Phosphoinositide 3-kinase γ plays a critical role in bleomycin-induced pulmonary inflammation and fibrosis in mice.
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.
Universidade Federal de Minas Gerais, Avenida Antônio Carlos, Belo Horizonte, MG, Brazil.
Remo C
RC
Russo
Cristiana C
CC
Garcia
Lucíola S
LS
Barcelos
Milene A
MA
Rachid
Rodrigo
R
Guabiraba
Ester
E
Roffê
Adriano L S
AL
Souza
Lirlândia P
LP
Sousa
Massimiliano
M
Mirolo
Andrea
A
Doni
Geovanni D
GD
Cassali
Vanessa
V
Pinho
Massimo
M
Locati
Mauro M
MM
Teixeira
D000818:Animals; D001761:Bleomycin / Q000633:toxicity*; D002478:Cells, Cultured; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D008168:Lung / Q000098:blood supply / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000276:immunology; D011014:Pneumonia / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology*; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology*
D001761:Bleomycin; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse