Inflammatory Lung Disease in Rett Syndrome

Hindawi Publishing Corporation Mediators of Inflammation Volume 2014, Article ID 560120, 15 pages http://dx.doi.org/10.1155/2014/560120 Clinical Study Inflammatory Lung Disease in Rett Syndrome Claudio De Felice,1 Marcello Rossi,2 Silvia Leoncini,3,4 Glauco Chisci,5 Cinzia Signorini,3 Giuseppina Lonetti,6 Laura Vannuccini,2 Donatella Spina,7 Alessandro Ginori,7 Ingrid Iacona,2 Alessio Cortelazzo,4,8 Alessandra Pecorelli,3,4 Giuseppe Valacchi,9 Lucia Ciccoli,3 Tommaso Pizzorusso,6,10 and Joussef Hayek4 1 Neonatal Intensive Care Unit, University Hospital Azienda Ospedaliera Universitaria Senese (AOUS), Viale M. Bracci 16, 53100 Siena, Italy 2 Respiratory Pathophysiology and Rehabilitation Unit, University Hospital, AOUS, Viale M. Bracci 16, 53100 Siena, Italy 3 Department of Molecular and Developmental Medicine, University of Siena, Via A. Moro 2, 53100 Siena, Italy 4 Child Neuropsychiatry Unit, University Hospital AOUS, Viale M. Bracci 16, 53100 Siena, Italy 5 Department of Maxillofacial Surgery, University of Siena, Viale M. Bracci 16, 53100 Siena, Italy 6 Institute of Neuroscience, CNR, Via G. Moruzzi 1, 56124 Pisa, Italy 7 Pathology Unit, University Hospital AOUS, Viale M. Bracci 16, 53100 Siena, Italy 8 Department of Medical Biotechnologies, University of Siena, Via A. Moro 2, 53100 Siena, Italy 9 Department of Life Sciences and Biotechnology, University of Ferrara, Via Borsari 46, 44100 Ferrara, Italy 10 Department of Neuroscience, Psychology, Drug Research and Child Health (Neurofarba), University of Florence, Area S. Salvi Pad. 26, 50135 Florence, Italy Correspondence should be addressed to Marcello Rossi; Received 11 October 2013; Revised 6 January 2014; Accepted 14 January 2014; Published 17 March 2014 Academic Editor: Paul Ashwood Copyright © 2014 Claudio De Felice et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Rett syndrome (RTT) is a pervasive neurodevelopmental disorder mainly linked to mutations in the gene encoding the methylCpG-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 nonprotein-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. 1. Introduction Rett syndrome (RTT), for a long time included among the Autism Spectrum Disorders (ASDs), is a nosologically distinct, genetically determined neurological entity associated in up to 95% of cases to de novo loss-of-function mutations in the X-chromosome-linked gene encoding the methyl-CpG-binding protein 2 (MeCP2) [1]. MeCP2, a ubiquitous protein particularly abundant in brain, is known to either activate or repress transcription [2, 3], is critical to the function of several types of cells (i.e., neurons and astroglial cells), and targets several genes essential for neuronal survival, dendritic growth, synaptogenesis, and activity dependent plasticity [4]. 2 In its classical clinical presentation, RTT affects heterozygous females and shows a typical 4-stage neurological regression after 6 to 18 months of apparently normal development. RTT is a relatively rare disease, affecting about 1 : 10,000 female live births, although it represents the second most common cause of severe intellectual disability in the female gender [5, 6]. Preserved speech, early seizure, and congenital are well-known atypical variants often linked to mutations in genes other than MECP2, that is, the cyclin-dependent kinase-like 5 (CDKL5) in the early seizure variant and the forkhead boxG1 (FOXG1) in the congenital variant [6, 7]. Breathing disorders are considered a hallmark feature of RTT and represent a major clinical challenge [8]. To date, a large number of studies have been focusing on this particular characteristic of the disease, both in the clinical and experimental environments. Breathing abnormalities in RTT variably include/feature breath holdings, apneas, apneusis, hyperventilation, rapid shallow breathing, and spontaneous Valsalva maneuvers [9]. In particular, a highly irregular respiratory rhythm particularly during daytime is considered among the key symptoms of RTT [9–11]. Cumulating evidence indicates a predominantly hyperventilatory pattern with increased respiratory frequency and decreased expiratory duration, which is associated with frequent episodes of breath-holding/obstructive apnea or Valsalva breathing against closed airways during wakefulness [12–14]. However, the breath-holding/obstructive apnea phenotype of RTT is often confused in the related clinical literature with central apnea, which has fundamentally distinct neurological mechanisms [9, 15–26]. The wide spectrum of respiratory disorders detectable in RTT patients has been historically credited to brainstem immaturity and/or cardiorespiratory autonomic dysautonomia [9, 27, 28]. However, as the pathogenesis of the respiratory dysfunction in RTT appears far from being completely understood, alternative or complementary hypotheses can be formulated [29]. In particular, the potential role of oxidative stress (OS) mediators and the role of the lung itself in the pathogenesis of the respiratory dysfunction in the human disease are incompletely understood. More recently, biochemical evidence of redox imbalance and, in particular, enhanced lipid peroxidation, in blood samples from RTT patients, was further confirmed in primary skin fibroblasts cultures from patients [30–37], although the nature of the relationship, that is, whether causal or correlational, between MECP2 gene mutation and abnormal redox homeostasis remains currently unclear. Significantly increased pulmonary alveolar-arterial gradient for O2 , highly suggestive for an abnormal pulmonary gas exchange, has been previously described by our group in the majority (...truncated)