Chronic lung injury and impaired pulmonary function in a mouse model of acid ceramidase deficiency
Bibliographic record
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.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".