Mechanisms in Cell Biology and Diseases Research Concentration, Clinical & Health Sciences, University of South Australia, Adelaide, South Australia, Australia.
Respiratory Environmental Health, Wal-yan Respiratory Research Centre, Telethon Kids Institute, Perth, Western Australia, Australia.
Am J Physiol Lung Cell Mol Physiol. 2024 Jun 1;326(6):L713-L726. doi: 10.1152/ajplung.00445.2022. Epub 2024 Mar 5.
Mucopolysaccharidosis type IIIA (MPS IIIA) is characterized by neurological and skeletal pathologies caused by reduced activity of the lysosomal hydrolase, sulfamidase, and the subsequent primary accumulation of undegraded heparan sulfate (HS). Respiratory pathology is considered secondary in MPS IIIA and the mechanisms are not well understood. Changes in the amount, metabolism, and function of pulmonary surfactant, the substance that regulates alveolar interfacial surface tension and modulates lung compliance and elastance, have been reported in MPS IIIA mice. Here we investigated changes in lung function in 20-wk-old control and MPS IIIA mice with a closed and open thoracic cage, diaphragm contractile properties, and potential parenchymal remodeling. MPS IIIA mice had increased compliance and airway resistance and reduced tissue damping and elastance compared with control mice. The chest wall impacted lung function as observed by an increase in airway resistance and a decrease in peripheral energy dissipation in the open compared with the closed thoracic cage state in MPS IIIA mice. Diaphragm contractile forces showed a decrease in peak twitch force, maximum specific force, and the force-frequency relationship but no change in muscle fiber cross-sectional area in MPS IIIA mice compared with control mice. Design-based stereology did not reveal any parenchymal remodeling or destruction of alveolar septa in the MPS IIIA mouse lung. In conclusion, the increased storage of HS which leads to biochemical and biophysical changes in pulmonary surfactant also affects lung and diaphragm function, but has no impact on lung or diaphragm structure at this stage of the disease. Heparan sulfate storage in the lungs of mucopolysaccharidosis type IIIA (MPS IIIA) mice leads to changes in lung function consistent with those of an obstructive lung disease and includes an increase in lung compliance and airway resistance and a decrease in tissue elastance. In addition, diaphragm muscle contractile strength is reduced, potentially further contributing to lung function impairment. However, no changes in parenchymal lung structure were observed in mice at 20 wk of age.
黏多糖贮积症 IIIA 型（MPS IIIA）的特征是神经和骨骼病理学，这是由溶酶体水解酶、磺基转移酶活性降低以及随后未降解的硫酸乙酰肝素（HS）的主要积累引起的。在 MPS IIIA 中，呼吸病理学被认为是次要的，其机制尚不清楚。已经报道了 MPS IIIA 小鼠中肺表面活性物质的量、代谢和功能发生变化，肺表面活性物质是调节肺泡界面表面张力并调节肺顺应性和弹性的物质。在这里，我们研究了 20 周龄对照和 MPS IIIA 小鼠的肺功能变化，包括胸廓、膈肌收缩特性以及潜在的实质重塑。与对照小鼠相比，MPS IIIA 小鼠的顺应性增加，气道阻力增加，组织阻尼和弹性降低。与闭合胸廓相比，胸廓壁的影响使气道阻力增加，在外周能量耗散减少，在 MPS IIIA 小鼠中观察到这种情况。与对照小鼠相比，MPS IIIA 小鼠的膈肌收缩力表现为峰值抽搐力、最大比肌力和力频关系下降，但肌肉纤维横截面积无变化。基于设计的体视学没有发现 MPS IIIA 小鼠肺实质重塑或肺泡隔破坏。总之，HS 的储存增加导致肺表面活性物质的生化和生物物理变化也会影响肺和膈肌功能，但在疾病的这个阶段对肺或膈肌结构没有影响。黏多糖贮积症 IIIA 型（MPS IIIA）小鼠肺部的 HS 储存导致与阻塞性肺病一致的肺功能变化，包括肺顺应性和气道阻力增加，组织弹性降低。此外，膈肌肌肉收缩强度降低，可能进一步导致肺功能障碍。然而，在 20 周龄的小鼠中，没有观察到实质肺结构的变化。
