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Mucopolysaccharidosis (MPS IIIA) mice have increased lung compliance and airway resistance, decreased diaphragm strength, and no change in alveolar structure

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dc.contributor.authorPaget, T.L.
dc.contributor.authorLarcombe, A.N.
dc.contributor.authorPinniger, G.J.
dc.contributor.authorTsioutsias, I.
dc.contributor.authorSchneider, J.P.
dc.contributor.authorParkinson-Lawrence, E.J.
dc.contributor.authorOrgeig, S.
dc.date.issued2024
dc.description.abstractMucopolysaccharidosis 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.<b>NEW & NOTEWORTHY</b> 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.
dc.identifier.citationAmerican Journal of Physiology - Lung Cellular and Molecular Physiology, 2024; 326(6):L713-L726
dc.identifier.doi10.1152/ajplung.00445.2022
dc.identifier.issn1040-0605
dc.identifier.issn1522-1504
dc.identifier.urihttps://hdl.handle.net/11541.2/39031
dc.language.isoen
dc.publisherAMER PHYSIOLOGICAL SOC
dc.relation.fundingCommonwealth Government of Australia Commonwealth Scholarships for South Australia Program
dc.rightsCopyright 2024 the American Physiological Society
dc.source.urihttps://doi.org/10.1152/ajplung.00445.2022
dc.subjectDiaphragm
dc.subjectLung
dc.subjectPulmonary Alveoli
dc.subjectAnimals
dc.subjectMice, Inbred C57BL
dc.subjectMice
dc.subjectMucopolysaccharidosis III
dc.subjectDisease Models, Animal
dc.subjectAirway Resistance
dc.subjectLung Compliance
dc.subjectMuscle Contraction
dc.subjectMale
dc.subjectMuscle Strength
dc.titleMucopolysaccharidosis (MPS IIIA) mice have increased lung compliance and airway resistance, decreased diaphragm strength, and no change in alveolar structure
dc.typeJournal article
pubs.publication-statusPublished
ror.mmsid9916864329601831

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