Increased Alveolar Heparan Sulphate and Reduced Pulmonary Surfactant Amount and Function in the Mucopolysaccharidosis IIIA Mouse
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Published on: December 26, 2012
Tamara L Paget1, Emma J Parkinson-Lawrence1, Paul J Trim2
1Mechanisms in Cell Biology and Disease Group, UniSA Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia.
Abstract:
Mucopolysaccharidosis IIIA (MPS IIIA) is a lysosomal storage disease with significant neurological and skeletal pathologies. Respiratory dysfunction is a secondary pathology contributing to mortality in MPS IIIA patients. Pulmonary surfactant is crucial to optimal lung function and has not been investigated in MPS IIIA. We measured heparan sulphate (HS), lipids and surfactant proteins (SP) in pulmonary tissue and bronchoalveolar lavage fluid (BALF), and surfactant activity in healthy and diseased mice (20 weeks of age). Heparan sulphate, ganglioside GM3 and bis(monoacylglycero)phosphate (BMP) were increased in MPS IIIA lung tissue. There was an increase in HS and a decrease in BMP and cholesteryl esters (CE) in MPS IIIA BALF. Phospholipid composition remained unchanged, but BALF total phospholipids were reduced (49.70%) in MPS IIIA. There was a reduction in SP-A, -C and -D mRNA, SP-D protein in tissue and SP-A, -C and -D protein in BALF of MPS IIIA mice. Captive bubble surfactometry showed an increase in minimum and maximum surface tension and percent surface area compression, as well as a higher compressibility and hysteresis in MPS IIIA surfactant upon dynamic cycling. Collectively these biochemical and biophysical changes in alveolar surfactant are likely to be detrimental to lung function in MPS IIIA.
Insights
Mucopolysaccharidosis IIIA (MPS IIIA) impairs lung function due to altered pulmonary surfactant. This study reveals biochemical and biophysical changes in surfactant, impacting respiratory health in MPS IIIA mice.
Area of Science:
- Biochemistry
- Pulmonary Medicine
- Lysosomal Storage Diseases
Background:
- Mucopolysaccharidosis IIIA (MPS IIIA) is a genetic disorder causing neurological and skeletal issues.
- Respiratory dysfunction is a significant cause of mortality in MPS IIIA patients.
- Pulmonary surfactant's role in MPS IIIA lung function has not been previously studied.
Purpose of the Study:
- To investigate the biochemical and biophysical properties of pulmonary surfactant in MPS IIIA.
- To assess the impact of MPS IIIA on surfactant composition and function.
Main Methods:
- Analysis of heparan sulphate, lipids, and surfactant proteins in lung tissue and bronchoalveolar lavage fluid (BALF) from MPS IIIA and healthy mice.
- Measurement of surfactant activity using captive bubble surfactometry.
- Quantification of mRNA and protein levels for surfactant proteins.
Main Results:
- Increased heparan sulphate, ganglioside GM3, and bis(monoacylglycero)phosphate in MPS IIIA lung tissue.
- Altered heparan sulphate, bis(monoacylglycero)phosphate, and cholesteryl esters in MPS IIIA BALF.
- Reduced surfactant protein (SP-A, SP-C, SP-D) expression and altered surfactant biophysical properties (increased surface tension, compressibility, hysteresis) in MPS IIIA mice.
Conclusions:
- Biochemical alterations in pulmonary surfactant components are present in MPS IIIA.
- Impaired surfactant biophysical function contributes to respiratory compromise in MPS IIIA.
- These surfactant changes are likely detrimental to lung function in MPS IIIA patients.
