PI3K gamma-deficient mice have reduced levels of allergen-induced eosinophilic inflammation and airway remodeling.
In this study, we have examined the role of phosphoinositide 3 kinase gamma (PI3Kgamma), a class Ib PI3K, in contributing to airway remodeling utilizing PI3Kgamma-deficient mice exposed to chronic allergen challenge. Wild-type (WT) mice sensitized to ovalbumin (OVA) and chronically challenged with OVA for 1 mo developed significantly increased levels of eosinophilic inflammation and airway remodeling. In contrast, PI3Kgamma-deficient mice challenged with OVA had significantly reduced numbers of bronchoalveolar lavage and peribronchial eosinophils compared with WT mice. There was no significant difference in the number of bone marrow or circulating peripheral blood eosinophils when comparing WT mice and PI3Kgamma-deficient mice, suggesting that trafficking of eosinophils into the lung was reduced in PI3Kgamma-deficient mice. PI3Kgamma-deficient and WT mice had similar levels of IL-5 and eotaxin-1. The reduced eosinophil recruitment to the airway in PI3Kgamma-deficient mice challenged with OVA was associated with significantly reduced numbers of TGF-beta1+ peribronchial cells, reduced numbers of pSmad 2/3+ airway epithelial cells, and pSmad 2/3+ peribronchial cells, as well as significantly reduced levels of peribronchial fibrosis (quantitated by trichrome staining and image analysis as well as by lung collagen levels). In addition, the area of peribronchial alpha-smooth muscle staining was significantly reduced in PI3Kgamma-deficient compared with WT mice. Overall, this study demonstrates an important role for PI3Kgamma in mediating allergen-induced eosinophilic airway inflammation and airway remodeling, suggesting that PI3Kgamma may be a novel therapeutic target in asthma.
Lim
Dae Hyun
DH
Department of Medicine, University of California San Diego, San Diego, CA, USA.
Cho
Jae Youn
JY
Song
Dae Jin
DJ
Lee
Sang Yeub
SY
Miller
Marina
M
Broide
David H
DH
D000485:Allergens / Q000276:immunology*; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000276:immunology / Q000473:pathology*; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D054413:Chemokine CCL11 / Q000378:metabolism; D058544:Class Ib Phosphatidylinositol 3-Kinase; D004804:Eosinophils / Q000276:immunology / Q000473:pathology*; D015151:Immunoblotting; D015848:Interleukin-5 / Q000378:metabolism; D007527:Isoenzymes / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009130:Muscle, Smooth / Q000166:cytology / Q000378:metabolism; D010047:Ovalbumin / Q000008:administration & dosage; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D011014:Pneumonia / Q000209:etiology / Q000473:pathology*; D012137:Respiratory System / Q000166:cytology / Q000473:pathology*; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
D000485:Allergens; D054413:Chemokine CCL11; D015848:Interleukin-5; D007527:Isoenzymes; D051899:Smad2 Protein; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1; D010047:Ovalbumin; D019869:Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse