Galli Francesco, Battistoni Andrea, Gambari Roberto, Pompella Alfonso, Bragonzi Alessandra, Pilolli Francesca, Iuliano Luigi, Piroddi Marta, Dechecchi Maria Cristina, Cabrini Giulio
Department of Internal Medicine, Laboratory of Clinical Biochemistry and Nutrition, University of Perugia, Italy.
Biochim Biophys Acta. 2012 May;1822(5):690-713. doi: 10.1016/j.bbadis.2011.12.012. Epub 2011 Dec 28.
Cystic fibrosis is a lethal autosomal recessive condition caused by a defect of the transmembrane conductance regulator gene that has a key role in cell homeostasis. A dysfunctional cystic fibrosis transmembrane conductance regulator impairs the efflux of cell anions such as chloride and bicarbonate, and also that of other solutes such as reduced glutathione. This defect produces an increased viscosity of secretions together with other metabolic defects of epithelia that ultimately promote the obstruction and fibrosis of organs. Recurrent pulmonary infections and respiratory dysfunction are main clinical consequences of these pathogenetic events, followed by pancreatic and liver insufficiency, diabetes, protein-energy malnutrition, etc. This complex comorbidity is associated with the extensive injury of different biomolecular targets by reactive oxygen species, which is the biochemical hallmark of oxidative stress. These biological lesions are particularly pronounced in the lung, in which the extent of oxidative markers parallels that of inflammatory markers between chronic events and acute exacerbations along the progression of the disease. Herein, an abnormal flux of reactive oxygen species is present by the sustained activation of neutrophils and other cystic fibrosis-derived defects in the homeostatic processes of pulmonary epithelia and lining fluids. A sub-optimal antioxidant protection is believed to represent a main contributor to oxidative stress and to the poor control of immuno-inflammatory pathways in these patients. Observed defects include an impaired reduced glutathione metabolism and lowered intake and absorption of fat-soluble antioxidants (vitamin E, carotenoids, coenzyme Q-10, some polyunsaturated fatty acids, etc.) and oligoelements (such as Se, Cu and Zn) that are involved in reactive oxygen species detoxification by means of enzymatic defenses. Oral supplements and aerosolized formulations of thiols have been used in the antioxidant therapy of this inherited disease with the main aim of reducing the extent of oxidative lesions and the rate of lung deterioration. Despite positive effects on laboratory end points, poor evidence was obtained on the side of clinical outcome so far. These aspects examined in this critical review of the literature clearly suggest that further and more rigorous trials are needed together with new generations of pharmacological tools to a more effective antioxidant and anti-inflammatory therapy of cystic fibrosis patients. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.
囊性纤维化是一种致命的常染色体隐性疾病，由跨膜传导调节基因缺陷引起，该基因在细胞内环境稳定中起关键作用。功能失调的囊性纤维化跨膜传导调节因子会损害细胞阴离子（如氯离子和碳酸氢根离子）以及其他溶质（如还原型谷胱甘肽）的外流。这种缺陷会导致分泌物粘度增加以及上皮细胞的其他代谢缺陷，最终促进器官的阻塞和纤维化。反复肺部感染和呼吸功能障碍是这些致病事件的主要临床后果，其次是胰腺和肝功能不全、糖尿病、蛋白质 - 能量营养不良等。这种复杂的合并症与活性氧对不同生物分子靶点的广泛损伤有关，这是氧化应激的生化标志。这些生物损伤在肺部尤为明显，在疾病进展过程中，慢性事件和急性加重期之间，氧化标志物的程度与炎症标志物的程度平行。在此，由于中性粒细胞的持续激活以及肺部上皮细胞和衬液稳态过程中其他囊性纤维化衍生的缺陷，活性氧存在异常通量。据信，次优的抗氧化保护是这些患者氧化应激以及免疫炎症途径控制不佳的主要原因。观察到的缺陷包括还原型谷胱甘肽代谢受损、脂溶性抗氧化剂（维生素E、类胡萝卜素、辅酶Q - 10、一些多不饱和脂肪酸等）和微量元素（如硒、铜和锌）的摄入和吸收降低，这些物质通过酶防御参与活性氧解毒。硫醇的口服补充剂和气雾剂制剂已用于这种遗传性疾病的抗氧化治疗，主要目的是减少氧化损伤的程度和肺部恶化的速度。尽管对实验室终点有积极影响，但迄今为止在临床结果方面的证据不足。本文献综述中探讨的这些方面清楚地表明，需要进行进一步更严格的试验以及新一代药理工具，以对囊性纤维化患者进行更有效的抗氧化和抗炎治疗。本文是名为：疾病中的抗氧化剂和抗氧化治疗的特刊的一部分。
