Stimulation of Sphingosine 1-Phosphate Signaling as an Alveolar Cell Survival Strategy in Emphysema

Diab, Khalil; Adamowicz, Jeremy; Kamocki, Krzysztof; Rush, Natalia; Garrison, Jana; Gu, Yuan; Schweitzer, Kelly S.; Skobeleva, Anastasia; Gangaraju, Rajashekhar; Hubbard, Walter C.; Berdyshev, Evgeny; Petrache, Irina

doi:10.1164/rccm.200906-0826oc

Cited by 66 publications

(61 citation statements)

References 47 publications

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“…For example, induction of apoptosis by imatinib in a human cell line (K562) increased the CER/S1P ratio, while sphingosine addition increased S1P and reduced this ratio (Baran et al, 2007). In a lung cell culture, induction of emphysema by angiogenesis inhibition, the CER/S1P ratio obtained was 1.1, while the addition of S1P reduced emphysema and the ratio CER/S1P to 0.7 (Diab et al, 2010). Similarly, in the present study, the S1P/CER ratio was higher in healthy than atretic antral follicles.…”

Section: Discussionmentioning

confidence: 99%

Sphingosine-1-phosphate and ceramide are associated with health and atresia of bovine ovarian antral follicles

Hernández‐Coronado

Guzmán

Espinosa-Cervantes

et al. 2015

Animal

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The follicle destiny towards ovulation or atresia is multi-factorial in nature and involves outcries, paracrine and endocrine factors that promote cell proliferation and survival (development) or unchain apoptosis as part of the atresia process. In several types of cells, sphingosine-1-phospate (S1P) promotes cellular proliferation and survival, whereas ceramide (CER) triggers cell death, and the S1P/CER ratio may determine the fate of the cell. The aim of present study was to quantify S1P and CER concentrations and their ratio in bovine antral follicles of 8 to 17 mm classified as healthy and atretic antral follicles. Follicles were dissected from cow ovaries collected from a local abattoir. The theca cell layer, the granulosa cells and follicular fluid were separated, and 17β-estradiol (E2) and progesterone (P4) concentrations were measured in the follicular fluid by radioimmunoassay. Based on the E2/P4 ratio, the follicles were classified as healthy (2.2 ± 0.3) or atretic (0.2 ± 0.3). In both follicular compartments (granulosa and theca cell layer), sphingolipids were extracted and S1P and CER concentrations were quantified by HPLC (XTerra RP18; 5 µm, 3.0 × 150 mm column). Results showed that in both follicular compartments, S1P concentrations were higher in healthy antral follicles than in atretic antral follicles (P < 0.05). The concentration of CER in the granulosa cells was higher in atretic antral follicles than in healthy antral follicles, but no differences were observed in the theca cell layer. The S1P/CER ratio in both follicular compartments was also higher in healthy antral follicles. Interestingly, in these follicles, there was a 45-fold greater concentration of S1P than CER in the granulosa cells (P < 0.05), whereas in the theca cell layer, S1P had only a 14-fold greater concentration than CER when compared with atretic antral follicles. These results suggest that S1P plays a role in follicle health, increasing cellular proliferation and survival. In contrast, reduction of S1P and the S1P/CER in the antral follicle could trigger cellular death and atresia.Keywords: bovine, antral follicle, atresia, ceramide, sphingosine-1-phospohate Implications Follicular development involves selection of a follicle apt to grow in response to stimuli (FSH and LH) that induce proliferation and survival of follicular cells so that it reaches ovulation. However, if follicles do not receive these stimuli (reduction in FSH and LH or their receptors), cellular death signals are triggered and the follicle fate will be atresia. Sphingosine-1-phospohate (S1P) induces survival and proliferation of cells, whereas ceramide (CER) is involved in cellular death. The present study reveals that S1P and CER concentrations differ within follicular status suggesting these sphingolipids may participate in follicular health or atresia.Knowledge of signals that control follicular development and atresia may help us to improve follicular development and thus reproductive performance. IntroductionThe development of bovine ovarian follic...

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Section: Discussionmentioning

confidence: 99%

Sphingosine-1-phosphate and ceramide are associated with health and atresia of bovine ovarian antral follicles

Hernández‐Coronado

Guzmán

Espinosa-Cervantes

et al. 2015

Animal

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“…The incomplete recovery of histology, sphingolipid levels and lung function after D-sphingosine treatment and the absence of a significant difference in these parameters between hyperoxic mice with and without D-sphingosine might be due to dose and/or timing of the supplementation, or might have been missed due to relatively small numbers of observations. Our D-sphingosine dose was based on a study by DIAB et al [35] who showed that adult mice injected with D-sphingosine at 20 mg per mouse for five consecutive days had significantly increased sphingosine-1-phosphate (a pro-survival sphingolipid) levels in homogenised lung tissue at day 5 after the start of administration. The administration of D-sphingosine in our model started after hyperoxia exposure and lasted for 5 days.…”

