Comprehensive Attenuation Of IL-25-Induced Allergen Independent Asthma Like Symptoms By PI3K Pan-inhibitor

Backgroud: We have previously observed in vitro studies that IL-25 promotes the production of basic fibroblast growth factor(bFGF)and vascular endothelial growth factor(VEGF)by human umbilical vein endothelial cells(HUVEC)through PI3 Ks signaling pathway,thereby promotes the formation of angiogenesis.And PI3 K inhibitor LY294002 can effectively inhibit the formation of IL-25 induced angiogenesis.In vivo experiments also showed that IL-25 induces the inflammatory response and airways remodelling in mice,such as the accumulation of eosinophils,the deposition of collagen,mucus secretion and angiogenesis.Objective: This study aimed to confirm the inhibition of IL-25 induce asthma-like symptoms by PI3 K inhibitor in animal model,to further explore the role of IL-25 in the pathogenesis of asthma and the potential application of PI3 K inhibitors in the treatment of asthma.Methods: BALB/c mice were serially intranasally challenged with IL-25 according to an established protocol to induce airways inflammation,hyperresponsiveness and remodelling.A subgroup was administered additional intranasal LY294002 2 hours before the administration of IL-25,and an additional group of saline serve as negative control group,containing solvent(DMSO,dimethyl sulfoxide).Lung function and airways cytokine and chemokine concentrations(IL-5,IL-13,IL-1,IL-6,Eotaxin and KC)as well as growth factors VEGF and TGF-beta and cellular infiltration and remodelling changes assessed by histological staining [(hematoxylin and eosin(HE)staining,Congo red staining,Masson staining and PAS staining)] and immunohistochemistry(alpha –SMA and CD31 staining)were measured at specific time points,to observe the changes of airway inflammation,collagen deposition,mucus secretion,smooth muscle hyperplasia and angiogenesis.Results: Compared with the control group,intranasal administration of LY294002 significantly inhibited IL-25-induced airway hyperresponsiveness(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.Conclusion: The results showed that PI3 K pan-inhibitor LY294002 attenuated not only IL-25-induced asthma-like AHR and airways inflammation but also remodelling in this model,suggesting that PI3 K is a major downstream messenger for IL-25 signalling and that targeting this pathway might reduce asthma symptoms in the short term and airways remodelling in the longer term.