title: Phosphatidylinositol 3-kinase inhibitor suppresses inducible nitric oxide synthase expression in bronchiole epithelial cells in asthmatic rats.
abstract: Inducible nitric oxide synthase (iNOS) is known to produce nitric oxide (NO), which is a main contributor to asthmatic airway inflammation. Recent studies have shown that phosphatidylinositol 3-kinase (PI3K) is ubiquitously expressed in airway epithelial cells and its inhibition could relieve airway inflammation and hyperresponsiveness. This study aimed to explore the interaction of PI3K and NO signaling in allergic asthma. We investigated the effects of PI3K inhibitor wortmannin on iNOS expression in bronchiole epithelial cells and NO, IL-4 and IFN-γ levels in lung tissues of asthmatic rat model, which was prepared by 10% OVA solution sensitization and 1% OVA aerosol challenge. Our results showed that the ratio of eosinophils to total cells in BALF, PI3K activity, NO and IL-4 levels in lung tissues was increased after OVA sensitization and challenge, but then was attenuated by the administration of wortmannin. In contrast, IFN-γ level in lung tissues was decreased after OVA sensitization and challenge and increased after the administration of wortmannin. The expression of iNOS protein in bronchiole epithelial cells, iNOS mRNA level and iNOS activity in lung tissues was markedly upregulated after OVA sensitization and challenge, but the upregulation was significantly antagonized by wortmannin. Taken together, these data provide evidence that PI3K functions upstream to modulate iNOS/NO signaling, which then promotes the development of airway inflammation in asthmatic animal model. PI3K inhibitor wortmannin could lead to reduced iNOS expression and NO production, therefore inhibiting airway inflammatory responses.
authors.affiliation: Department of Respiratory Medicine, The Second Affiliated Hospital of Wenzhou Medical College, and Department of Pathophysiology, Wenzhou Medical College, Wenzhou, 325027, Zhejiang, China. xia_xiao_dong@hotmail.com
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Xia
authors.forename: Xiaoguang
authors.initials: X
authors.lastname: Hu
authors.forename: Hui
authors.initials: H
authors.lastname: Xu
authors.forename: Liqin
authors.initials: L
authors.lastname: Wu
authors.forename: Yuanrong
authors.initials: Y
authors.lastname: Dai
authors.forename: Lei
authors.initials: L
authors.lastname: Yang
authors.forename: Zhengjie
authors.initials: Z
authors.lastname: Xu
mesh_terms: D000730:Androstadienes / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D055745:Bronchioles / Q000473:pathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000188:drug therapy; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D004791:Enzyme Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D000077191:Wortmannin