Sphingolipids in Ventilator Induced Lung Injury: Role of Sphingosine-1-Phosphate Lyase

Suryadevara, Vidyani; Fu, Panfeng; Ebenezer, David L.; Berdyshev, Evgeny; Huang, Long Shuang; Harijith, Anantha; Natarajan, Viswanathan

doi:10.3390/ijms19010114

Cited by 27 publications

(18 citation statements)

References 73 publications

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“…Impacted lungs had elevated levels of transcripts consistent with respiratory damage such as increased expression of HIMF, which is involved in activation of lung endothelial cells in response to lung inflammation (37). We also found increased levels of Sgpl1, a molecule associated with lung injury (38) and known to be increased in mechanically ventilated mice (39). A prominent finding in infected K18-hACE2 mice system was vasculitis.…”

Section: Discussion Golden Jw Et Al Sars-cov-2 Pathogenesis In K18-hsupporting

confidence: 52%

Human angiotensin-converting enzyme 2 transgenic mice infected with SARS-CoV-2 develop severe and fatal respiratory disease

Golden

Cline

Zeng

et al. 2020

Preprint

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ABSTRACTThe emergence of SARS-CoV-2 has created an international health crisis. Small animal models mirroring SARS-CoV-2 human disease are essential for medical countermeasure (MCM) development. Mice are refractory to SARS-CoV-2 infection due to low affinity binding to the murine angiotensin-converting enzyme 2 (ACE2) protein. Here we evaluated the pathogenesis of SARS-CoV-2 in male and female mice expressing the human ACE2 gene under the control of the keratin 18 promotor. In contrast to non-transgenic mice, intranasal exposure of K18-hACE2 animals to two different doses of SARS-CoV-2 resulted in acute disease including weight loss, lung injury, brain infection and lethality. Vasculitis was the most prominent finding in the lungs of infected mice. Transcriptomic analysis from lungs of infected animals revealed increases in transcripts involved in lung injury and inflammatory cytokines. In the lower dose challenge groups, there was a survival advantage in the female mice with 60% surviving infection whereas all male mice succumbed to disease. Male mice that succumbed to disease had higher levels of inflammatory transcripts compared to female mice. This is the first highly lethal murine infection model for SARS-CoV-2. The K18-hACE2 murine model will be valuable for the study of SARS-CoV-2 pathogenesis and the assessment of MCMs.

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Section: Discussion Golden Jw Et Al Sars-cov-2 Pathogenesis In K18-hsupporting

confidence: 52%

Human angiotensin-converting enzyme 2 transgenic mice infected with SARS-CoV-2 develop severe and fatal respiratory disease

Golden

Cline

Zeng

et al. 2020

Preprint

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“…Studies on in vitro alveolar epithelial cell cultures using mechanical stretch suggest that a 5 to 12% elongation is physiological, while mechanical stretch at 37 to 50% elongation is associated with pathophysiological conditions produced by mechanical ventilation (34,38,39). Therefore, in the present study, a 15% elongation for 48 h was used as a stimulus for 16HBE cells.…”

Section: Discussionmentioning

confidence: 96%

Transient receptor potential canonical 1 channel mediates the mechanical stress‑induced epithelial‑mesenchymal transition of human bronchial epithelial (16HBE) cells

