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

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) 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 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 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 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.

Acid Ceramidase Deficiency in Mice Leads to Severe Ocular Pathology and Visual Impairment

“…Evans Blue Dye accumulation was measured in various organs in Asah1 P361R/P361R mice. 22 Although not reported in that study, qualitatively, Asah1 P361R/P361R mouse eyes were more intensely stained than controls. Inflammatory cytokines, such as monocyte chemoattractant proteins 1, 3, and 5, increase in serum and organs from Asah1 P361R/P361R animals.…”

“…An increased prevalence of inflammatory cells has been previously reported in the lungs, brain, and hematopoietic organs in this mouse model of FD. 21,22,32 Thus, finding that a deficiency in ACDase activity also leads to inflammation in the eye and optic nerve could be expected. Through the use of noninvasive ocular imaging, the formation of granulomas and nodules was noted in the anterior chambers.…”

“…We previously reported increased vascular permeability in the Asah1 P361R/P361R mice. 22 Although that study was primarily focused on lung pathology, one experiment involved a tail vein injection of Evans Blue Dye. Evans Blue Dye accumulation was measured in various organs in Asah1 P361R/P361R mice.…”

Novel mechanisms regulating endothelial barrier function in the pulmonary microcirculation

“…The recognition of ASM‐dependent stimulated albumin transcytosis across the pulmonary endothelium opens up several new avenues for consideration in that it (a) challenges the classic view of total protein or albumin content in the bronchoalveolar lavage (BAL) as a marker of paracellular leak in inflammatory lung disorders, (b) poses a potential window for targeted drug delivery to the pulmonary endo‐ and epithelium, and (c) may provide for an intriguing hypothetical explanation for the pulmonary phenotype in Farber disease, a deficiency in acid ceramidase which results in accumulation of ceramide in lung tissue and a striking accumulation of proteins including albumin, IgG and IgM in the alveolar space (Yu et al . ). It should, however, be duly noted that at present the in vivo relevance of endothelial transcytosis versus paracellular permeability for quantitative protein leak in the injured lung remains speculative.…”

Acid Sphingomyelinase Deficiency Ameliorates Farber Disease

“…The latter two models retained sufficient residual Ac activity to overcome the apoptotic threshold during early embryogenesis and yielded viable offsprings with a variety of pathological manifestation of FD. These include severely shortened lifespan, tissue infiltration with lipid-laden macrophages, joint pathologies, perturbed hematopoiesis, changes in plasma cytokine levels, central nervous system abnormalities, pulmonary inflammation, visual impairments, hepatic fibrosis, muscular dystrophy, and reduced renal function [19][20][21][22][23][24][25].…”