Section: Discussionmentioning

confidence: 99%

Amelioration of hyperoxia-induced lung injury using a sphingolipid-based intervention

et al. 2012

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The aim of this study was to characterise lung function and bronchoalveolar lavage sphingolipid profile in newborn mice during hyperoxia exposure and recovery in room air, and to examine the effect of D-sphingosine supplementation during recovery.Newborn mice were exposed to 80% oxygen for 4 weeks and allowed to recover in room air for another 4 weeks. Lung function measurements and morphometrical analysis of lung tissue were performed and bronchoalveolar lavage fluid was collected during hyperoxia and recovery with and without D-sphingosine supplementation.Hyperoxia exposure altered lung function, which partially recovered in room air. Lungs had fewer and enlarged alveoli which persisted during recovery. Multiple sphingolipids were significantly increased after hyperoxia. Ceramides were increased after 2 weeks of recovery, but normalised to control values after 4 weeks. The addition of D-sphingosine during the first 5 days of recovery accelerated the normalisation of ceramide levels at 2 weeks and partially reversed the hyperoxia-induced increase in alveolar size and arrest in alveolarisation at 4 weeks.Exposure of newborn mice to hyperoxia caused restrictive and obstructive lung function changes that partially recovered in room air, while alveolar morphology remained abnormal. Hyperoxia increased ceramide levels, with normalisation after recovery. D-sphingosine addition during recovery reduced ceramide levels and ameliorated hyperoxia-induced alveolar arrest. @ERSpublications D-sphingosine during recovery reduced ceramide levels and ameliorated hyperoxia-induced alveolar arrest in mice

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“…In addition, ceramide species identification and quantification, as well as sphingosine-1 phosphate content, were determined by liquid chromatography/tandem mass spectrometry (12). Sphingolipid levels were normalized by lipid phosphorus (12).…”

Section: Sphingolipid Measurementmentioning

confidence: 99%

RTP801 Is Required for Ceramide-Induced Cell-Specific Death in the Murine Lung

Kamocki

Demark²,

Fisher³

et al. 2013

Am J Respir Cell Mol Biol

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Key host responses to the stress induced by environmental exposure to cigarette smoke (CS) are responsible for initiating pathogenic effects that may culminate in emphysema development. CS increases lung ceramides, sphingolipids involved in oxidative stress, structural alveolar cell apoptosis, and inhibition of apoptotic cell clearance by alveolar macrophages, leading to the development of emphysemalike pathology. RTP801, a hypoxia and oxidative stress sensor, is also increased by CS, and has been recently implicated in both apoptosis and inflammation. We investigated whether inductions of ceramide and RTP801 are mechanistically linked, and evaluated their relative importance in lung cell apoptosis and airspace enlargement in vivo. As reported, direct lung instillation of either RTP801 expression plasmid or ceramides in mice triggered alveolar cell apoptosis and oxidative stress. RTP801 overexpression up-regulated lung ceramide levels 2.6-fold. In turn, instillation of lung ceramides doubled the lung content of RTP801. Cell sorting after lung tissue dissociation into single-cell suspension showed that ceramide triggers both endothelial and epithelial cell apoptosis in vivo. Interestingly, mice lacking rtp801 were protected against ceramide-induced apoptosis of epithelial type II cells, but not type I or endothelial cells. Furthermore, rtp801-null mice were protected from ceramide-induced alveolar enlargement, and exhibited improved static lung compliance compared with wild-type mice. In conclusion, ceramide and RTP801 participate in alveolar cell apoptosis through a process of mutual up-regulation, which may result in self-amplification loops, leading to alveolar damage.Keywords: emphysema; sphingolipids; apoptosis; cigarette smoke; stress responseThe abnormal enlargement of distal airspaces in the lungs, which occurs through the destruction of the alveolar walls, is the hallmark of emphysema, a disease included in the chronic obstructive pulmonary disease (COPD) spectrum. There is an increased need to identify molecular mechanisms that link the environmental stress induced by cigarette smoke (CS) and air pollution, which are the main causes of alveolar destruction and emphysema in COPD. COPD is a prevalent disease, which carries high morbidity and mortality rates. Although removal of the etiological agent, most commonly the exposure to CS, is an important intervention (1), the ongoing tissue destruction may progress even after CS cessation (2). There is ample evidence that mechanisms of amplification of lung injury lead to destruction of alveolar walls and persistence of inflammatory systemic and lung responses (3, 4). Ceramide and RTP801 have been identified as potential signaling relays that are engaged early by CS exposure, which may interact and therefore amplify alveolar wall injury in emphysema (5-7). Because both ceramide and RTP801 are involved in apoptosis, we sought to investigate if ceramide and RTP801 are mechanistically linked in vivo.RTP801, also known as REDD1, is a stress response protein and si...

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Stimulation of Sphingosine 1-Phosphate Signaling as an Alveolar Cell Survival Strategy in Emphysema

Cited by 66 publications

References 47 publications

Sphingosine-1-phosphate and ceramide are associated with health and atresia of bovine ovarian antral follicles

Sphingosine-1-phosphate and ceramide are associated with health and atresia of bovine ovarian antral follicles

Amelioration of hyperoxia-induced lung injury using a sphingolipid-based intervention

RTP801 Is Required for Ceramide-Induced Cell-Specific Death in the Murine Lung

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