An anti-inflammatory role for a phosphoinositide 3-kinase inhibitor LY294002 in a mouse asthma model

• Published in: International immunopharmacology Vol. 5; no. 3; pp. 495 - 502
• Main Authors: Duan, Wei, Aguinaldo Datiles, Ana M.K., Leung, Bernard P., Vlahos, Chris J., Wong, W.S. Fred
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 01.03.2005; Elsevier
• Subjects: Airway hyperresponsiveness; Akt; Animals; Anti-Inflammatory Agents - pharmacology; Asthma - chemically induced; Asthma - drug therapy; Biological and medical sciences; Bronchoalveolar Lavage Fluid - chemistry; Bronchoalveolar Lavage Fluid - cytology; Cell Movement - drug effects; Chromones - pharmacology; Cytokines - metabolism; Disease Models, Animal; Eosinophilia; Eosinophils - cytology; Lung - drug effects; Lung - metabolism; Male; Medical sciences; Mice; Mice, Inbred BALB C; Morpholines - pharmacology; Mucus - metabolism; Mucus hypersecretion; Ovalbumin; Ovalbumin - immunology; Ovalbumin - pharmacology; Pharmacology. Drug treatments; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphorylation - drug effects; Protein-Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; Pulmonary Eosinophilia - drug therapy; Pulmonary Eosinophilia - pathology; Respiratory Hypersensitivity - chemically induced; Respiratory Hypersensitivity - drug therapy; Respiratory system; Ovalbumin; Akt; Mucus hypersecretion; Eosinophilia; Airway hyperresponsiveness; Animal model; Protein kinase B; Hyperreactivity; Hemopathy; Mucus; Respiratory system; Respiratory tract; Bronchus disease; Obstructive pulmonary disease; Lung disease; Respiratory disease; Enzyme; Transferases; Rodentia; Antiinflammatory agent; Enzyme inhibitor; Hypersecretion; 1-Phosphatidylinositol 3-kinase; Asthma; Vertebrata; Mammalia; Mouse
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2004.10.015

Phosphoinositide 3-kinase (PI3K) exhibits broad functional effects in immune cells. We investigated the role of PI3K in allergic airway inflammation using LY294002, a specific PI3K inhibitor, in a mouse asthma model. BALB/c mice were sensitized and challenged with ovalbumin (OVA), and developed airway eosinophilia, mucus hypersecretion, elevation in cytokine levels, and airway hyperresponsiveness. Intratracheal administration of LY294002 significantly inhibited OVA-induced increases in total cell counts, eosinophil counts, and IL-5, IL-13, and eotaxin levels in bronchoalveolar lavage fluid. Histological studies show that LY294002 dramatically inhibited OVA-induced lung tissue eosinophilia and airway mucus production. In addition, LY294002 significantly suppressed OVA-induced airway hyperresponsiveness to inhaled methacholine. Western blot analysis of whole lung lysates shows that LY294002 markedly attenuated OVA-induced serine phosphorylation of Akt, a direct downstream substrate of PI3K. Taken together, our findings suggest that inhibition of PI3K signaling pathway can suppress T-helper type 2 (Th2) cytokine production, eosinophil infiltration, mucus production, and airway hyperresponsiveness in a mouse asthma model and may have therapeutic potential for the treatment of allergic airway inflammation.