Inflammatory lung disease in Rett syndrome.

Abstract

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.

• Authors: Claudio De Felice, Marcello Rossi, Silvia Leoncini, Glauco Chisci, Cinzia Signorini, Giuseppina Lonetti, Laura Vannuccini, Donatella Spina, Alessandro Ginori, Ingrid Iacona, Alessio Cortelazzo, Alessandra Pecorelli, Giuseppe Valacchi, Lucia Ciccoli, Tommaso Pizzorusso, Joussef Hayek
• Journal: Mediators of inflammation (Mediators Inflamm) Vol. 2014 Pg. 560120 ( 2014) ISSN: 1466-1861 [Electronic] United States
• PMID: 24757286 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antioxidants
• MECP2 protein, human
• Methyl-CpG-Binding Protein 2
• Glutathione

Topics

• Adolescent
• Adult
• Animals
• Antioxidants (metabolism)
• Child
• Child, Preschool
• Disease Models, Animal
• Female
• Glutathione (metabolism)
• Humans
• Infant
• Inflammation (pathology)
• Lung (pathology)
• Lung Diseases (physiopathology)
• Methyl-CpG-Binding Protein 2 (metabolism)
• Mice
• Mice, Inbred C57BL
• Mutation
• Oxidation-Reduction
• Pulmonary Gas Exchange
• Rett Syndrome (metabolism, physiopathology)
• Young Adult