De Felice Claudio, Rossi Marcello, Leoncini Silvia, Chisci Glauco, Signorini Cinzia, Lonetti Giuseppina, Vannuccini Laura, Spina Donatella, Ginori Alessandro, Iacona Ingrid, Cortelazzo Alessio, Pecorelli Alessandra, Valacchi Giuseppe, Ciccoli Lucia, Pizzorusso Tommaso, Hayek Joussef
Neonatal Intensive Care Unit, University Hospital Azienda Ospedaliera Universitaria Senese (AOUS), Viale M. Bracci 16, 53100 Siena, Italy.
Respiratory Pathophysiology and Rehabilitation Unit, University Hospital, AOUS, Viale M. Bracci 16, 53100 Siena, Italy.
Mediators Inflamm. 2014;2014:560120. doi: 10.1155/2014/560120. Epub 2014 Mar 17.
Rett syndrome (RTT) is a pervasive neurodevelopmental disorder mainly linked to mutations in the gene encoding the methyl-CpG-binding protein 2 (MeCP2). Respiratory dysfunction, historically credited to brainstem immaturity, represents a major challenge in RTT. Our aim was to characterize the relationships between pulmonary gas exchange abnormality (GEA), upper airway obstruction, and redox status in patients with typical RTT (n = 228) and to examine lung histology in a Mecp2-null mouse model of the disease. GEA was detectable in ~80% (184/228) of patients versus ~18% of healthy controls, with "high" (39.8%) and "low" (34.8%) patterns dominating over "mixed" (19.6%) and "simple mismatch" (5.9%) types. Increased plasma levels of non-protein-bound iron (NPBI), F2-isoprostanes (F2-IsoPs), intraerythrocyte NPBI (IE-NPBI), and reduced and oxidized glutathione (i.e., GSH and GSSG) were evidenced in RTT with consequently decreased GSH/GSSG ratios. Apnea frequency/severity was positively correlated with IE-NPBI, F2-IsoPs, and GSSG and negatively with GSH/GSSG ratio. A diffuse inflammatory infiltrate of the terminal bronchioles and alveoli was evidenced in half of the examined Mecp2-mutant mice, well fitting with the radiological findings previously observed in RTT patients. Our findings indicate that GEA is a key feature of RTT and that terminal bronchioles are a likely major target of the disease.
雷特综合征（RTT）是一种广泛性神经发育障碍，主要与编码甲基CpG结合蛋白2（MeCP2）的基因突变有关。呼吸功能障碍在历史上被认为是脑干发育不成熟所致，是雷特综合征面临的一项重大挑战。我们的目的是明确典型雷特综合征患者（n = 228）的肺气体交换异常（GEA）、上气道阻塞与氧化还原状态之间的关系，并在该疾病的Mecp2基因敲除小鼠模型中检查肺组织学。约80%（184/228）的患者可检测到GEA，而健康对照者中这一比例约为18%，其中“高”（39.8%）和“低”（34.8%）模式占主导，超过“混合”（19.6%）和“单纯不匹配”（5.9%）类型。雷特综合征患者血浆中非蛋白结合铁（NPBI）、F2 - 异前列腺素（F2 - IsoPs）、红细胞内NPBI（IE - NPBI）水平升高，还原型和氧化型谷胱甘肽（即GSH和GSSG）水平降低，因此GSH/GSSG比值下降。呼吸暂停频率/严重程度与IE - NPBI、F2 - IsoPs和GSSG呈正相关，与GSH/GSSG比值呈负相关。在半数接受检查的Mecp2突变小鼠中，终末细支气管和肺泡出现弥漫性炎性浸润，这与先前在雷特综合征患者中观察到的放射学结果高度相符。我们的研究结果表明，GEA是雷特综合征的一个关键特征，终末细支气管可能是该疾病的主要靶点。
