title: Inhibition of phosphoinositide 3-kinase delta attenuates allergic airway inflammation and hyperresponsiveness in murine asthma model.
abstract: P110delta phosphoinositide 3-kinase (PI3K) plays a pivotal role in the recruitment and activation of certain inflammatory cells. Recent findings revealed that the activity of p110delta also contributes to allergen-IgE-induced mast cell activation and vascular permeability. We investigated the role of p110delta in allergic airway inflammation and hyperresponsiveness using IC87114, a selective p110delta inhibitor, in a mouse asthma model. BALB/c mice were sensitized with OVA and, upon OVA aerosol challenge, developed airway eosinophilia, mucus hypersecretion, elevation in cytokine and chemokine levels, up-regulation of ICAM-1 and VCAM-1 expression, and airway hyperresponsiveness. Intratracheal administration of IC87114 significantly (P<0.05) attenuated OVA-induced influx into lungs of total leukocytes, eosinophils, neutrophils, and lymphocytes, as well as levels of IL-4, IL-5, IL-13, and RANTES in a dose-dependent manner. IC87114 also significantly (P<0.05) reduced the serum levels of total IgE and OVA-specific IgE and LTC(4) release into the airspace. Histological studies show that IC87114 inhibited OVA-induced lung tissue eosinophilia, airway mucus production, and inflammation score. In addition, IC87114 significantly (P<0.05) suppressed OVA-induced airway hyperresponsiveness to inhaled methacholine. Western blot analyses of whole lung tissue lysates shows that IC87114 markedly attenuated the OVA-induced increase in expression of IL-4, IL-5, IL-13, ICAM-1, VCAM-1, RANTES, and eotaxin. Furthermore, IC87114 treatment markedly attenuated OVA-induced serine phosphorylation of Akt, a downstream effector of PI3K signaling. Taken together, our findings implicate that inhibition of p110delta signaling pathway may have therapeutic potential for the treatment of allergic airway inflammation.
authors.affiliation: Department of Internal Medicine, Research Center for Allergic Immune Diseases, Chonbuk National University Medical School, Jeonju, South Korea.
authors.forename: Kyung S
authors.initials: KS
authors.lastname: Lee
authors.forename: Ho K
authors.initials: HK
authors.lastname: Lee
authors.forename: Joel S
authors.initials: JS
authors.lastname: Hayflick
authors.forename: Yong C
authors.initials: YC
authors.lastname: Lee
authors.forename: Kamal D
authors.initials: KD
authors.lastname: Puri
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000032:analysis / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001249:Asthma / Q000473:pathology / Q000628:therapy*; D016535:Bronchial Hyperreactivity / Q000473:pathology / Q000628:therapy; D001985:Bronchial Provocation Tests; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D018925:Chemokines / Q000096:biosynthesis; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D058534:Class I Phosphatidylinositol 3-Kinases; D016207:Cytokines / Q000096:biosynthesis; D004802:Eosinophilia / Q000209:etiology / Q000517:prevention & control; D005260:Female; D008168:Lung / Q000201:enzymology; D016210:Methacholine Chloride; D051379:Mice; D008807:Mice, Inbred BALB C; D023421:Models, Animal; D009093:Mucus / Q000378:metabolism; D010047:Ovalbumin; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000032:analysis / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000225:Adenine; D015815:Cell Adhesion Molecules; D018925:Chemokines; D058534:Class I Phosphatidylinositol 3-Kinases; D016207:Cytokines; D016210:Methacholine Chloride; D010047:Ovalbumin; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; C477872:IC 87114; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse