Sphingolipid-mediated Inhibition of Apoptotic Cell Clearance by Alveolar Macrophages

Petrusca, Daniela N.; Gu, Yuan; Adamowicz, Jeremy; Rush, Natalia; Hubbard, Walter C.; Smith, Patricia; Berdyshev, E.; Birukov, Konstantin G.; Lee, Chao Hung; Tuder, Rubin M.; Twigg, Homer L.; Vandivier, R. William; Petrache, Irina

doi:10.1074/jbc.m110.137604

Cited by 77 publications

(78 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In some other studies, sphingosine was found to exert its functions through the inhibition of protein kinase C [107]. This particular sphingolipid also has regulative functions for phagocytosis as shown in alveolar macrophages [108]. In this study, conversion of ceramides into sphingosine impaired clearance of apoptotic bodies by macrophages in a dose-dependent manner.…”

Section: B) Sphingosine Derivatives: Sphingosine and S1psupporting

confidence: 53%

Bioactive Sphingolipids in Response to Chemotherapy: A Scope on Leukemias

Ekiz

Baran²

2011

ACAMC

View full text Add to dashboard Cite

Sphingolipids are major constituents of the cells with emerging roles in the regulation of cellular processes. Deregulation of sphingolipid metabolism is reflected as various pathophysiological conditions including metabolic disorders and several forms of cancer. Ceramides, ceramide-1-phosphate (C1P), glucosyl ceramide (GluCer), sphingosine and sphingosine-1-phosphate (S1P) are among the bioactive sphingolipid species that have important roles in the regulation of cell death, survival and chemotherapeutic resistance. Some of those species are known to accumulate in the cells upon chemotherapy while some others are known to exhibit an opposite pattern. Even though the length of fatty acid chain has a deterministic effect, in general, upregulation of ceramides and sphingosine is known to induce apoptosis. However, S1P, C1P and GluCer are proliferative for cells and they are involved in the development of chemoresistance. Therefore, sphingolipid metabolism appears as a good target for the development of novel therapeutics or supportive interventions to increase the effectiveness of the chemotherapeutic drugs currently in hand. Some approaches involve manipulation of the synthesis pathways yielding the increased production of apoptotic sphingolipids while the proliferative ones are suppressed. Some others are trying to take advantage of cytotoxic sphingolipids like short chain ceramide analogs by directly delivering them to the malignant cells as a distinct chemotherapeutic intervention. Numerous studies in the literature show the feasibility of those approaches especially in acute and chronic leukemias. This review compiles the current knowledge about sphingolipids and their roles in chemotherapeutic response with the particular attention to leukemias.

show abstract

Section: B) Sphingosine Derivatives: Sphingosine and S1psupporting

confidence: 53%

Bioactive Sphingolipids in Response to Chemotherapy: A Scope on Leukemias

Ekiz

Baran²

2011

ACAMC

View full text Add to dashboard Cite

show abstract

“…Ceramide is a prototypic lipid signaling molecule, which we have shown to amplify lung injury due to CS (5,6,9,10,18). Our prior studies have also highlighted that ceramide not only amplifies oxidative stress, but that its synthesis is triggered by reactive oxygen species (5).…”

Section: Discussionmentioning

confidence: 95%

“…CS increases lung ceramides both in vivo and in cultured primary lung epithelial and endothelial cells and, in turn, increases in ceramide levels trigger alveolar cell apoptosis (5,6,9). We previously described direct intratracheal instillation of ceramides as a reductionistic model of their effects seen in the setting of CS-triggered lung injury (5,6,10). This approach eliminates the ceramide-independent effects caused by CS, while mimicking its induction of endogenous lung ceramides.…”

mentioning

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

Self Cite

View full text Add to dashboard Cite

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...

show abstract

“…Current data indicate that the mechanisms by which ceramides contribute to emphysema development involve increased oxidative stress and structural alveolar cell apoptosis, which are linked via mutual interaction and self-amplification (38). In addition, de novo synthesized ceramides, and especially downstream production of sphingosine via acid ceramidase, profoundly inhibit the clearance of apoptotic cells by specialized alveolar macrophages (40). This is yet another self-perpetuating cycle triggered by ceramides (Figure 2) in which they both increase apoptosis of structural endothelial and epithelial cells in the lung and inhibit their clearance by macrophages, a process which may contribute to increased inflammation in the lungs of smokers and patients with COPD (66).…”

Section: Significance Of Ceramide-mediated Pulmonary Vascular Responsmentioning

confidence: 99%