An anti-inflammatory role for a phosphoinositide 3-kinase inhibitor LY294002 in a mouse asthma model.
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.
Duan
Wei
W
Department of Pharmacology, Faculty of Medicine, National University of Singapore, MD2 18 Medical Drive, 117597 Singapore.
Aguinaldo Datiles
Ana M K
AM
Leung
Bernard P
BP
Vlahos
Chris J
CJ
Wong
W S Fred
WS
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001249:Asthma / Q000139:chemically induced / Q000188:drug therapy*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002465:Cell Movement / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004804:Eosinophils / Q000166:cytology; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009025:Morpholines / Q000494:pharmacology*; D009093:Mucus / Q000378:metabolism; D010047:Ovalbumin / Q000276:immunology / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011657:Pulmonary Eosinophilia / Q000188:drug therapy / Q000473:pathology; D012130:Respiratory Hypersensitivity / Q000139:chemically induced / Q000188:drug therapy
D000893:Anti-Inflammatory Agents; D002867:Chromones; D016207:Cytokines; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011518:Proto-Oncogene Proteins; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D010047:Ovalbumin; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt