Faculty Collaboration Database

Chronic lung injury and impaired pulmonary function in a mouse model of acid ceramidase deficiency. Am J Physiol Lung Cell Mol Physiol 2018 Mar 01;314(3):L406-L420

Date

11/24/2017

Pubmed ID

29167126

Pubmed Central ID

PMC5900354

DOI

10.1152/ajplung.00223.2017

Scopus ID

2-s2.0-85041372176 (requires institutional sign-in at Scopus site)   30 Citations

Abstract

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 ( Asah1^P361R/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 Asah1^P361R/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 Asah1^P361R/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 Asah1^P361R/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.

Author List

Yu FPS, Islam D, Sikora J, Dworski S, Gurka J, López-Vásquez L, Liu M, Kuebler WM, Levade T, Zhang H, Medin JA

Author

Jeffrey A. Medin PhD Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Acid Ceramidase
Animals
Bronchoalveolar Lavage Fluid
Ceramides
Disease Models, Animal
Homozygote
Lung
Lung Injury
Mice
Mice, Knockout
Phenotype
Phospholipids
Respiratory Function Tests