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1.
J Leukoc Biol ; 89(2): 269-82, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21048214

RESUMO

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-ß(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.


Assuntos
Bleomicina/toxicidade , Classe Ib de Fosfatidilinositol 3-Quinase/fisiologia , Pneumonia/enzimologia , Pneumonia/patologia , Fibrose Pulmonar/enzimologia , Fibrose Pulmonar/patologia , Animais , Células Cultivadas , Classe Ib de Fosfatidilinositol 3-Quinase/deficiência , Classe Ib de Fosfatidilinositol 3-Quinase/genética , Modelos Animais de Doenças , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/enzimologia , Humanos , Pulmão/irrigação sanguínea , Pulmão/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neovascularização Fisiológica/imunologia , Pneumonia/induzido quimicamente , Fibrose Pulmonar/induzido quimicamente
2.
Am J Respir Cell Mol Biol ; 40(4): 410-21, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18836137

RESUMO

Pulmonary fibrosis is characterized by chronic inflammation and excessive collagen deposition. Neutrophils are thought to be involved in the pathogenesis of lung fibrosis. We hypothesized that CXCR2-mediated neutrophil recruitment is essential for the cascade of events leading to bleomycin-induced pulmonary fibrosis. CXCL1/KC was detected as early as 6 hours after bleomycin instillation and returned to basal levels after Day 8. Neutrophils were detected in bronchoalveolar lavage and interstitium from 12 hours and peaked at Day 8 after instillation. Treatment with the CXCR2 receptor antagonist, DF2162, reduced airway neutrophil transmigration but led to an increase of neutrophils in lung parenchyma. There was a significant reduction in IL-13, IL-10, CCL5/RANTES, and active transforming growth factor (TGF)-beta(1) levels, but not on IFN-gamma and total TGF-beta(1,) and enhanced granulocyte macrophage-colony-stimulating factor production in DF2162-treated animals. Notably, treatment with the CXCR2 antagonist led to an improvement of the lung pathology and reduced collagen deposition. Using a therapeutic schedule, DF2162 administered from Days 8 to 16 after bleomycin reduced pulmonary fibrosis and levels of active TGF-beta(1) and IL-13. DF2162 treatment reduced bleomycin-induced expression of von Willebrand Factor, a marker of angiogenesis, in the lung. In vitro, DF2162 reduced the angiogenic activity of IL-8 on human umbilical vein endothelial cells. In conclusion, we show that CXCR2 plays an important role in mediating fibrosis after bleomycin instillation. The compound blocks angiogenesis and the production of pro-angiogenic cytokines, and decreases IL-8-induced endothelial cell activation. An effect on neutrophils does not appear to account for the major effects of the blockade of CXCR2 in the system.


Assuntos
Pneumonia/complicações , Pneumonia/metabolismo , Fibrose Pulmonar/complicações , Fibrose Pulmonar/metabolismo , Receptores de Interleucina-8B/metabolismo , Animais , Benzenoacetamidas/administração & dosagem , Benzenoacetamidas/farmacologia , Bleomicina , Líquido da Lavagem Broncoalveolar , Movimento Celular/efeitos dos fármacos , Quimiocinas/biossíntese , Relação Dose-Resposta a Droga , Humanos , Cinética , Masculino , Mesilatos/administração & dosagem , Mesilatos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Neovascularização Patológica/metabolismo , Neutrófilos/citologia , Neutrófilos/efeitos dos fármacos , Pneumonia/induzido quimicamente , Pneumonia/patologia , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia , Receptores de Interleucina-8B/antagonistas & inibidores , Fatores de Tempo
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