Departments of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213. USA; Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213. USA.
Departments of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213. USA.
Free Radic Biol Med. 2018 Feb 1;115:31-42. doi: 10.1016/j.freeradbiomed.2017.11.009. Epub 2017 Nov 10.
Endogenous electrophilic fatty acids mediate anti-inflammatory responses by modulating metabolic and inflammatory signal transduction and gene expression. Nitro-fatty acids and other electrophilic fatty acids may thus be useful for the prevention and treatment of immune-mediated diseases, including inflammatory skin disorders. In this regard, subcutaneous (SC) injections of nitro oleic acid (OA-NO), an exemplary nitro-fatty acid, inhibit skin inflammation in a model of allergic contact dermatitis (ACD). Given the nitration of unsaturated fatty acids during metabolic and inflammatory processes and the growing use of fatty acids in topical formulations, we sought to further study the effect of nitro-fatty acids on cutaneous inflammation. To accomplish this, the effect of topically applied OA-NO on skin inflammation was evaluated using established murine models of contact hypersensitivity (CHS). In contrast to the effects of subcutaneously injected OA-NO, topical OA-NO potentiated hapten-dependent inflammation inducing a sustained neutrophil-dependent inflammatory response characterized by psoriasiform histological features, increased angiogenesis, and an inflammatory infiltrate that included neutrophils, inflammatory monocytes, and γδ T cells. Consistent with these results, HPLC-MS/MS analysis of skin from psoriasis patients displayed a 56% increase in nitro-conjugated linoleic acid (CLA-NO) levels in lesional skin compared to non-lesional skin. These results suggest that nitro-fatty acids in the skin microenvironment are products of cutaneous inflammatory responses and, in high local concentrations, may exacerbate inflammatory skin diseases.
内源性亲电脂肪酸通过调节代谢和炎症信号转导以及基因表达来介导抗炎反应。因此，硝基脂肪酸和其他亲电脂肪酸可用于预防和治疗免疫介导的疾病，包括炎症性皮肤病。在这方面，皮下（SC）注射硝基油酸（OA-NO），一种典型的硝基脂肪酸，可抑制过敏性接触性皮炎（ACD）模型中的皮肤炎症。鉴于不饱和脂肪酸在代谢和炎症过程中的硝化以及脂肪酸在局部制剂中的广泛使用，我们试图进一步研究硝基脂肪酸对皮肤炎症的影响。为此，使用已建立的接触超敏反应（CHS）小鼠模型评估了局部应用 OA-NO 对皮肤炎症的影响。与皮下注射 OA-NO 的作用相反，局部 OA-NO 增强了半抗原依赖性炎症，引起了持续的中性粒细胞依赖性炎症反应，其特征为银屑病样组织学特征、增加的血管生成以及包括中性粒细胞、炎症单核细胞和 γδ T 细胞在内的炎症浸润。与这些结果一致，对银屑病患者皮肤的 HPLC-MS/MS 分析显示，病变皮肤中硝基共轭亚油酸（CLA-NO）水平比非病变皮肤高 56%。这些结果表明，皮肤微环境中的硝基脂肪酸是皮肤炎症反应的产物，并且在局部浓度较高时，可能会加重炎症性皮肤病。
