Abstract：
The wingless/integrase-1 (WNT) pathway involved in the pathogenesis of inflammatory airway diseases has recently generated considerable research interest. Montelukast, a leukotriene receptor antagonist, provides therapeutic benefits in allergic asthma involving eosinophils. We aimed to investigate the role of the WNT pathway in the therapeutic actions of montelukast (MT) in a mixed type of allergic-acute airway inflammation model induced by ovalbumin (OVA) and lipopolysaccharide (LPS) in mice. Female mice were sensitized with intraperitoneal OVA-Al(OH)3 administration in the initiation phase and intranasal OVA followed by LPS administration in the challenge phase. The mice were divided into eight groups: control, asthmatic, and control/asthmatic treated with XAV939 (inhibitor of the canonical WNT pathway), LGK-974 (inhibitor of the secretion of WNT ligands), or MT at different doses. The inhibition of the WNT pathway prevented tracheal 5-HT and bradykinin hyperreactivity, while only the inhibition of the canonical WNT pathway partially reduced 5-HT and bradykinin contractions compared to the inflammation group. Therefore, MT treatment hindered 5-HT and bradykinin hyperreactivity associated with airway inflammation. Furthermore, MT prevented the increases in the phosphorylated GSK-3β and WNT5A levels, which had been induced by airway inflammation, in a dose-dependent manner. Conversely, the MT application caused a further increase in the fibronectin levels, while there was no significant alteration in the phosphorylation of the Smad-2 levels in the isolated lungs of the mice. The MT treatment reversed the increase in the mRNA expression levels of interleukin-17A. An increase in eosinophil and neutrophil counts was observed in bronchoalveolar lavage fluid samples obtained from the mice in the inflammation group, which was hampered by the MT treatment. The inhibition of the WNT pathway did not alter inflammatory cytokine expression or cell infiltration. The WNT pathway mediated the therapeutic effects of MT due to the inhibition of GSK-3β phosphorylation as well as the reduction of WNT5A levels in a murine airway inflammation model.
摘要：
最近，炎性气道疾病的发病机制中涉及的无翼/整合酶-1（WNT）途径引起了相当大的研究兴趣。孟鲁司特,白三烯受体拮抗剂，在涉及嗜酸性粒细胞的过敏性哮喘中提供治疗益处。我们旨在研究WNT通路在孟鲁司特（MT）在卵清蛋白（OVA）和脂多糖（LPS）诱导的小鼠混合型过敏性急性气道炎症模型中的作用。雌性小鼠在起始阶段用腹膜内OVA-Al(OH)3给药致敏,在攻击阶段用鼻内OVA给药,然后用LPS给药致敏。将小鼠分为八组：对照组，哮喘,和对照/哮喘用XAV939（经典WNT途径的抑制剂）治疗，LGK-974（WNT配体分泌抑制剂），或不同剂量的MT。WNT通路的抑制阻止了气管5-HT和缓激肽高反应性,与炎症组相比，仅经典WNT途径的抑制部分减少了5-HT和缓激肽的收缩。因此,MT治疗阻碍与气道炎症相关的5-HT和缓激肽高反应性。此外，MT阻止了磷酸化GSK-3β和WNT5A水平的增加，这是由气道炎症引起的，以剂量依赖的方式。相反，MT的应用导致纤连蛋白水平进一步增加，而小鼠离体肺中Smad-2水平的磷酸化没有显著改变。MT治疗逆转了白细胞介素-17AmRNA表达水平的增加。在从炎症组小鼠获得的支气管肺泡灌洗液样品中观察到嗜酸性粒细胞和中性粒细胞计数增加，受到MT治疗的阻碍。WNT途径的抑制不改变炎性细胞因子表达或细胞浸润。由于在鼠气道炎症模型中GSK-3β磷酸化的抑制以及WNT5A水平的降低,WNT途径介导MT的治疗作用。
