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Background: PDGFR-inhibition by the tyrosine kinase inhibitor (TKI) nintedanib attenuates the progress of idiopathic pulmonary fibrosis (IPF). However, the effects of PDGF-BB on the airway tone are almost unknown. We studied this issue and the mechanisms beyond, using isolated perfused lungs (IPL) of guinea pigs (GPs) and precision-cut lung slices (PCLS) of GPs and humans.Methods: IPL: PDGF-BB was perfused after or without pre-treatment with the TKI imatinib (perfused/nebulised) and its effects on the tidal volume (TV), the dynamic compliance (Cdyn) and the resistance were studied.Pcls (gp): The bronchoconstrictive effects of PDGF-BB and the mechanisms beyond were evaluated. PCLS (human): The bronchoconstrictive effects of PDGF-BB and the bronchorelaxant effects of imatinib were studied. All changes of the airway tone were measured by videomicroscopy and indicated as changes of the initial airway area.Results: PCLS (GP/human): PDGF-BB lead to a contraction of airways. IPL: PDGF-BB decreased TV and Cdyn, whereas the resistance did not increase significantly. In both models, inhibition of PDGFR-(β) (imatinib/SU6668) prevented the bronchoconstrictive effect of PDGF-BB. The mechanisms beyond PDGF-BB-induced bronchoconstriction include activation of MAP2K and TP-receptors, actin polymerisation and Ca2+-sensitisation, whereas the increase of Ca2+ itself and the activation of EP1-4-receptors were not of relevance. In addition, imatinib relaxed pre-constricted human airways.Conclusions: PDGFR regulates the airway tone. In PCLS from GPs, this regulatory mechanism depends on the β-subunit. Hence, PDGFR-inhibition may not only represent a target to improve chronic airway disease such as IPF, but may also provide acute bronchodilation in asthma. Since asthma therapy uses topical application. This is even more relevant, as nebulisation of imatinib also appears to be effective. [ABSTRACT FROM AUTHOR]

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 TH1‐directed lung diseases like cystic fibrosis and acute lung injury. Here, we define the role of ASM in TH2‐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 TH2 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 TH2 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 TH2 cytokines. Conclusion: Asm deficiency could induce higher numbers of TH2 cells in the lung, but those cells release decreased TH2 cytokine levels. Hereby, Asm−/− animals are protected from bronchial asthma, which possibly offers novel therapeutic strategies, for example, with ASM blockade. [ABSTRACT FROM AUTHOR]

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 T H 1-directed lung diseases like cystic fibrosis and acute lung injury. Here, we define the role of ASM in T H 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 T H 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 T H 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 T H 2 cytokines., Conclusion: Asm deficiency could induce higher numbers of T H 2 cells in the lung, but those cells release decreased T H 2 cytokine levels. Hereby, Asm -/- animals are protected from bronchial asthma, which possibly offers novel therapeutic strategies, for example, with ASM blockade., (© 2020 The Authors. Allergy published by John Wiley & Sons Ltd.)