Characterization of lungs in a transgenic acid sphingomyelinase mouse model

The expression and activity of the acid sphingomyelinase (ASM), a central enzyme of sphingolipid metabolism, has been identified as an important factor in a variety of pathological settings, including major depression as well as inflammatory and infectious diseases. To study the influence of the ASM in various diseases, Asm knockout mice are being widely used and are well characterized. It is of equal interest, however, to study the effects of increased ASM activity as well as the efficacy of drugs targeting such an overly active ASM. The aim of this dissertation is to characterize genetically modified mice, which constitutively overexpress the acid sphingomyelinase. Special emphasis was placed on examining the lung phenotype of these mice. The lipid composition was determined using mass spectrometric analysis. Confocal microscopy in conjunction with histological and immunofluorescence stainings were employed to investigate the lungs in more detail with respect to morphology, inflammatory status, and cellular infiltration. The activity of the Asm was assessed using an established enzyme assay. Since the Asm has been shown to control autophagy, proteins associated with this pathway were analyzed as well. It was shown that the transgenic mice display very high Asm activity compared to wildtype mice. There were no uniformly consistent changes in the lipid composition, however. Overall, the unchallenged transgenic mice did not show a phenotype divergent from that of wildtype mice. For the most part, the mice did not display pathologic alterations in their lung tissue. One notable exception to this is the distribution of ceramide, the product of the reaction catalyzed by Asm, within the lungs. Ceramide accumulations in bronchial epithelial cells are much more prominent in transgenic compared to wildtype mice. The implications of this have been touched upon in previous publications, but bear further investigation. As the acid sphingomyelinase can be activated by a diverse sets of stressors, the model presented here can be of significance in various fields of study. Numerous pathologies have already been linked to the ASM/ceramide system, which can now be studied using this new model system. As the mice do not differ significantly from wildtype mice, they lend themselves as an ideal model to investigate Asm-related effects specific to the stressor applied.



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