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

Abstract

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-β(1) 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.

• Authors: Remo C Russo, Cristiana C Garcia, Lucíola S Barcelos, Milene A Rachid, Rodrigo Guabiraba, Ester Roffê, Adriano L S Souza, Lirlândia P Sousa, Massimiliano Mirolo, Andrea Doni, Geovanni D Cassali, Vanessa Pinho, Massimo Locati, Mauro M Teixeira
• Journal: Journal of leukocyte biology (J Leukoc Biol) Vol. 89 Issue 2 Pg. 269-82 (Feb 2011) ISSN: 1938-3673 [Electronic] England
• PMID: 21048214 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Bleomycin
• Class Ib Phosphatidylinositol 3-Kinase
• Pik3cg protein, mouse

Topics

• Animals
• Bleomycin (toxicity)
• Cells, Cultured
• Class Ib Phosphatidylinositol 3-Kinase (deficiency, genetics, physiology)
• Disease Models, Animal
• Endothelium, Vascular (cytology, drug effects, enzymology)
• Humans
• Lung (blood supply, immunology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Neovascularization, Physiologic (immunology)
• Pneumonia (chemically induced, enzymology, pathology)
• Pulmonary Fibrosis (chemically induced, enzymology, pathology)