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Comprehensive attenuation of IL-25-induced airway hyperresponsiveness, inflammation and remodelling by the PI3K inhibitor LY294002

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机构: [1]Department of Immunology, School of Basic Medical Sciences, Capital Medical University, [2]Department of Respiratory and Critical Care Medicine, Beijing Chao-Yang Hospital, Capital Medical University & Beijing Institute of Respiratory Medicine, [3]Department of Laboratory Animal Sciences, Capital Medical University, [4]Department of Respiratory Medicine, Beijing Tongren Hospital, Capital Medical University, Beijing, China [5]Division of Asthma, Allergy & Lung Biology, King’s College London, MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, London, UK
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关键词: airway inflammation asthma interleukin-25 phosphoinositide 3-kinase inhibitors remodelling

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Background and objectiveExisting in vitro and in vivo studies suggest that both IL-25 and phosphoinositide 3-kinases (PI3Ks) exhibit broad effects on the functions of immune cells implicated in the pathogenesis of asthma. Whether the blockade of PI3K signalling directly inhibits the asthma relevant pathogenetic changes induced by IL-25 in an in vivo condition is still unclear. Using an established IL-25-induced murine model of asthma, we undertook a comprehensive evaluation of the effects of co-administered LY294002, a pharmacological pan-inhibitor of PI3K on IL-25-induced changes on this model, with particular regard to airway remodelling. Methods BALB/c mice were serially intranasally challenged with IL-25 according to an established protocol to induce airway inflammation, hyperresponsiveness (AHR) and remodelling. In an additional subgroup LY294002 was administered intranasally. Lung function and airway cytokine and chemokine concentrations and cellular infiltration and remodelling changes assessed by histology and immunohistochemistry were measured at specific time points. ResultsIntranasal administration of LY294002 significantly inhibited IL-25-induced AHR and recruitment of inflammatory cells into bronchoalveolar lavage fluid. LY294002 also attenuated IL-25-induced increased concentrations of cytokines and chemokines in lung tissue. Histological and immunohistochemical analysis showed that LY294002 also significantly inhibited IL-25-induced lung tissue eosinophilia, mucus production, collagen deposition, smooth muscle hypertrophy and angiogenesis. ConclusionThe PI3K pan-inhibitor LY294002 attenuated not only IL-25-induced asthma-like AHR and airway inflammation but also remodelling in this model, suggesting that PI3K is a major downstream messenger for IL-25 and that targeting this pathway might reduce asthma symptoms in the short term and airway remodelling in the longer term. The phosphoinositide 3-kinase (PI3K) pan-inhibitor LY294002 effectively attenuated IL-25-induced airway inflammation, hyperresponsiveness and remodelling in a murine asthma model in an in vivo condition.

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出版当年[2016]版:
大类 | 2 区 医学
小类 | 3 区 呼吸系统
最新[2023]版:
大类 | 2 区 医学
小类 | 2 区 呼吸系统
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出版当年[2015]版:
Q2 RESPIRATORY SYSTEM
最新[2023]版:
Q1 RESPIRATORY SYSTEM

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第一作者机构: [1]Department of Immunology, School of Basic Medical Sciences, Capital Medical University,
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通讯机构: [1]Department of Immunology, School of Basic Medical Sciences, Capital Medical University, [5]Division of Asthma, Allergy & Lung Biology, King’s College London, MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, London, UK [*1]Department of Immunology, School of Basic Medical Sciences, Capital Medical University, #10 Xitoutiao, Youanmenwai, Fengtai District, Beijing 100069, China.
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