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

Int Immunopharmacol. 2005 Mar;5(3):495-502. doi: 10.1016/j.intimp.2004.10.015.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Asthma / chemically induced
  • Asthma / drug therapy*
  • Bronchoalveolar Lavage Fluid / chemistry
  • Bronchoalveolar Lavage Fluid / cytology
  • Cell Movement / drug effects
  • Chromones / pharmacology*
  • Cytokines / metabolism
  • Disease Models, Animal
  • Eosinophils / cytology
  • Lung / drug effects
  • Lung / metabolism
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Morpholines / pharmacology*
  • Mucus / metabolism
  • Ovalbumin / immunology
  • Ovalbumin / pharmacology
  • Phosphoinositide-3 Kinase 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

Substances

  • Anti-Inflammatory Agents
  • Chromones
  • Cytokines
  • Morpholines
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Ovalbumin
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt