Reactive nitrogen and oxygen species activate different sphingomyelinases to induce apoptosis in airway epithelial cells

Castillo, S. Sianna; Levy, Michal; Thaikoottathil, Jyoti; Goldkorn, Tzipora

doi:10.1016/j.yexcr.2007.04.002

Cited by 88 publications

(66 citation statements)

References 29 publications

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“…At the same time, we have shown that reactive oxidants up-regulate ceramide generation and cause pathological cell death in HAE cells (15,19,29,42). We thus proposed that there must be a specific SMase that is modulated by ROS in lung epithelial cells.…”

Section: Discussionmentioning

confidence: 93%

“…Ceramide accumulation may play a crucial role in the induction of stress-stimulated apoptosis in the lung (5,19,28,29). We reported previously that ceramide production is responsible for apoptosis induction in HBE1 and A549 adenocarcinoma cells exposed to H 2 O 2 or to CS, and that ceramide generation in these cells is upstream of caspase cascades (16,17,19).…”

Section: Ceramide Generation and Dna Fragmentation In The Lungs Of MImentioning

confidence: 95%

“…We compared our findings of silencing nSMase2 in cell culture (19,29) with in vivo silencing studies, as described by Zhang and colleagues (24), by administrating biotin-labeled nSMase2 siRNA, which had been specially synthesized for our laboratory. As shown in Figure 6A, 129/Sv mice were administered intranasal murine nSMase2 siRNA (2 mg/kg of body weight) for the indicated time points.…”

Section: In Vivo Sirna Silencing Of Nsmase2 In 129/sv Micementioning

confidence: 99%

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Neutral Sphingomyelinase 2

Filosto

Castillo

Danielson³

et al. 2011

Am J Respir Cell Mol Biol

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Chronic obstructive pulmonary disease (COPD) is caused by exposure to cigarette smoke (CS). One mechanism of CS-induced lung injury is aberrant generation of ceramide, which leads to elevated apoptosis of epithelial and endothelial cells in the alveolar spaces. Recently, we discovered that CS-induced ceramide generation and apoptosis in pulmonary cells is governed by neutral sphingomyelinase (nSMase) 2. In the current experiments, we expanded our studies to investigate whether nSMase2 governs ceramide generation and apoptosis in vivo using rodent and human models of CSinduced lung injury. We found that exposure of mice or rats to CS leads to colocalizing elevations of ceramide levels and terminal deoxynucleotidyl transferase mediated X-dUTP nick end labelingpositive cells in lung tissues. These increases are nSMase2 dependent, and are abrogated by treatment with N-acetyl cysteine or antinSMase2 small interfering RNA (siRNA). We further showed that mice that are heterozygous for nSMase2 demonstrate significant decrease in ceramide generation after CS exposure, whereas acidic sphingomyelinase (aSMase) knockout mice maintain wild-type ceramide levels, confirming our previous findings (in human airway epithelial cells) that only nSMase2, and not aSMase, is activated by CS exposure. Lastly, we found that lung tissues from patients with emphysema (smokers) display significantly higher levels of nSMase2 expression compared with lung tissues from healthy control subjects. Taken together, these data establish the central in vivo role of nSMase2 in ceramide generation, aberrant apoptosis, and lung injury under CS exposure, underscoring its promise as a novel target for the prevention of CS-induced airspace destruction.

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Section: Discussionmentioning

confidence: 93%

Section: Ceramide Generation and Dna Fragmentation In The Lungs Of MImentioning

confidence: 95%

Section: In Vivo Sirna Silencing Of Nsmase2 In 129/sv Micementioning

confidence: 99%

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Neutral Sphingomyelinase 2

Filosto

Castillo

Danielson³

et al. 2011

Am J Respir Cell Mol Biol

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“…aSMase, on the other hand, is induced by various stress stimuli, such as UV and ionizing radiation, ligation of death receptors, and chemotherapeutic agents such as platinum, paclitaxel, and histone deacetylase inhibitors. Recent studies also implicate an activation of aSMase by reactive oxygen species and nitrosative stress (46). Interestingly, activation of aSMase in response to phorbol esters and to UV radiation has been shown to lead to an increase in Cer formation through the salvage (or recycling) pathway, i.e., by inducing formation of Cer, then Sph, which is recycled back to Cer (3).…”

Section: Inducers Of Sl Enzymesmentioning

confidence: 99%

Bioactive sphingolipids: metabolism and function

Bartke

Hannun

2009

Journal of Lipid Research

579

512

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Sphingolipids (SLs) are essential constituents of eukaryotic cells. Besides playing structural roles in cellular membranes, some metabolites, including ceramide, sphingosine, and sphingosine-1-phosphate, have drawn attention as bioactive signaling molecules involved in the regulation of cell growth, differentiation, senescence, and apoptosis. Understanding the many cell regulatory functions of SL metabolites requires an advanced knowledge of how and where in the cell they are generated, converted, or degraded. This review will provide a short overview of the metabolism, localization, and compartmentalization of SLs. Also, a discussion on bioactive members of the SL family and inducers of SL enzymes that lead to ceramide generation will be presented. First discovered by J. L. W. Thudichum in 1876, for a long time SLs were considered to play primarily structural roles in membrane formation. However, intensive research on SL metabolism and function has revealed members of the SL family, including ceramide (Cer), sphingosine (Sph), Sph-1-phosphate (S1P), and Cer-1-phosphate (C1P), as bioactive molecules playing roles from regulation of signal transduction pathways, through direction of protein sorting to the mediation of cell-to-cell interactions and recognition. SLs have also been reported to dynamically cluster with sterols to form lipid microdomains or rafts, which function as hubs for effective signal transduction and protein sorting (1).Various stimuli such as tumor necrosis factor-a (TNF-a), interleukin (IL)-1, Fas ligand, ionizing radiation (2), phorbol esters (3), heat stress (4), oxidative stress (5), and chemotherapeutics (6) induce the formation of Cer.Understanding the complex regulatory mechanisms of bioactive SLs requires a broad knowledge of how these molecules are generated, degraded, or converted, and how and where they are located or metabolized. Recent molecular advances in identifying enzymes involved in the SL metabolism as well as technical advances in analytical measurements by mass spectrometry have shed light on their roles and regulation and involvement in cellular processes.In this review, we will briefly summarize the current knowledge of these aspects. For more detailed insights, the reader is referred to recent references and reviews (7-9). METABOLISM OF BIOACTIVE SLSThe SL metabolic pathway displays an intricate network of reactions resulting in the formation of a multitude of SLs, with Cer [and dihydroceramide (dhCer)] as the center of SL biosynthesis, catabolism, and as precursors of complex SLs. Cer can be produced in at least two distinct ways. First, it can be synthesized through the de novo pathway, and second, through the hydrolysis of complex lipids, especially sphingomyelin (SM) (Fig. 1). The de novo pathway commences with the condensation of serine and palmitoyl-CoA catalyzed by serine palmitoyl transferase to generate 3-ketodihydrosphingosine. 3-Keto-dihydrosphingosine is subsequently reduced to form dihydrosphingosine (sphinganine), which is then N-acylated by (dh)...

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“…The sphingolipids ceramide and sphingosine-1 phosphate (S1P) are signaling mediators involved in the regulation of lung epithelial and endothelial cell apoptosis and survival, respectively (9)(10)(11)(12). CFTR, an ATP-binding cassette transporter localized in ceramide-rich membrane microdomains, has been involved in the regulation of sphingolipid, particularly S1P, transport across the plasma membrane (13).…”

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confidence: 99%