Improved Pulmonary Function by Acid Sphingomyelinase Inhibition in a Newborn Piglet Lavage Model

Bismarck, Philipp von; Wistädt, Carlos-Francisco García; Klemm, Karsten; Winoto-Morbach, Supandi; Uhlig, Ulrike; Schütze, Stefan; Adam, Dieter; Lachmann, Burkhard; Uhlig, Stefan; Krause, Martín

doi:10.1164/rccm.200705-752oc

Cited by 54 publications

(58 citation statements)

References 42 publications

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“…Our results are also in agreement with other recent reports showing that the sphingolipid signaling pathway, and ASM activation in particular, is involved in the pathogenesis of acute lung injury induced by a number of different extrinsic factors [e.g., 37,41,42]. It may therefore be particularly useful to target this pathway for Cell Physiol Biochem 2010; 26:749-760 …”

Section: Discussionsupporting

confidence: 92%

Acid Sphingomyelinase Deficiency Attenuates Bleomycin-Induced Lung Inflammation and Fibrosis in Mice

Dhami

Schuchman

2010

Cell Physiol Biochem

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Background/Aims: The sphingomyelin/ceramide signaling pathway is an important component of many cellular processes implicated in the pathogenesis of lung disease. Acid sphingomyelinase (ASM) is a key mediator of this pathway, but its specific role in pulmonary fibrosis has not been previously investigated. Here we used the bleomycin model of pulmonary fibrosis to investigate fibrotic responses in normal and ASM knockout (ASM^-/-) mice, and in NIH3T3 fibroblasts with and without ASM siRNA treatment. Methods: Mice and cells with and without ASM activity were treated with bleomycin, and the effects on lung inflammation, formation of collagen producing myofibroblasts, and apoptosis were assessed. Results: The development of bleomycin-induced inflammation and fibrosis in wildtype mice correlated with the rapid activation of ASM, and was markedly attenuated in the absence of ASM activity. Along with the elevated ASM activity, there also was an elevation of acid ceramidase (AC) activity, which was sustained for up to 14 days post-bleomycin treatment. Studies in NIH3T3 fibroblasts confirmed these findings, and revealed a direct effect of ASM/AC activation on the formation of myofibroblasts. Cell studies also showed that a downstream effect of bleomycin treatment was the production of sphingosine-1-phosphate. Conclusions: These data demonstrate that the sphingomyelin/ceramide signaling pathway is involved in the pathogenesis of bleomycin-induced pulmonary fibrosis, and suggest that inhibition of ASM may potentially slow the fibrotic process in the lung.

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Section: Discussionsupporting

confidence: 92%

Acid Sphingomyelinase Deficiency Attenuates Bleomycin-Induced Lung Inflammation and Fibrosis in Mice

Dhami

Schuchman

2010

Cell Physiol Biochem

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“…The authors speculate that, due to the high abundance of S-ASM from endothelial cells, injured lung capillary endothelial cells aggravate cellular damage in a vicious cycle, resulting in the sustained lung damage observed in patients despite smoking cessation. In a neonatal pigled model of pulmonary inflammation, S-ASM activity and ceramide concentration are reduced in serum after treatment of lungs with inhaled surfactant factor combined with the FIASMA imipramine (von Bismarck et al, 2008;Preuß et al, 2012).…”

Section: S-asm In Pulmonary Edemamentioning

confidence: 99%

Secretory sphingomyelinase in health and disease

Kornhuber

Rhein

Müller

et al. 2015

Biological Chemistry

124

138

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Acid sphingomyelinase (ASM), a key enzyme in sphingolipid metabolism, hydrolyzes sphingomyelin to ceramide and phosphorylcholine. In mammals, the expression of a single gene, SMPD1, results in two forms of the enzyme that differ in several characteristics. Lysosomal ASM (L-ASM) is located within the lysosome, requires no additional Zn 2+ ions for activation and is glycosylated mainly with high-mannose oligosaccharides. By contrast, the secretory ASM (S-ASM) is located extracellularly, requires Zn 2+ ions for activation, has a complex glycosylation pattern and has a longer in vivo half-life. In this review, we summarize current knowledge regarding the physiology and pathophysiology of S-ASM, including its sources and distribution, molecular and cellular mechanisms of generation and regulation and relevant in vitro and in vivo studies. Polymorphisms or mutations of SMPD1 lead to decreased S-ASM activity, as detected in patients with Niemann-Pick disease B. Thus, lower serum/ plasma activities of S-ASM are trait markers. No genetic causes of increased S-ASM activity have been identified. Instead, elevated activity is the result of enhanced release (e.g., induced by lipopolysaccharide and cytokine stimulation) or increased enzyme activation (e.g., induced by oxidative stress). Increased S-ASM activity in serum or plasma is a state marker of a wide range of diseases. In particular, high S-ASM activity occurs in inflammation of the endothelium and liver. Several studies have demonstrated a correlation between S-ASM activity and mortality induced by severe inflammatory diseases. Serial measurements of S-ASM reveal prolonged activation and, therefore, the measurement of this enzyme may also provide information on past inflammatory processes. Thus, S-ASM may be both a promising clinical chemistry marker and a therapeutic target.

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“…by supplementing additives [146][147][148][149][150][151][152][153][154]. In general, surfactantprotective strategies should not only target the intraalveolar but also the intracellular pool (i.e.…”

Section: Surfactant In Lung Ischemia/reperfusion Injurymentioning

confidence: 99%

The Closer we Look the more we See? Quantitative Microscopic Analysis of the Pulmonary Surfactant System

Ochs

2010

Cell Physiol Biochem

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The surfactant system of the lung has essential biophysical and immunomodulatory functions. Only at the electron microscopic level does surfactant reveal its morphological complexity - and beauty. Therefore, morphological tools are indispensible to characterize the surfactant system in health and disease. Stereology provides the gold standard for obtaining quantitative (morphometric) data in microscopy. The combination of microscopy and stereology allows for qualitative and quantitative analysis of the intraalveolar as well as the intracellular surfactant pool, both in its preserved microorganization and localization within the lung. Surfactant-producing alveolar epithelial type II cells can be counted and sampled for size estimation with physical disectors at a high magnification light microscopic level. The number of their surfactant storing lamellar bodies can be estimated using physical disectors at the electron microscopic level. Electron tomography allows for high resolution 3D visualization of lamellar body fusion pores. Intraalveolar surfactant subtypes can be quantitated in situ, thus reflecting the functional state of the intraalveolar surfactant pool. By immunoelectron microscopy, surfactant protein distribution can be analyzed. These methods allow for a comprehensive quantitative analysis of surfactant (ultra-)structure. Here, we give an overview on the analysis of the normal and disordered surfactant system by electron microscopy and stereology.

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Improved Pulmonary Function by Acid Sphingomyelinase Inhibition in a Newborn Piglet Lavage Model

Abstract: We conclude that stabilization of exogenous surfactant by adding imipramine to create a "fortified surfactant preparation" improves lung function in a clinically relevant piglet model, and that this effect can be attributed to the inhibition of a-SMase as evidenced in the mouse model.

Cited by 54 publications

References 42 publications

Acid Sphingomyelinase Deficiency Attenuates Bleomycin-Induced Lung Inflammation and Fibrosis in Mice

Acid Sphingomyelinase Deficiency Attenuates Bleomycin-Induced Lung Inflammation and Fibrosis in Mice

Secretory sphingomyelinase in health and disease

The Closer we Look the more we See? Quantitative Microscopic Analysis of the Pulmonary Surfactant System

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