Role of acid sphingomyelinase and IL-6 as mediators of endotoxin-induced pulmonary vascular dysfunction

Pandolfi, Rachele; Barreira, Bianca; Moreno, Enrique; Lara-Acedo, Victor; Morales‐Cano, Daniel; Martínez‐Ramas, Andrea; Navarro, Beatriz de Olaiz; Herrero, Raquel; Lorente, José A.; Cogolludo, Ángel; Pérez‐Vizcaíno, Francisco; Moreno, Laura

doi:10.1136/thoraxjnl-2015-208067

Cited by 55 publications

(50 citation statements)

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“…LPS, a major component of the outer membrane of Gram‐negative bacteria, plays a critical role in the pathogenesis of periodontitis (Jain & Darveau, ). Since our laboratory and others have shown that ASMase is activated by LPS and plays an important role in LPS‐induced inflammation response (Cuschieri, Bulger, Billgrin, Garcia, & Maier, ; Jin et al, ; Pandolfi et al, ), it is important to determine whether ASMase is involved in experimental periodontitis.…”

Section: Introductionmentioning

confidence: 99%

Acid sphingomyelinase deficiency exacerbates LPS‐induced experimental periodontitis

Zhang

et al. 2020

Oral Diseases

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Background Mutation of the gene for acid sphingomyelinase (ASMase) causes Niemann–Pick disease. However, the effect of ASMase deficiency on periodontal health is unknown. Periodontal disease is a disease resulting from infection and inflammation of periodontal tissue and alveolar bone that support the teeth. The goal of this study was to determine the role of ASMase deficiency in periodontal inflammation and alveolar bone loss. Methods We induced periodontitis in wild‐type and ASMase‐deficient (ASMase−/−) mice with periodontal lipopolysaccharide (LPS) injection and compared the alveolar bone loss and periodontal inflammation between these mice. Results Results showed that ASMase deficiency did not significantly change metabolic parameters, but exacerbated LPS‐induced alveolar bone loss, osteoclastogenesis, and periodontal tissue inflammation. To understand the mechanisms by which ASMase deficiency aggravates LPS‐induced periodontitis, we analyzed sphingolipids in periodontal tissues. Results showed that ASMase deficiency led to increases in not only sphingomyelin, but also ceramide (CER), a bioactive sphingolipid known to promote inflammation. Results further showed that ASMase deficiency increased CER de novo synthesis. Conclusion ASMase deficiency exacerbated LPS‐induced alveolar bone loss and periodontal inflammation. ASMase deficiency leads to an unexpected CER increase by stimulating de novo synthesis CER, which is likely to be involved in the ASMase deficiency‐exacerbated periodontitis.

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Section: Introductionmentioning

confidence: 99%

Acid sphingomyelinase deficiency exacerbates LPS‐induced experimental periodontitis

Zhang

et al. 2020

Oral Diseases

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“…Mayers et al have demonstrated that TNF‐α decreases HPV during perfusion and ventilation of isolated canine pulmonary lobes during administration of recombinant human TNF‐α followed by hypoxia and measurement of PVR. Also, Pandolfi et al have described exogenous IL‐6 causing a blunting of rat pulmonary vascular constriction to hypoxia using isolated pulmonary arterial wire myograph experiments. Though these preclinical results are intriguing, clinical studies with human lungs are required to further validate these findings.…”

Section: Discussionmentioning

confidence: 99%

“…The change in PVR (DPVR) remains robust in healthy lungs without pulmonary vascular endothelial dysfunction. There is a blunting of the DPVR in disease, representative of pulmonary vascular dysfunction (14)(15)(16)(17)(18)(19)(20). Given the simplicity and reproducibility of HPV, we hypothesize that HPV is a more sensitive parameter over P/F ratio in assessing lung quality during EVLP.…”

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confidence: 99%

A Decrease in Hypoxic Pulmonary Vasoconstriction Correlates With Increased Inflammation During Extended Normothermic Ex Vivo Lung Perfusion

et al. 2017

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Normothermic ex vivo lung perfusion (EVLP) is an evolving technology to evaluate function of donor lungs to determine suitability for transplantation. We hypothesize that hypoxic pulmonary vasoconstriction (HPV) during EVLP will provide a more sensitive parameter of lung function to determine donor lung quality for lung transplantation. Eight porcine lungs were procured, and subsequently underwent EVLP with autologous blood and STEEN solution for 10 h. Standard physiologic parameters including dynamic compliance, peak airway pressure, and pulmonary vascular resistance (PVR) remained stable (P = 0.055), mean oxygenation (PO /FiO ) was 400 ± 18 mm Hg on average throughout perfusion. Response to hypoxia resulted in a robust increase in PVR (ΔPVR) up to 4 h of perfusion, however the HPV response then blunted beyond T6 (P < 0.01). The decrease in HPV response inversely correlated to cytokine concentrations of Interleukin-6 and tumor necrosis factor-α (P < 0.01). Despite acceptable lung oxygenation and standard physiologic parameters during 10 h of EVLP, there is a subclinical deterioration of lung function. HPV challenges can be performed during EVLP as a simple and more sensitive index of pulmonary vascular reactivity.

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“…Further to pro-proliferative effects, the proinflammatory role of sphingolipids may be relevant in PAH, where dysregulated inflammation is recognised. The endotoxin-induced ceramide release from PASMC in this study11 is relevant to PH in ARDS and also chronic respiratory diseases, where acute exacerbations are characterised by a reversible increase in pulmonary arterial pressure, which is related to acute hypoxia (eg, in COPD). Chronic repeated inflammation is likely also to cause progressive pulmonary vascular remodelling and PH,20 as suggested in patients with frequent COPD exacerbations 21…”

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confidence: 95%

“…The article by Pandolfi and coworkers11 adds to the evidence that inflammatory mechanisms contribute to the pathogenesis of PH in ARDS. In particular, their study addresses whether IL-6 and acid sphingomyelinase (aSMase) contribute to pulmonary vascular dysfunction in a rat model of inhaled lipopolysaccharide (LPS)-induced ARDS.…”

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confidence: 99%

Pulmonary hypertension in ARDS: inflammation matters!

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Wort

2017

Thorax

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Role of acid sphingomyelinase and IL-6 as mediators of endotoxin-induced pulmonary vascular dysfunction

Abstract: Our data indicate that aSMase and IL-6 are not simply biomarkers of poor outcomes but pathogenic mediators of pulmonary vascular dysfunction in ARDS secondary to Gram-negative infections.

Cited by 55 publications

References 46 publications

Acid sphingomyelinase deficiency exacerbates LPS‐induced experimental periodontitis

Acid sphingomyelinase deficiency exacerbates LPS‐induced experimental periodontitis

A Decrease in Hypoxic Pulmonary Vasoconstriction Correlates With Increased Inflammation During Extended Normothermic Ex Vivo Lung Perfusion

Pulmonary hypertension in ARDS: inflammation matters!

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