title: Comprehensive attenuation of IL-25-induced airway hyperresponsiveness, inflammation and remodelling by the PI3K inhibitor LY294002.
abstract: Existing 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.
  
  
  
  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.
  
  
  
  Intranasal 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.
  
  
  
  The 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.
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Huang
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.|Department of Respiratory and Critical Care Medicine, Beijing Chao-Yang Hospital, Capital Medical University & Beijing Institute of Respiratory Medicine, Beijing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
authors.forename: Ze
authors.initials: Z
authors.lastname: Lv
authors.affiliation: Department of Laboratory Animal Sciences, Capital Medical University, Beijing, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Respiratory Medicine, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Respiratory Medicine, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
authors.forename: Xiujuan
authors.initials: X
authors.lastname: Yao
authors.affiliation: Division of Asthma, Allergy & Lung Biology, King's College London, MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, London, UK.
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Corrigan
authors.affiliation: Department of Respiratory and Critical Care Medicine, Beijing Chao-Yang Hospital, Capital Medical University & Beijing Institute of Respiratory Medicine, Beijing, China.
authors.forename: Kewu
authors.initials: K
authors.lastname: Huang
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.|Division of Asthma, Allergy & Lung Biology, King's College London, MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, London, UK.
authors.forename: Sun
authors.initials: S
authors.lastname: Ying
mesh_terms: D056151:Airway Remodeling / Q000187:drug effects / Q000276:immunology; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002867:Chromones / Q000494:pharmacology*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007378:Interleukins / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009025:Morpholines / Q000494:pharmacology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012129:Respiratory Function Tests / Q000379:methods; D012130:Respiratory Hypersensitivity / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D002867:Chromones; D004791:Enzyme Inhibitors; D007378:Interleukins; D009025:Morpholines; C442281:Mydgf protein, mouse; D000081082:Phosphoinositide-3 Kinase Inhibitors; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
keywords: airway inflammation; asthma; interleukin-25; phosphoinositide 3-kinase inhibitors; remodelling