Therapy of CF-Patients with Amitriptyline and Placebo - a Randomised, Double-Blind, Placebo-Controlled Phase IIb Multicenter, Cohort-Study

Naehrlich, Lutz; Mainz, Jochen G.; Adams, Constantin; Engel, Corinna; Herrmann, Gloria; Icheva, Vanya; Lauer, Josefine; Deppisch, Caroline; Wirth, Andreas; Unger, Katy; Graepler-Mainka, Ute; Hector, Andreas; Heyder, S.; Stern, Martin; Döring, Gerd; Gulbins, Erich; Riethmüller, Joachim

doi:10.1159/000350071

Cited by 1,958 publications

(36 citation statements)

References 17 publications

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“…Such a reduction of ceramide might be achieved with the functional acid sphingomyelinase inhibitor amitriptyline, which reduces activity of the acid sphingomyelinase and normalizes ceramide levels and cell death of epithelial cells in CF mice [16]. Treatment with amitriptyline also normalized inflammation in the lungs of CF mice and, most importantly improved lung function in CF patients [16,41] consistent with the present studies that used a genetic approach to target the acid sphingomyelinase in CF mice.…”

Section: Discussionsupporting

confidence: 77%

Invariant Natural Killer T (iNKT) Cells Prevent Autoimmunity, but Induce Pulmonary Inflammation in Cystic Fibrosis

Siegmann

Worbs

Effinger

et al. 2014

Cell Physiol Biochem

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Background/Aims: Inflammation is a major and critical component of the lung pathology in the hereditary disease cystic fibrosis. The molecular mechanisms of chronic inflammation in cystic fibrosis require definition. Methods: We used several genetic mouse models to test a role of iNKT cells and ceramide in pulmonary inflammation of cystic fibrosis mice. Inflammation was determined by the pulmonary cytokine profil and the abundance of inflammatory cells in the lung. Results: Here we provide a new concept how inflammation in the lung of individuals with cystic fibrosis is initiated. We show that in cystic fibrosis mice the mutation in the Cftr gene provokes a significant up-regulation of iNKT cells in the lung. Accumulation of iNKT cells serves to control autoimmune disease, which is triggered by a ceramide-mediated induction of cell death in CF organs. Autoimmunity becomes in particular overt in cystic fibrosis mice lacking iNKT cells and although suppression of the autoimmune response by iNKT cells is beneficial, IL-17⁺ iNKT cells attract macrophages and neutrophils to CF lungs resulting in chronic inflammation. Genetic deletion of iNKT cells in cystic fibrosis mice prevents inflammation in CF lungs. Conclusion: Our data demonstrate an important function of iNKT cells in the chronic inflammation affecting cystic fibrosis lungs. iNKT cells suppress the auto-immune response induced by ceramide-mediated death of epithelial cells in CF lungs, but also induce a chronic pulmonary inflammation.

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Section: Discussionsupporting

confidence: 77%

Invariant Natural Killer T (iNKT) Cells Prevent Autoimmunity, but Induce Pulmonary Inflammation in Cystic Fibrosis

Siegmann

Worbs

Effinger

et al. 2014

Cell Physiol Biochem

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“…Treatment of cystic fibrosis patients with amitriptyline, a functional inhibitor of the acid sphingomyelinase, has been shown to improve lung functions, in particular the forced expiratory volume [32,47]. The present studies suggest that normalization of ceramide levels should also reduce or even prevent the chronic inflammation present in the airways of cystic fibrosis patients.…”

Section: Discussionmentioning

confidence: 70%

“…The accumulation of ceramide in Cftr -deficient cells is corrected by pharmacological inhibition of the acid sphingomyelinase or upon reduction of the gene dose of the acid sphingomyelinase in mice deficient for Cftr and only heterozygous for the acid sphingomyelinase. The beneficial effect of a pharmacological inhibition of the acid sphingomyelinase in CF lungs was recently also demonstrated in clinical studies treating CF patients with the pharmacological inhibitor of the acid sphingomyelinase amitriptyline [32]. …”

