Chronic lung injury and impaired pulmonary function in a mouse model of acid ceramidase deficiency

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11110%2F18%3A10376632" target="_blank" >RIV/00216208:11110/18:10376632 - isvavai.cz</a>

Alternative codes found

RIV/00023001:_____/18:00076549 RIV/00064165:_____/18:10376632

Result on the web

<a href="https://doi.org/10.1152/ajplung.00223.2017" target="_blank" >https://doi.org/10.1152/ajplung.00223.2017</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1152/ajplung.00223.2017" target="_blank" >10.1152/ajplung.00223.2017</a>

Result language

angličtina

Original language name

Chronic lung injury and impaired pulmonary function in a mouse model of acid ceramidase deficiency

Original language description

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 (Asah1P361R/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 Asah1P361R/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 Asah1P361R/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 Asah1P361R/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.

Czech name

—

Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

10600 - Biological sciences

Project

<a href="/en/project/LM2015091" target="_blank" >LM2015091: National Center for Medical Genomic</a><br>

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)<br>I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2018

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

American Journal of Physiology - Lung Cellular and Molecular Physiology

ISSN

1040-0605

e-ISSN

—

Volume of the periodical

314

Issue of the periodical within the volume

3

Country of publishing house

US - UNITED STATES

Number of pages

15

Pages from-to

"L406"-"L420"

UT code for WoS article

000428403800007

EID of the result in the Scopus database

2-s2.0-85041372176