Life-threatening asthma attack during prolonged fingolimod treatment: case report

Zecca, Chiara; Caporro, Matteo; Györik, Sándor; Gobbi, Claudio

doi:10.2147/ppa.s65708

Cited by 4 publications

(3 citation statements)

References 7 publications

(15 reference statements)

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“…Intranasal application of FTY720 was shown to decrease ORMDL3 expression and is effective for reducing airway inflammation and hyperreactivity and mucus hypersecretion in house dust mite-challenged mice [ 108 ]. On the other hand, it has been reported that prolonged FTY720 treatment induces life-threatening asthma attacks and deterioration [ 109 ]. Further investigations of therapeutic effects of FTY720 or other S1P/S1PR related-compounds for asthma diseases are expected.…”

Section: Therapeutic Potential Through Targeting Local S1p/s1pr Fumentioning

confidence: 99%

Sphingosine-1-Phosphate Signaling in Immune Cells and Inflammation: Roles and Therapeutic Potential

Aoki

Ramanathan

et al. 2016

Mediators of Inflammation

154

212

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Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite involved in many critical cell processes. It is produced by the phosphorylation of sphingosine by sphingosine kinases (SphKs) and exported out of cells via transporters such as spinster homolog 2 (Spns2). S1P regulates diverse physiological processes by binding to specific G protein-binding receptors, S1P receptors (S1PRs) 1–5, through a process coined as “inside-out signaling.” The S1P concentration gradient between various tissues promotes S1PR1-dependent migration of T cells from secondary lymphoid organs into the lymphatic and blood circulation. S1P suppresses T cell egress from and promotes retention in inflamed peripheral tissues. S1PR1 in T and B cells as well as Spns2 in endothelial cells contributes to lymphocyte trafficking. FTY720 (Fingolimod) is a functional antagonist of S1PRs that induces systemic lymphopenia by suppression of lymphocyte egress from lymphoid organs. In this review, we summarize previous findings and new discoveries about the importance of S1P and S1PR signaling in the recruitment of immune cells and lymphocyte retention in inflamed tissues. We also discuss the role of S1P-S1PR1 axis in inflammatory diseases and wound healing.

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Section: Therapeutic Potential Through Targeting Local S1p/s1pr Fumentioning

confidence: 99%

Sphingosine-1-Phosphate Signaling in Immune Cells and Inflammation: Roles and Therapeutic Potential

Aoki

Ramanathan

et al. 2016

Mediators of Inflammation

154

212

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“…48 Although there are 2 recent case reports that prolonged systemic treatment of patients with multiple sclerosis worsened their asthma, 49,50 local administration of FTY720 abrogates allergen-induced asthma in animals without causing systemic lymphopenia. 38,40 In agreement with this, we found that intranasal administration of FTY720 to mice exposed to HDM significantly reduced ORMDL3 expression, ceramide level increase, AHR, airway inflammation, and mucus hypersecretion, substantiating the correlation between asthma severity, ORMDL3, and ceramide levels.…”

Section: Discussionmentioning

confidence: 99%

Aberrant ORM (yeast)–like protein isoform 3 (ORMDL3) expression dysregulates ceramide homeostasis in cells and ceramide exacerbates allergic asthma in mice

Oyeniran

Sturgill

Hait

et al. 2015

Journal of Allergy and Clinical Immunology

101

155

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Background Asthma, a chronic inflammatory condition defined by episodic shortness of breath with expiratory wheezing and cough, is a serious health concern affecting more than 250 million persons. Genome-wide association studies have identified ORM (yeast)–like protein isoform 3 (ORMDL3) as a gene associated with susceptibility to asthma. Although its yeast ortholog is a negative regulator of de novo ceramide biosynthesis, how ORMDL3 contributes to asthma pathogenesis is not known. Objectives We sought to decipher the molecular mechanism for the pathologic functions of ORMDL3 in asthma and the relationship to its evolutionarily conserved role in regulation of ceramide homeostasis. Methods We determined the relationship between expression of ORMDL3 and ceramide in epithelial and inflammatory cells and in asthma pathogenesis in mice. Results Although small increases in ORMDL3 expression decrease ceramide levels, remarkably, higher expression in lung epithelial cells and macrophages in vitro and in vivo increased ceramide production, which promoted chronic inflammation, airway hyperresponsiveness, and mucus production during house dust mite–induced allergic asthma. Moreover, nasal administration of the immunosuppressant drug FTY720/fingolimod reduced ORMDL3 expression and ceramide levels and mitigated airway inflammation and hyperreactivity and mucus hypersecretion in house dust mite–challenged mice. Conclusions Our findings demonstrate that overexpression of ORMDL3 regulates ceramide homeostasis in cells in a complex manner and suggest that local FTY720 administration might be a useful therapeutic intervention for the control of allergic asthma.

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“…It is well-documented that a prolonged daily administration of sphingosine analogs at low doses can increase the risk of pulmonary side effects ( Cohen et al, 2010 ), which likely relates to the immunosuppressive activities of this class of agents. Over a period of time that exceeds months, FTY720 might even be associated with asthma exacerbations as exemplified by two case studies ( van Rossum et al, 2014 ; Zecca et al, 2014 ). Importantly, such effect was never reported in clinical trials over a short period of time.…”

Section: Discussionmentioning

confidence: 99%

A Phosphorylatable Sphingosine Analog Induces Airway Smooth Muscle Cytostasis and Reverses Airway Hyperresponsiveness in Experimental Asthma

et al. 2017

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In asthma, excessive bronchial narrowing associated with thickening of the airway smooth muscle (ASM) causes respiratory distress. Numerous pharmacological agents prevent experimental airway hyperresponsiveness (AHR) when delivered prophylactically. However, most fail to resolve this feature after disease is instated. Although sphingosine analogs are primarily perceived as immune modulators with the ability to prevent experimental asthma, they also influence processes associated with tissue atrophy, supporting the hypothesis that they could interfere with mechanisms sustaining pre-established AHR. We thus assessed the ability of a sphingosine analog (AAL-R) to reverse AHR in a chronic model of asthma. We dissected the pharmacological mechanism of this class of agents using the non-phosphorylatable chiral isomer AAL-S and the pre-phosphorylated form of AAL-R (AFD-R) in vivo and in human ASM cells. We found that a therapeutic course of AAL-R reversed experimental AHR in the methacholine challenge test, which was not replicated by dexamethasone or the non-phosphorylatable isomer AAL-S. AAL-R efficiently interfered with ASM cell proliferation in vitro, supporting the concept that immunomodulation is not necessary to interfere with cellular mechanisms sustaining AHR. Moreover, the sphingosine-1-phosphate lyase inhibitor SM4 and the sphingosine-1-phosphate receptor antagonist VPC23019 failed to inhibit proliferation, indicating that intracellular accumulation of sphingosine-1-phosphate or interference with cell surface S1P1/S1P3 activation, are not sufficient to induce cytostasis. Potent AAL-R-induced cytostasis specifically related to its ability to induce intracellular AFD-R accumulation. Thus, a sphingosine analog that possesses the ability to be phosphorylated in situ interferes with cellular mechanisms that beget AHR.

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Life-threatening asthma attack during prolonged fingolimod treatment: case report

Cited by 4 publications

References 7 publications

Sphingosine-1-Phosphate Signaling in Immune Cells and Inflammation: Roles and Therapeutic Potential

Sphingosine-1-Phosphate Signaling in Immune Cells and Inflammation: Roles and Therapeutic Potential

Aberrant ORM (yeast)–like protein isoform 3 (ORMDL3) expression dysregulates ceramide homeostasis in cells and ceramide exacerbates allergic asthma in mice

A Phosphorylatable Sphingosine Analog Induces Airway Smooth Muscle Cytostasis and Reverses Airway Hyperresponsiveness in Experimental Asthma

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