Inflammatory lung disease in Rett syndrome.
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.
Neonatal Intensive Care Unit, University Hospital Azienda Ospedaliera Universitaria Senese (AOUS), Viale M. Bracci 16, 53100 Siena, Italy.
Claudio
C
De Felice
Respiratory Pathophysiology and Rehabilitation Unit, University Hospital, AOUS, Viale M. Bracci 16, 53100 Siena, Italy.
Marcello
M
Rossi
Department of Molecular and Developmental Medicine, University of Siena, Via A. Moro 2, 53100 Siena, Italy ; Child Neuropsychiatry Unit, University Hospital AOUS, Viale M. Bracci 16, 53100 Siena, Italy.
Silvia
0000-0002-7027-1207
S
Leoncini
Department of Maxillofacial Surgery, University of Siena, Viale M. Bracci 16, 53100 Siena, Italy.
Glauco
G
Chisci
Department of Molecular and Developmental Medicine, University of Siena, Via A. Moro 2, 53100 Siena, Italy.
Cinzia
0000-0003-0006-9414
C
Signorini
Institute of Neuroscience, CNR, Via G. Moruzzi 1, 56124 Pisa, Italy.
Giuseppina
G
Lonetti
Respiratory Pathophysiology and Rehabilitation Unit, University Hospital, AOUS, Viale M. Bracci 16, 53100 Siena, Italy.
Laura
L
Vannuccini
Pathology Unit, University Hospital AOUS, Viale M. Bracci 16, 53100 Siena, Italy.
Donatella
D
Spina
Pathology Unit, University Hospital AOUS, Viale M. Bracci 16, 53100 Siena, Italy.
Alessandro
0000-0003-2807-846X
A
Ginori
Respiratory Pathophysiology and Rehabilitation Unit, University Hospital, AOUS, Viale M. Bracci 16, 53100 Siena, Italy.
Ingrid
I
Iacona
Child Neuropsychiatry Unit, University Hospital AOUS, Viale M. Bracci 16, 53100 Siena, Italy ; Department of Medical Biotechnologies, University of Siena, Via A. Moro 2, 53100 Siena, Italy.
Alessio
A
Cortelazzo
Department of Molecular and Developmental Medicine, University of Siena, Via A. Moro 2, 53100 Siena, Italy ; Child Neuropsychiatry Unit, University Hospital AOUS, Viale M. Bracci 16, 53100 Siena, Italy.
Alessandra
0000-0002-5207-068X
A
Pecorelli
Department of Life Sciences and Biotechnology, University of Ferrara, Via Borsari 46, 44100 Ferrara, Italy.
Giuseppe
0000-0002-8792-0947
G
Valacchi
Department of Molecular and Developmental Medicine, University of Siena, Via A. Moro 2, 53100 Siena, Italy.
Lucia
L
Ciccoli
Institute of Neuroscience, CNR, Via G. Moruzzi 1, 56124 Pisa, Italy ; Department of Neuroscience, Psychology, Drug Research and Child Health (Neurofarba), University of Florence, Area S. Salvi Pad. 26, 50135 Florence, Italy.
Tommaso
T
Pizzorusso
Child Neuropsychiatry Unit, University Hospital AOUS, Viale M. Bracci 16, 53100 Siena, Italy.
Joussef
J
Hayek
D000293:Adolescent; D000328:Adult; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004195:Disease Models, Animal; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007223:Infant; D007249:Inflammation / Q000473:pathology*; D008168:Lung / Q000473:pathology; D008171:Lung Diseases / Q000503:physiopathology*; D051783:Methyl-CpG-Binding Protein 2 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D010084:Oxidation-Reduction; D011659:Pulmonary Gas Exchange; D015518:Rett Syndrome / Q000378:metabolism / Q000503:physiopathology*; D055815:Young Adult
D000975:Antioxidants; C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2; D005978:Glutathione