RESUMO
In chronic schistosomiasis, liver fibrosis is linked to portal hypertension, which is a condition associated with high mortality and morbidity. High mobility group box 1 (HMGB1) was originally described as a nuclear protein that functions as a structural co-factor in transcriptional regulation. However, HMGB1 can also be secreted into the extracellular milieu under appropriate signal stimulation. Extracellular HMGB1 acts as a multifunctional cytokine that contributes to infection, injury, inflammation, and immune responses by binding to specific cell-surface receptors. HMGB1 is involved in fibrotic diseases. From a clinical perspective, HMGB1 inhibition may represent a promising therapeutic approach for treating tissue fibrosis. In this study, we demonstrate elevated levels of HMGB1 in the sera in experimental mice or in patients with schistosomiasis. Using immunohistochemistry, we demonstrated that HMGB1 trafficking in the hepatocytes of mice suffering from acute schistosomiasis was inhibited by Glycyrrhizin, a well-known HMGB1 direct inhibitor, as well as by DIC, a novel and potential anti-HMGB1 compound. HMGB1 inhibition led to significant downregulation of IL-6, IL4, IL-5, IL-13, IL-17A, which are involved in the exacerbation of the immune response and liver fibrogenesis. Importantly, infected mice that were treated with DIC or GZR to inhibit HMGB1 pro-inflammatory activity showed a significant increase in survival and a reduction of over 50% in the area of liver fibrosis. Taken together, our findings indicate that HMGB1 is a key mediator of schistosomotic granuloma formation and liver fibrosis and may represent an outstanding target for the treatment of schistosomiasis.
Assuntos
Granuloma , Proteína HMGB1/imunologia , Cirrose Hepática , Fígado , Schistosoma mansoni/imunologia , Esquistossomose mansoni , Animais , Citocinas/imunologia , Feminino , Granuloma/imunologia , Granuloma/parasitologia , Granuloma/patologia , Humanos , Fígado/imunologia , Fígado/parasitologia , Fígado/patologia , Cirrose Hepática/imunologia , Cirrose Hepática/parasitologia , Cirrose Hepática/patologia , Masculino , Camundongos Endogâmicos BALB C , Esquistossomose mansoni/imunologia , Esquistossomose mansoni/patologiaRESUMO
Schistosomiasis is a major cause of portal hypertension worldwide. It associates with portal fibrosis that develops during chronic infection. The mechanisms by which the pathogen evokes these host responses remain unclear. We evaluated the hypothesis that schistosome eggs release factors that directly stimulate liver cells to produce osteopontin (OPN), a pro-fibrogenic protein that stimulates hepatic stellate cells to become myofibroblasts. We also investigated the utility of OPN as a biomarker of fibrosis and/or severity of portal hypertension. Cultured cholangiocytes, Kupffer cells and hepatic stellate cells were treated with soluble egg antigen (SEA); OPN production was quantified by quantitative reverse transcriptase polymerase chain reaction (qRTPCR) and ELISA; cell proliferation was assessed by BrdU (5-bromo-2'-deoxyuridine). Mice were infected with Schistosoma mansoni for 6 or 16 weeks to cause early or advanced fibrosis. Liver OPN was evaluated by qRTPCR and immunohistochemistry (IHC) and correlated with liver fibrosis and serum OPN. Livers from patients with schistosomiasis mansoni (early fibrosis n=15; advanced fibrosis n=72) or healthy adults (n=22) were immunostained for OPN and fibrosis markers. Results were correlated with plasma OPN levels and splenic vein pressures. SEA-induced cholangiocyte proliferation and OPN secretion (P<0.001 compared with controls). Cholangiocytes were OPN (+) in Schistosoma-infected mice and humans. Liver and serum OPN levels correlated with fibrosis stage (mice: r=0.861; human r=0.672, P=0.0001) and myofibroblast accumulation (mice: r=0.800; human: r=0.761, P=0.0001). Numbers of OPN (+) bile ductules strongly correlated with splenic vein pressure (r=0.778; P=0.001). S. mansoni egg antigens stimulate cholangiocyte proliferation and OPN secretion. OPN levels in liver and blood correlate with fibrosis stage and portal hypertension severity.
Assuntos
Proliferação de Células , Hipertensão Portal/metabolismo , Cirrose Hepática/metabolismo , Osteopontina/metabolismo , Esquistossomose mansoni/metabolismo , Adolescente , Adulto , Animais , Antígenos de Helmintos/farmacologia , Ductos Biliares/citologia , Ductos Biliares/efeitos dos fármacos , Ductos Biliares/metabolismo , Linhagem Celular , Células Cultivadas , Feminino , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Interações Hospedeiro-Parasita , Humanos , Hipertensão Portal/genética , Hipertensão Portal/parasitologia , Imuno-Histoquímica , Células de Kupffer/efeitos dos fármacos , Células de Kupffer/metabolismo , Cirrose Hepática/genética , Cirrose Hepática/parasitologia , Masculino , Camundongos , Pessoa de Meia-Idade , Osteopontina/sangue , Osteopontina/genética , Ratos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Schistosoma/fisiologia , Esquistossomose mansoni/genética , Esquistossomose mansoni/parasitologia , Adulto JovemRESUMO
This study aimed to determine if the OMNI scale with cycle ergometer pictorial format can be used to estimate perceived exertion threshold (PETOMNI) and nonexhaustive PET (PETOMNI5-8) and to compare and to correlate these PET estimates with PETBorg, PETBorg14-17, and critical power (CP). During different days, 13 men performed 4 different high-intensity constant-loads work bouts until exhaustion on a cycle ergometer using the Borg scale, whereas the OMNI scale was used during the other 4 work bouts using previous constant loads. The PET for both scales was determined by plotting the increasing rates of perceived exertion against power outputs, PET being the intersection point of the regression line. In addition, a hyperbolic relationship between power and time to exhaustion was used to determine CP. The PETOMNI (183+/-36 W) was similar to PETBorg (178+/-46 W), and they were also significantly correlated (r=0.77). The PETOMNI5-8 (175+/-36 W) was similar to PETBorg14-17 (181+/-38 W); however, they were not significantly correlated (r=0.36). All the PET estimates were similar to CPOMNI (167+/-36 W) and CPBorg (169+/-40 W) and also significantly correlated (r=0.79-0.94), excepting PETOMNI5-8 (r=0.46). In conclusion, OMNI cycling scale can be used to estimate PET and CP with high accuracy. However, the nonexhaustive PET derived from the 5-8 range in the OMNI scale did not provide a valid estimate of maximal sustainable power output because of the absence of correlation with PETBorg14-17 and with CP. Therefore, professionals and practitioners can assess the subjects' aerobic fitness through the PET estimation using the OMNI scale during exhaustive tests.