Inhibition of Phosphoinositide 3-kinase Delta Attenuates Allergic Airway Inflammation and Hyperresponsiveness in Murine Asthma Model.
From: Department of Internal Medicine, Research Center for Allergic Immune Diseases, Chonbuk National University Medical School, Jeonju, South Korea.
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
- Publish Date: Mar 2006
- ISSN: 1530-6860
- Volume: 20
- Issue: 3
- Pages: 455-65
- Medium: Internet
- Language: English
- Citation (JAMA): Lee Kyung S, Lee Ho K, Hayflick Joel S, et al. Inhibition of Phosphoinositide 3-kinase Delta Attenuates Allergic Airway Inflammation and Hyperresponsiveness in Murine Asthma Model.. FASEB J. Mar 2006;20:455-65
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.
Mesh Headings (Keywords): 1-Phosphatidylinositol 3-Kinase, Adenine, Animals, Asthma, Bronchial Hyperreactivity, Bronchial Provocation Tests, Bronchoalveolar Lavage Fluid, Cell Adhesion Molecules, Chemokines, Chemotaxis, Leukocyte, Cytokines, Eosinophilia, Female, Lung, Methacholine Chloride, Mice, Mice, Inbred BALB C, Models, Animal, Mucus, Ovalbumin, Phosphorylation, Protein Processing, Post-Translational, Proto-Oncogene Proteins c-akt, Quinazolines
Check for Full Text / PubMed Unique Identifier (PMID): 16507763
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