro-inflammatory cytokines (TNF-alpha, IL-1 beta, IL-6 and IL-33). Depending on the time point, LXA(4) increased the levels of anti-inflammatory cytokines (TGF-beta and IL10). LXA(4) significantly attenuated UV radiation-induced oxidative damage returning the oxidative status to baseline levels in parameters such as ferric reducing ability, scavenging of free radicals, GSH levels, catalase activity and superoxide anion production. LXA(4) also reduced UV radiation-induced gp91(P)(hox) [nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) subunit] mRNA expression and enhanced nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream target enzyme nicotinamide adenine dinucleotide (phosphate) quinone oxidoreductase (Nqo1) mRNA expression. Conclusion: LXA(4) inhibited UV radiation-induced skin inflammation by diminishing pro-inflammatory cytokine production and oxidative stress as well as inducing anti-inflammatory cytokines and Nrf2. (C) 2018 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.