RESUMO
Pulmonary fibrosis (PF) is a fatal respiratory disease with no effective medical treatments available. TGF-ß/Smads signaling has been implicated to play an essential in the pathogenesis of PF, in which Smad3 act as the integrator of pro-fibrosis signals. In this study, we determined the effect of SIS3, a specific inhibitor of Smad3, in an experimental mouse model of lung fibrosis. We observed that SIS3 treatment significantly reduced bleomycin (BLM)-induced pathological changes and collagen deposition in the lung as indicated by Masson staining, real-time PCR and hydroxyproline content assay. As expected, the levels of Smad3 phosphorylation were decreased in the lung of mice treated with SIS3. Furthermore, SIS3 treatment also suppressed BLM-induced infiltration of inflammatory cells in the lung. Taken together, our results suggest that SIS3 ameliorated BLM-induced PF in mouse lungs. Thus, targeting Smad3 with SIS3 may be an effective approach for treatment of fibrotic disorders.
Assuntos
Isoquinolinas/uso terapêutico , Pulmão/efeitos dos fármacos , Fibrose Pulmonar/tratamento farmacológico , Piridinas/uso terapêutico , Pirróis/uso terapêutico , Proteína Smad3/antagonistas & inibidores , Animais , Bleomicina , Colágeno Tipo I/análise , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/patologia , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação/efeitos dos fármacos , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia , Proteína Smad3/análiseRESUMO
Listeria monocytogenes is a Gram-positive intracellular bacterium that was transmitted through contaminated food and causes sepsis and even death. IL-37 has been described as an important anti-inflammatory factor, but little is known about the function of IL-37 in host defense against Liseria monocytogenes (Lm) infection. In mice model of systemic infection, we found that mice treated with IL-37 were more sensitive to Lm infection compared with PBS-treated mice. This reduced resistance to Lm in IL-37-treated mice is accompanied with increased bacterial burden and liver damage. Serum levels of colony-stimulating factors were decreased in IL-37-treated mice. IL-37 treatment reduced bactericidal ability of bone marrow derived macrophages (BMDMs) in vitro, which contribute to the inability of IL-37-treated mice to combat Lm infection. Furthermore, increased apoptosis was observed in Lm-infected macrophages treated with IL-37. Increased macrophage apoptosis reduced percentage in liver macrophages was observed in IL-37-treated mice following Lm infection. These results indicate the negative regulatory effect of IL-37 on host resistance during immune defense against Lm.
Assuntos
Resistência à Doença/efeitos dos fármacos , Interleucina-1/farmacologia , Listeria monocytogenes/efeitos dos fármacos , Listeriose/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Carga Bacteriana/efeitos dos fármacos , Células Cultivadas , Citocinas/sangue , Modelos Animais de Doenças , Resistência à Doença/imunologia , Citometria de Fluxo , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Listeria monocytogenes/imunologia , Listeria monocytogenes/fisiologia , Listeriose/sangue , Listeriose/microbiologia , Fígado/efeitos dos fármacos , Fígado/microbiologia , Fígado/patologia , Macrófagos/imunologia , Macrófagos/microbiologia , Camundongos Endogâmicos BALB C , Análise de SobrevidaRESUMO
IL-37 is a novel pro-angiogenic cytokine that potently promotes endothelial cell activation and pathological angiogenesis in our previous study, but the mechanisms behind the pro-angiogenic effect of IL-37 are less well understood. Extending our observations, we found that TGF-ß interacts with IL-37, and potently enhances the binding affinity of IL-37 to the ALK1 receptor complex, thus allowing IL-37 to signal through ALK1 to activate pro-angiogenic responses. We further show that TGF-ß and ALK1 are required in IL-37 induced pro-angiogenic response in ECs and in the mouse model of Matrigel plug and oxygen-induced retinopathy. The result suggests that IL-37 induces pro-angiogenic responses through TGF-ß, which may act as the bridging molecule that mediates IL-37 binding to the TGF-ß receptor complex.