Pathogenesis of Lethal Aspiration Pneumonia in Mecp2-null Mouse Model for Rett Syndrome

Hiroshi Kida,Toyojiro Matsuishi,Takayuki Taniwaki,Takashi Kinoshita,Tomoyuki Takahashi,Ken-Ichiro Kosai,Satoko Okayama,Yuki Nakamura,Masaki Okamoto,Keiichiro Nakamura,Yushiro Yamashita,Munetsugu Hara

doi:10.1038/s41598-017-12293-8

Hiroshi Kida, Toyojiro Matsuishi + Show 10 more

Open Access

https://doi.org/10.1038/s41598-017-12293-8

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Abstract

Rett syndrome (RTT) is a neurodevelopmental disorder mainly caused by mutations in the gene encoding the transcriptional regulator Methyl-CpG-binding protein 2 (MeCP2), located on the X chromosome. Many RTT patients have breathing abnormalities, such as apnea and breathing irregularity, and respiratory infection is the most common cause of death in these individuals. Previous studies showed that MeCP2 is highly expressed in the lung, but its role in pulmonary function remains unknown. In this study, we found that MeCP2 deficiency affects pulmonary gene expression and structures. We also found that Mecp2-null mice, which also have breathing problems, often exhibit inflammatory lung injury. These injuries occurred in specific sites in the lung lobes. In addition, polarizable foreign materials were identified in the injured lungs of Mecp2-null mice. These results indicated that aspiration might be a cause of inflammatory lung injury in Mecp2-null mice. On the other hand, MeCP2 deficiency affected the expression of several neuromodulator genes in the lower brainstem. Among them, neuropeptide substance P (SP) immunostaining was reduced in Mecp2-null brainstem. These findings suggest that alteration of SP expression in brainstem may be involved in autonomic dysregulation, and may be one of the causes of aspiration in Mecp2-null mice.

Highlights

Among the most prominent clinical features of Rett syndrome (RTT) are breathing irregularities, including breath holding, apnea, apneusis, hyperventilation, and rapid shallow breathing[11,12,13,14,15]
Macroscopic observation revealed that 60% (18/30) of Mecp2-null mice had lung abnormalities (Fig. 1a)
Postmortem examination revealed that over 80% (29/34 cases) of dead mutant mice had lung abnormalities (Fig. 1a and Supplementary Fig. S1). These results indicate that lung abnormalities in Mecp2-null mice occurred in specific pulmonary lobes

Summary

Introduction

Among the most prominent clinical features of RTT are breathing irregularities, including breath holding, apnea, apneusis, hyperventilation, and rapid shallow breathing[11,12,13,14,15]. The respiratory dysfunctions observed in RTT patients have been replicated in several mutant mouse models[16,17,18]. Recent studies suggest that the respiratory dysfunction observed in RTT may result from abnormalities of the pulmonary system itself[19,20,21,22,23,24]. (f) Incidence of abnormalities in each pulmonary lobe of Mecp2-null lungs (n = 15). The pathogenesis of inflammatory lung injury in MeCP2-deficient mice and RTT patients remains to be elucidated. We investigated developmental mechanisms of inflammatory lung injury and examined the effects of MeCP2 deficiency in the respiratory system itself. Aspiration pneumonia might be a cause of inflammatory lung injury in the Mecp2-null mouse model of RTT

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