Xanthoulea Sofia, Deliaert An, Romano Andrea, Rensen Sander S, Buurman Wim A, van der Hulst Rene' R W J
Department of Plastic Surgery, Maastricht University Medical Center, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands; Department of Surgery, NUTRIM School for Nutrition, Toxicology & Metabolism, Maastricht University Medical Centre, Maastricht, The Netherlands.
Int Immunopharmacol. 2013 Dec;17(4):1155-64. doi: 10.1016/j.intimp.2013.10.022. Epub 2013 Nov 6.
The aim of the current study was to investigate the effect of nicotine in an experimental mouse model of cutaneous injury and healing responses, during the inflammatory phase of repair. Nicotine injection in full-thickness excisional skin wounds minimally affected inflammatory mediators like TNF, IL-6 and IL-12 while it induced a down-regulation in the expression of growth factors like VEGF, PDGF, TGF-β1 and TGF-β2, and the anti-inflammatory cytokine IL-10. Analysis of wound closure rate indicated no significant differences between nicotine and saline injected controls. In-vitro studies using bone marrow derived macrophages, resident peritoneal macrophages and RAW 264.7 macrophages, indicated that nicotine down-regulates TNF production. Moreover, nicotine was shown to down-regulate VEGF, PDGF and TGF-β1 in both bone marrow derived macrophages and RAW 264.7 cells. Using an NF-κB luciferase reporter RAW 264.7 cell line, we show that nicotine effects are minimally dependent on NF-κB inhibition. Moreover, nicotinic acetylcholine receptor (nAChR) subunit expression analyses indicated that while β2 nAChR subunit is expressed in mouse macrophages, α7 nAChR is not. In conclusion, while skin inflammatory parameters were not significantly affected by nicotine, a down-regulation of growth factor expression in both mouse skin and macrophages was observed. Reduced growth factor expression by nicotine might contribute, at least in part, to the overall detrimental effects of tobacco use in wound healing and skin diseases.
本研究的目的是在皮肤损伤和愈合反应的实验小鼠模型中，研究修复炎症期尼古丁的作用。在全层切除皮肤伤口中注射尼古丁对炎症介质如肿瘤坏死因子（TNF）、白细胞介素-6（IL-6）和白细胞介素-12（IL-12）影响极小，而它可导致血管内皮生长因子（VEGF）、血小板衍生生长因子（PDGF）、转化生长因子-β1（TGF-β1）和转化生长因子-β2（TGF-β2）等生长因子以及抗炎细胞因子白细胞介素-10（IL-10）的表达下调。伤口闭合率分析表明，注射尼古丁的小鼠与注射生理盐水的对照组之间无显著差异。使用骨髓来源的巨噬细胞、腹腔常驻巨噬细胞和RAW 264.7巨噬细胞进行的体外研究表明，尼古丁可下调TNF的产生。此外，在骨髓来源的巨噬细胞和RAW 264.7细胞中，尼古丁均可下调VEGF、PDGF和TGF-β1的表达。利用NF-κB荧光素酶报告基因RAW 264.7细胞系，我们发现尼古丁的作用对NF-κB抑制的依赖性极小。此外，烟碱型乙酰胆碱受体（nAChR）亚基表达分析表明，虽然β2 nAChR亚基在小鼠巨噬细胞中表达，但α7 nAChR不表达。总之，虽然尼古丁对皮肤炎症参数无显著影响，但在小鼠皮肤和巨噬细胞中均观察到生长因子表达下调。尼古丁导致生长因子表达降低可能至少部分地导致了烟草使用对伤口愈合和皮肤疾病的总体有害影响。
