Chronic lung injury and impaired pulmonary function in a mouse model of acid ceramidase deficiency.
Chronic lung injury and impaired pulmonary function in a mouse model of acid ceramidase deficiency.
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DOI：
10.1152/ajplung.00223.2017
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发表时间：
2018-03
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影响因子：
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通讯作者：
Fabian P. S. Yu;D. Islam;J. Sikora;Shaalee Dworski;Jiri Gurka;Lucía López-Vásquez;Mingyao Liu;W. Kuebler;T. Levade;Haibo Zhang;J. Medin
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文献类型：
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作者：
Fabian P. S. Yu;D. Islam;J. Sikora;Shaalee Dworski;Jiri Gurka;Lucía López-Vásquez;Mingyao Liu;W. Kuebler;T. Levade;Haibo Zhang;J. Medin
Farber病(FD)是一种由于ASAH1基因突变导致的酸性神经酰胺酶(ACDase)活性不足引起的衰弱的溶酶体储存障碍(LSD)。ACDase缺乏的患者可能会出现一系列的临床表型。严重的FD病例常常与神经系统受累、生长发育不良和呼吸道并发症有关。人类FD患者ASAH1基因突变的纯合子(Asah1P361R/P361R)小鼠。在这项研究中，我们发现在ACDase缺乏的小鼠模型中，肺功能显著受损，包括顺应性降低和气道阻力增加。Farber小鼠的肺力学受损导致血液氧合降低和红细胞生成增加。炎症细胞被招募到肺的血管周围和支气管周围区域。我们观察到大的空泡化泡沫组织细胞，其中充满了储存物质。血管通透性的增加导致Asah1P361R/P361R小鼠肺内蛋白质渗漏、水肿，并影响肺表面活性物质的稳态。支气管肺泡灌洗液(BALF)的提取和分析显示聚集了一种高度混浊的脂蛋白样物质，该物质由部分表面活性物质、磷脂和神经酰胺组成。Asah1P361R/P361R小鼠BALF的磷脂组成发生严重改变，磷脂酰乙醇胺(PE)和鞘磷脂(SM)均升高。与野生型动物相比，Asah1P361R/P361R小鼠BALF和肺组织中神经酰胺的水平也显著升高。我们证明，ACDase缺乏会导致鞘磷脂和磷脂失衡，由显著炎症引起的慢性肺损伤，以及血管通透性增加，导致肺功能受损。
Farber disease (FD) is a debilitating lysosomal storage disorder (LSD) caused by a deficiency of acid ceramidase (ACDase) activity due to mutations in the gene ASAH1. Patients with ACDase deficiency may develop a spectrum of clinical phenotypes. Severe cases of FD are frequently associated with neurological involvement, failure to thrive, and respiratory complications. Mice homozygous ( Asah1P361R/P361R) for an orthologous patient mutation in Asah1 recapitulate human FD. In this study, we show significant impairment in lung function, including low compliance and increased airway resistance in a mouse model of ACDase deficiency. Impaired lung mechanics in Farber mice resulted in decreased blood oxygenation and increased red blood cell production. Inflammatory cells were recruited to both perivascular and peribronchial areas of the lung. We observed large vacuolated foamy histiocytes that were full of storage material. An increase in vascular permeability led to protein leakage, edema, and impacted surfactant homeostasis in the lungs of Asah1P361R/P361R mice. Bronchial alveolar lavage fluid (BALF) extraction and analysis revealed accumulation of a highly turbid lipoprotein-like substance that was composed in part of surfactants, phospholipids, and ceramides. The phospholipid composition of BALF from Asah1P361R/P361R mice was severely altered, with an increase in both phosphatidylethanolamine (PE) and sphingomyelin (SM). Ceramides were also found at significantly higher levels in both BALF and lung tissue from Asah1P361R/P361R mice when compared with levels from wild-type animals. We demonstrate that a deficiency in ACDase leads to sphingolipid and phospholipid imbalance, chronic lung injury caused by significant inflammation, and increased vascular permeability, leading to impaired lung function.