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Beyond Upper Airway Involvement: Evidence of Intrinsic Lung Disease in a Mouse Model of Mucopolysaccharidosis I
Martin Donnelley1,2,3, Ronan Smith1,2,3, Patricia Cmielewski1,2,3
1Robinson Research Institute, Adelaide University, Adelaide, South Australia.
Abstract:
Almost all patients with mucopolysaccharidosis (MPS) develop respiratory dysfunction of varying severity during disease progression. While respiratory disease in MPS has traditionally been attributed to upper airway obstruction caused by glycosaminoglycan (GAG) accumulation in the trachea and bronchi, involvement of the intrapulmonary conducting airways and lung parenchyma remains poorly defined. Here, we characterised lung disease in a mouse model of MPS I using a combination of non-invasive X-ray Velocimetry (XV) functional lung imaging and gold-standard flexiVent respiratory mechanics testing, complemented by lung volume measurements and histological analysis. XV provides regional ventilation information across the entire lung during tidal breathing. MPS I mice demonstrated reduced mean specific ventilation (the average regional expansion of lung tissue across the respiratory cycle), driven predominantly by reduced ventilation in the inner (mediastinal-adjacent) lung regions, with evidence of spatially heterogeneous ventilation distribution. Lung mechanics testing showed increased conducting airway resistance, increased respiratory system compliance and reduced tissue elastance, consistent with impaired elastic recoil and expiratory flow limitation. Lung volume analysis revealed reduced opening pressure following degassing together with increased residual volume, functional residual capacity and vital capacity. Histological analysis demonstrated heterogeneous parenchymal architecture with regions of enlarged airspaces. Together, these findings demonstrate that respiratory dysfunction in MPS I is not limited to upper airway obstruction but also involves intrinsic abnormalities of the intrapulmonary conducting airways and lung parenchyma. This intrinsic pulmonary pathology likely contributes to obstructive lung disease and may underlie the susceptibility to respiratory failure observed in patients with MPS I.
Insights
Respiratory dysfunction in mucopolysaccharidosis type I (MPS I) involves more than just upper airway obstruction. Intrinsic lung abnormalities in conducting airways and parenchyma contribute to breathing difficulties in MPS I mice.
Area of Science:
- Pulmonary Medicine
- Rare Diseases
- Genetics
Background:
- Respiratory dysfunction is common in mucopolysaccharidosis (MPS).
- Traditionally attributed to upper airway obstruction from GAG accumulation.
- Intrapulmonary airway and lung parenchyma involvement is poorly understood.
Purpose of the Study:
- To characterize lung disease in a mouse model of MPS I.
- To investigate intrapulmonary airway and lung parenchyma abnormalities.
- To understand the mechanisms of respiratory dysfunction in MPS I.
Main Methods:
- Non-invasive X-ray Velocimetry (XV) functional lung imaging.
- FlexiVent respiratory mechanics testing.
- Lung volume measurements and histological analysis.
Main Results:
- MPS I mice showed reduced specific ventilation, particularly in inner lung regions.
- Increased conducting airway resistance, compliance, and reduced tissue elastance.
- Histology revealed heterogeneous lung parenchyma with enlarged airspaces.
Conclusions:
- Respiratory dysfunction in MPS I extends beyond upper airway obstruction.
- Intrinsic pulmonary pathology contributes to obstructive lung disease.
- Abnormalities in conducting airways and parenchyma likely increase respiratory failure risk.
