Phosphoinositide 3-kinase γ plays a critical role in bleomycin-induced pulmonary inflammation and fibrosis in mice

PI3Kγ is important to drive the fibrotic processes by regulation of pulmonary inflammation and angiogenesis in mice, suggesting PI3Kγ as therapeutic target for pulmonary fibrosis. PI3Kγ is central in signaling diverse arrays of cellular functions and inflammation. Pulmonary fibrosis is associated wi...

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Bibliographic Details
Published in:Journal of leukocyte biology 2011-02, Vol.89 (2), p.269-282
Main Authors: Russo, Remo C., Garcia, Cristiana C., Barcelos, Lucíola S., Rachid, Milene A., Guabiraba, Rodrigo, Roffê, Ester, Souza, Adriano L. S., Sousa, Lirlândia P., Mirolo, Massimiliano, Doni, Andrea, Cassali, Geovanni D., Pinho, Vanessa, Locati, Massimo, Teixeira, Mauro M.
Format: Article
Language:English
Subjects:
Animals
Bleomycin - toxicity
Cells, Cultured
chemokine
Class Ib Phosphatidylinositol 3-Kinase - deficiency
Class Ib Phosphatidylinositol 3-Kinase - genetics
Class Ib Phosphatidylinositol 3-Kinase - physiology
Disease Models, Animal
Endothelium, Vascular - cytology
Endothelium, Vascular - drug effects
Endothelium, Vascular - enzymology
Human health and pathology
Humans
Immunology
Life Sciences
Lung - blood supply
Lung - immunology
lung angiogenesis
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Neovascularization, Physiologic - immunology
PI3Kγ
Pneumonia - chemically induced
Pneumonia - enzymology
Pneumonia - pathology
Pulmonary Fibrosis - chemically induced
Pulmonary Fibrosis - enzymology
Pulmonary Fibrosis - pathology
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Summary:PI3Kγ is important to drive the fibrotic processes by regulation of pulmonary inflammation and angiogenesis in mice, suggesting PI3Kγ as therapeutic target for pulmonary fibrosis. PI3Kγ is central in signaling diverse arrays of cellular functions and inflammation. Pulmonary fibrosis is associated with pulmonary inflammation, angiogenesis, and deposition of collagen and is modeled by instillation of bleomycin. The role of PI3Kγ in mediating bleomycin‐induced pulmonary inflammation and fibrosis in mice and potential mechanisms involved was investigated here. WT or PI3Kγ KO mice were instilled with bleomycin and leukocyte subtype influx, cytokine and chemokine levels, and angiogenesis and tissue fibrosis evaluated. The activation of lung‐derived leukocytes and fibroblasts was evaluated in vitro. The relevance of PI3Kγ for endothelial cell function was evaluated in HUVECs. PI3Kγ KO mice had greater survival and weight recovery and less fibrosis than WT mice after bleomycin instillation. This was associated with decreased production of TGF‐β1 and CCL2 and increased production of IFN‐γ and IL‐10. There was reduced expression of collagen, fibronectin, α‐SMA, and von Willebrand factor and decreased numbers and activation of leukocytes and phosphorylation of AKT and IκB‐α. PI3Kγ KO mice had a reduced number and area of blood vessels in the lungs. In vitro, treatment of human endothelial cells with the PI3Kγ inhibitor AS605240 decreased proliferation, migration, and formation of capillary‐like structures. AS605240 also decreased production of collagen by murine lung‐derived fibroblasts. PI3Kγ deficiency confers protection against bleomycin‐induced pulmonary injury, angiogenesis, and fibrosis through the modulation of leukocyte, fibroblast, and endothelial cell functions. Inhibitors of PI3Kγ may be beneficial for the treatment of pulmonary fibrosis.
ISSN:0741-5400
1938-3673
DOI:10.1189/jlb.0610346