Svenja Böll1,2, Sebastian Ziemann2,3, Kim Ohl1, Patricia Klemm1, Annette D Rieg2,3, Erich Gulbins4,5, Katrin Anne Becker4, Markus Kamler6, Norbert Wagner1, Stefan Uhlig2, Christian Martin2, Klaus Tenbrock1, Eva Verjans1,2. 1. Department of Pediatrics, Medical Faculty, RWTH Aachen University, University Hospital Aachen, Aachen, Germany. 2. Institute of Pharmacology and Toxicology, RWTH Aachen University, University Hospital Aachen, Aachen, Germany. 3. Department of Anaesthesiology, Medical Faculty, RWTH Aachen University, University Hospital Aachen, Aachen, Germany. 4. Department of Molecular Biology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. 5. Department of Surgery, University of Cincinnati, Cincinnati, OH, USA. 6. Thoracic Transplantation, Thoracic and Cardiovascular Surgery, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
Abstract
BACKGROUND: Allergic diseases and especially allergic asthma are widespread diseases with high prevalence in childhood, but also in adults. Acid sphingomyelinase (ASM) is a key regulator of the sphingolipid pathway. Previous studies defined the association of ASM with the pathogenesis of TH 1-directed lung diseases like cystic fibrosis and acute lung injury. Here, we define the role of ASM in TH 2-regulated allergic bronchial asthma. METHODS: To determine the role of Asm under baseline conditions, wild-type (WT) and Asm-/- mice were ventilated with a flexiVent setup and bronchial hyperresponsiveness was determined using acetylcholine. Flow cytometry and cytokine measurements in bronchoalveolar lavage fluid and lung tissue were followed by in vitro TH 2 differentiations with cells from WT and Asm-/- mice and blockade of Asm with amitriptyline. As proof of principle, we conducted an ovalbumin-induced model of asthma in WT- and Asm-/- mice. RESULTS: At baseline, Asm-/- mice showed better lung mechanics, but unaltered bronchial hyperresponsiveness. Higher numbers of Asm-/- T cells in bronchoalveolar lavage fluid released lower levels of IL-4 and IL-5, and these results were paralleled by decreased production of typical TH 2 cytokines in Asm-/- T lymphocytes in vitro. This phenotype could be imitated by incubation of T cells with amitriptyline. In the ovalbumin asthma model, Asm-/- animals were protected from high disease activity and showed better lung functions and lower levels of eosinophils and TH 2 cytokines. CONCLUSION: Asm deficiency could induce higher numbers of TH 2 cells in the lung, but those cells release decreased TH 2 cytokine levels. Hereby, Asm-/- animals are protected from bronchial asthma, which possibly offers novel therapeutic strategies, for example, with ASM blockade.
BACKGROUND:Allergic diseases and especially allergic asthma are widespread diseases with high prevalence in childhood, but also in adults. Acid sphingomyelinase (ASM) is a key regulator of the sphingolipid pathway. Previous studies defined the association of ASM with the pathogenesis of TH 1-directed lung diseases like cystic fibrosis and acute lung injury. Here, we define the role of ASM in TH 2-regulated allergic bronchial asthma. METHODS: To determine the role of Asm under baseline conditions, wild-type (WT) and Asm-/- mice were ventilated with a flexiVent setup and bronchial hyperresponsiveness was determined using acetylcholine. Flow cytometry and cytokine measurements in bronchoalveolar lavage fluid and lung tissue were followed by in vitro TH 2 differentiations with cells from WT and Asm-/- mice and blockade of Asm with amitriptyline. As proof of principle, we conducted an ovalbumin-induced model of asthma in WT- and Asm-/- mice. RESULTS: At baseline, Asm-/- mice showed better lung mechanics, but unaltered bronchial hyperresponsiveness. Higher numbers of Asm-/- T cells in bronchoalveolar lavage fluid released lower levels of IL-4 and IL-5, and these results were paralleled by decreased production of typical TH 2 cytokines in Asm-/- T lymphocytes in vitro. This phenotype could be imitated by incubation of T cells with amitriptyline. In the ovalbuminasthma model, Asm-/- animals were protected from high disease activity and showed better lung functions and lower levels of eosinophils and TH 2 cytokines. CONCLUSION:Asm deficiency could induce higher numbers of TH 2 cells in the lung, but those cells release decreased TH 2 cytokine levels. Hereby, Asm-/- animals are protected from bronchial asthma, which possibly offers novel therapeutic strategies, for example, with ASM blockade.
Authors: Murad Abusukhun; Martin S Winkler; Stefan Pöhlmann; Onnen Moerer; Konrad Meissner; Björn Tampe; Heike Hofmann-Winkler; Michael Bauer; Markus H Gräler; Ralf A Claus Journal: Front Immunol Date: 2021-12-20 Impact factor: 7.561
Authors: Joanna M Poczobutt; Andrew M Mikosz; Christophe Poirier; Erica L Beatman; Karina A Serban; Fabienne Gally; Danting Cao; Alexandra L McCubbrey; Christina F Cornell; Kelly S Schweitzer; Evgeny V Berdyshev; Irina A Bronova; François Paris; Irina Petrache Journal: Am J Respir Cell Mol Biol Date: 2021-05 Impact factor: 6.914