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Inhibition of phosphoinositide 3-kinase attenuates allergic airway inflammation and hyperresponsiveness in murine asthma model

Kyung S. Lee^*, Ho K. Lee^*, Joel S. Hayflick, Yong C. Lee^*,1 and Kamal D. Puri^,1

^* Department of Internal Medicine, Research Center for Allergic Immune Diseases, Chonbuk National University Medical School, Jeonju, South Korea; and
ICOS Corporation, Bothell, Washington, USA

¹Correspondence: K.D.P., ICOS Corporation, 22021 20th Ave. SE, Bothell, WA 98021, USA. E-mail: kpuri{at}icos.com or Y.C.L., Department of Internal Medicine, Chonbuk National University Medical School, 634-18, Keumamdong, Jeonju, 561-712, South Korea. E-mail: leeyc{at}chonbuk.ac.kr

P110 phosphoinositide 3-kinase (PI3K) plays a pivotal role in the recruitment and activation of certain inflammatory cells. Recent findings revealed that the activity of p110 also contributes to allergen-IgE-induced mast cell activation and vascular permeability. We investigated the role of p110 in allergic airway inflammation and hyperresponsiveness using IC87114, a selective p110 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 LTC₄ 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 p110 signaling pathway may have therapeutic potential for the treatment of allergic airway inflammation.—Lee, K. S., Lee, H. K., Hayflick, J. S., Lee, Y. C., Puri, K. D. Inhibition of phosphoinositide 3-kinase attenuates allergic airway inflammation and hyperresponsiveness in murine asthma model.

Key Words: allergy • inflammation • cell activation • lung • cytokines • signal transduction

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