GAA deficiency disrupts distal airway cells in Pompe disease.
GAA deficiency disrupts distal airway cells in Pompe disease.
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GAA 缺乏会破坏庞贝病中的远端气道细胞。
DOI：
10.1152/ajplung.00032.2023
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
ElMallah,MaiK
中科院分区：
文献类型：
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作者：
ElHaddad,Léa;Lai,Elias;Murthy,PreetishKadurLakshminarasimha;Biswas,DebolinaD;Soufny,Rania;Roger,AngelaL;Tata,PurushothamaRao;ElMallah,MaiK
庞贝氏症是一种常染色体隐性遗传性糖原贮积病，由编码酸性α-葡糖苷酶（GAA）的基因突变引起，GAA是一种负责水解溶酶体糖原的酶。GAA缺乏导致全身性溶酶体糖原蓄积和细胞破坏。已知骨骼肌、运动神经元和气道平滑肌细胞中的糖原积聚导致庞贝氏症的呼吸功能不全。然而，GAA缺乏对远端肺泡1型和2型细胞（AT 1和AT 2）的影响尚未评估。AT 1细胞依赖于溶酶体的细胞内稳态，使它们可以保持气体交换的薄屏障，而AT 2细胞依赖于溶酶体样结构（板层体）的表面活性剂的生产。使用庞贝氏症的小鼠模型，theGaa−/−小鼠，我们研究了GAA缺乏对AT 1和AT 2细胞的影响，使用组织学，肺功能和力学，以及转录分析。组织学分析显示，Gaa −/−小鼠肺中溶酶体相关膜蛋白1（LAMP 1）的积累增加。此外，超微结构检查显示广泛的胞浆内空泡扩大和板层体肿胀。使用全身体积描记法和强迫呼吸测量法证实呼吸功能障碍。最后，转录组学分析证实了AT 2细胞中表面活性蛋白的失调，特别是Gaa −/−小鼠中表面活性蛋白D的水平降低。我们的结论是，GAA酶缺乏导致糖原积累在远端气道细胞，破坏表面活性物质的体内平衡，并有助于呼吸障碍在庞贝氏症。新&值得注意的是这项研究突出了庞贝氏症对远端气道细胞的影响。在这项工作之前，庞贝氏症的呼吸功能不全通常归因于呼吸肌和运动神经元的病理学。使用Pompe小鼠模型，我们注意到肺泡1型和2型细胞中的显著病理学，表面活性蛋白D减少，表面活性物质稳态破坏。这些新的发现突出了肺泡病理对庞贝氏症呼吸功能不全的潜在贡献。
Pompe disease is an autosomal recessive glycogen storage disease caused by mutations in the gene that encodes acid alpha-glucosidase (GAA)—an enzyme responsible for hydrolyzing lysosomal glycogen. GAA deficiency results in systemic lysosomal glycogen accumulation and cellular disruption. Glycogen accumulation in skeletal muscles, motor neurons, and airway smooth muscle cells is known to contribute to respiratory insufficiency in Pompe disease. However, the impact of GAA deficiency on the distal alveolar type 1 and type 2 cells (AT1 and AT2) has not been evaluated. AT1 cells rely on lysosomes for cellular homeostasis so that they can maintain a thin barrier for gas exchange, whereas AT2 cells depend on lysosome-like structures (lamellar bodies) for surfactant production. Using a mouse model of Pompe disease, theGaa−/−mouse, we investigated the consequences of GAA deficiency on AT1 and AT2 cells using histology, pulmonary function and mechanics, and transcriptional analysis. Histological analysis revealed increased accumulation of lysosomal-associated membrane protein 1 (LAMP1) in theGaa−/−mice lungs. Furthermore, ultrastructural examination showed extensive intracytoplasmic vacuoles enlargement and lamellar body engorgement. Respiratory dysfunction was confirmed using whole body plethysmography and forced oscillometry. Finally, transcriptomic analysis demonstrated dysregulation of surfactant proteins in AT2 cells, specifically reduced levels of surfactant protein D in theGaa−/−mice. We conclude that GAA enzyme deficiency leads to glycogen accumulation in the distal airway cells that disrupts surfactant homeostasis and contributes to respiratory impairments in Pompe disease.NEW & NOTEWORTHYThis research highlights the impact of Pompe disease on distal airway cells. Prior to this work, respiratory insufficiency in Pompe disease was classically attributed to pathology in respiratory muscles and motor neurons. Using the Pompe mouse model, we note significant pathology in alveolar type 1 and 2 cells with reductions in surfactant protein D and disrupted surfactant homeostasis. These novel findings highlight the potential contributions of alveolar pathology to respiratory insufficiency in Pompe disease.