Section: Introductionmentioning

confidence: 99%

Regulation of the Inflammasome by Ceramide in Cystic Fibrosis Lungs

Grassmé

Carpinteiro

Edwards

et al. 2014

Cell Physiol Biochem

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Background: Cystic fibrosis (CF), the most common autosomal recessive disorder in Western countries, is characterized by chronic pulmonary inflammation, reduced mucociliary clearance, and increased susceptibility to infection. Our studies using Cftr-deficient mice and human CF specimens showed that ceramide accumulates in CF lungs and mediates increased cell death, susceptibility to infections, and inflammation. Methods: We used Cftr-deficient and syngenic wildtype mice as well as Cftr-deficient mice heterozygous for the acid sphingomyelinase. We determined activation and topology of inflammasome components as well as expression of tight junction proteins by confocal microscopy, western blotting and ELISA. Results: We demonstrate an upregulation and membrane recruitment of the adapter protein apoptosis-associated speck-like protein (Asc), a major component of the inflammasome, and caspase 1, an activation of Jun N-terminal kinase as well as an altered distribution and a degradation of the tight junction proteins ZO-1, ZO-2 and Occludin in lungs of CF mice. All of these events are abrogated in CF mice that are heterozygous for the acid sphingomyelinase and, therefore, show normal levels of ceramide in their lungs. These alterations indicate an activation of the inflammasome by ceramide in the lungs of CF mice. Consistent with this notion, we observe a normalization of the increased levels of the cytokines IL-1β and KC/IL-8 in lungs of CF mice upon treatment with caspase 1 inhibitors. Conclusion: Our data suggest a signaling cascade from ceramide via the inflammasome to caspase 1, the release of cytokines and an alteration of tight junction proteins in CF epithelia.

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“…fingolimod, amitryptiline) (Nahrlich et al, 2013;Kappos et al, 2015). Sphingolipid metabolic rate is enhanced in early pregnancy in the first inflammatory implantation phase (Kaneko-Tarui et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

De novo ceramide synthesis is involved in acute inflammation during labor

Signorelli

Avagliano

Reforgiato

et al. 2016

Biological Chemistry

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Gestation is regulated by an inflammatory process that allows implantation and parturition. The comprehension of such inflammatory switches is important for the identification of therapeutic targets in pregnancy defects. Sphingolipids are a class of structural membrane components with important signaling functions. Among sphingolipids, ceramide is a well-known mediator of stress signals and pro-inflammatory responses. In this paper, we evaluated the association between ceramide increase and the inflammatory process of labor, comparing placentas from vaginal deliveries, including both spontaneous and induced labor, versus elective cesarean. We demonstrated that: (i) the inflammatory marker IL-6 is upregulated in labored placentas; (ii) IL-6 content inversely correlates with labor duration; (iii) ceramide content and expression of serine palmitoyl transferase (SPT, rate limiting enzyme for de novo ceramide synthesis) are increased in labored placentas; (iv) the expression of SPT directly correlates with inflammation and inversely with labor duration. These observations suggest that ceramide metabolism and signaling may be implicated in controlling important inflammatory mechanisms driving gestation: we hypothesize that ceramide can be a therapeutic target in inflammatory complications of parturition.

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Therapy of CF-Patients with Amitriptyline and Placebo - a Randomised, Double-Blind, Placebo-Controlled Phase IIb Multicenter, Cohort-Study

Cited by 1,958 publications

References 17 publications

Invariant Natural Killer T (iNKT) Cells Prevent Autoimmunity, but Induce Pulmonary Inflammation in Cystic Fibrosis

Invariant Natural Killer T (iNKT) Cells Prevent Autoimmunity, but Induce Pulmonary Inflammation in Cystic Fibrosis

Regulation of the Inflammasome by Ceramide in Cystic Fibrosis Lungs

De novo ceramide synthesis is involved in acute inflammation during labor

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