Wang

et al. 2020

Int J Mol Med

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Airway remodeling is a central event in the pathology of chronic obstructive pulmonary disease (cOPd) that leads to airway narrowing and subsequently, to increased mechanical pressure. High mechanical pressure can exacerbate airway remodeling. Thus, a treatment regimen aimed at disrupting this high-pressure airway remodeling vicious cycle may improve the prognosis of patients with cOPd. Recent studies have demonstrated that mechanical stress induces lung epithelial-mesenchymal transition (EMT), which is commonly present in airway epithelial cells of patients with cOPd. As TRPc1 functions as a mechanosensitive channel that mediates non-selective cation entry in response to increased membrane stretch, the present study investigated the role of TRPc1 in the occurrence of EMT induced by mechanical stress. In the present study, the expression of TRPc1 in the bronchial epithelium was examined in vivo by immunohistochemistry. In vitro, human bronchial epithelial (16HBE) cells were subjected to mechanical stretching for up to 48 h, and TRPc1 expression was then examined by RT-qPcR and western blot analysis. In addition, TRPc1 receptor function was assessed by ca 2+ imaging and siRNA transfection. EMT was identified using immunofluorescence, western blot analysis and RT-qPcR. It was found that TRPc1 expression was upregulated in patients with cOPd and in 16HBE cells subjected to mechanical stretch. The mechanical stress-induced activation of TRPc1 in 16HBE cells increased the intracellular calcium concentration and subsequently decreased the expression of cytokeratin 8 and E-cadherin, and increased the expression of α-smooth muscle actin, indicating the occurrence of EMT. On the whole, the findings of the present study demonstrate that TRPc1 plays a key role in the occurrence of EMT in human lung epithelial cells in response to mechanical stretch; thus, this protein may serve as a novel therapeutic target for progressive airway remodeling in cOPd.

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“…Sphingolipids modulate cell fates during lung development and the development of lung diseases [ 25 , 26 ]. Ceramides and sphingosine cause apoptosis and inflammatory response, while S1P facilitates proliferation and differentiation as well as protects against apoptosis and ventilation-induced lung injury [ 27 ]. In agreement with our findings, neonatal hyperoxia for four weeks augments sphingomyelin species (SM16:0, SM18:0, SM24:0, and SM24:1), long chain ceramides (Cer16:0 and Cer18:0), and very long chain ceramides (Cer24:0 and Cer24:1) in bronchoalveolar lavage fluid from mice [ 28 ], and ceramide is increased in tracheal aspirates of preterm infants [ 9 ].…”

Section: Discussionmentioning

confidence: 99%

Hyperoxic Exposure Caused Lung Lipid Compositional Changes in Neonatal Mice

Peterson

Carr

et al. 2020

Metabolites

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Treatments with supplemental oxygen in premature infants can impair lung development, leading to bronchopulmonary dysplasia (BPD). Although a stage-specific alteration of lung lipidome occurs during postnatal lung development, whether neonatal hyperoxia, a known mediator of BPD in rodent models, changes lipid profiles in mouse lungs is still to be elucidated. To answer this question, newborn mice were exposed to hyperoxia for 3 days and allowed to recover in normoxia until postnatal day (pnd) 7 and pnd14, time-points spanning the peak stage of alveologenesis. A total of 2263 lung lipid species were detected by liquid chromatography–mass spectrometry, covering 5 lipid categories and 18 lipid subclasses. The most commonly identified lipid species were glycerophospholipids, followed by sphingolipids and glycerolipids. In normoxic conditions, certain glycerophospholipid and glycerolipid species augmented at pnd14 compared to pnd7. At pnd7, hyperoxia generally increased glycerophospholipid, sphingolipid, and glycerolipid species. Hyperoxia increased NADPH, acetyl CoA, and citrate acid but reduced carnitine and acyl carnitine. Hyperoxia increased oxidized glutathione but reduced catalase. These changes were not apparent at pnd14. Hyperoxia reduced docosahexaenoic acid and arachidonic acid at pnd14 but not at pnd7. Altogether, the lung lipidome changes throughout alveolarization. Neonatal hyperoxia alters the lung lipidome, which may contribute to alveolar simplification and dysregulated vascular development.

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Sphingolipids in Ventilator Induced Lung Injury: Role of Sphingosine-1-Phosphate Lyase

Cited by 27 publications

References 73 publications

Human angiotensin-converting enzyme 2 transgenic mice infected with SARS-CoV-2 develop severe and fatal respiratory disease

Human angiotensin-converting enzyme 2 transgenic mice infected with SARS-CoV-2 develop severe and fatal respiratory disease

Transient receptor potential canonical 1 channel mediates the mechanical stress‑induced epithelial‑mesenchymal transition of human bronchial epithelial (16HBE) cells

Hyperoxic Exposure Caused Lung Lipid Compositional Changes in Neonatal Mice

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