Abstract
BackgroundThe aim of this manuscript was to characterize airway ceramide profiles in a rodent model of elastase-induced emphysema and to examine the effect of pharmacological intervention directed towards ceramide metabolism.MethodsAdult mice were anesthetized and treated with an intratracheal instillation of elastase. Lung function was measured, broncho-alveolar lavage fluid collected and histological and morphometrical analysis of lung tissue performed within 3 weeks after elastase injection, with and without sphingomyelinase inhibitors or serine palmitoyltransferase inhibitor. Ceramides in broncho-alveolar lavage (BAL) fluid were quantified by tandem mass spectrometry.ResultsBAL fluid showed a transient increase in total protein and IgM, and activated macrophages and neutrophils. Ceramides were transiently upregulated at day 2 after elastase treatment. Histology showed persistent patchy alveolar destruction at day 2 after elastase installation. Acid and neutral sphingomyelinase inhibitors had no effect on BAL ceramide levels, lung function or histology. Addition of a serine palmitoyltransferase inhibitor ameliorated lung function changes and reduced ceramides in BAL.ConclusionsCeramides were increased during the acute inflammatory phase of elastase-induced lung injury. Since addition of a serine palmitoyltransferase inhibitor diminished the rise in ceramides and ameliorated lung function, ceramides likely contributed to the early phase of alveolar destruction and are a potential therapeutic target in the elastase model of lung emphysema.
Highlights
The aim of this manuscript was to characterize airway ceramide profiles in a rodent model of elastase-induced emphysema and to examine the effect of pharmacological intervention directed towards ceramide metabolism
We investigated ceramide profiles in the lungs and examined the effect of pharmacological interventions targeting SMases and serine palmitoyltransferase (SPT) in an animal model of elastase-induced emphysema
broncho-alveolar lavage (BAL) analysis A 4-fold increase in total ceramide and dihydroceramide levels was found at day 2 after elastase instillation when compared to saline-treated controls (Figure 1 and Table 1)
Summary
The aim of this manuscript was to characterize airway ceramide profiles in a rodent model of elastase-induced emphysema and to examine the effect of pharmacological intervention directed towards ceramide metabolism. Ceramide has been shown to trigger apoptosis in an experimental mouse model of emphysema [22], and increased levels of apoptosis have been found in the lungs of patients with severe cigarette-induced emphysema [23]. Since ceramide levels are increased in the lungs of patients with smoke-induced emphysema [22] ceramide upregulation might be an important pathogenetic element in emphysema development. We investigated ceramide profiles in the lungs and examined the effect of pharmacological interventions targeting SMases and SPT in an animal model of elastase-induced emphysema
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