RESUMO
Reg2/RegIIIbeta is the murine homologue of the human secreted HIP/PAP C-type lectin. HIP/PAP transgenic mice were protected against acetaminophen-induced acute liver failure and were stimulated to regenerate post-hepatectomy. To assess the role of Reg2, we used Reg2-/- mice in a model of fulminant hepatitis induced by Fas and in the post-hepatectomy regeneration. Within 4 hours of J0-2 treatment (0.5 microg/g), only 50% of the Reg2-/- mice were alive but with an increased sensitivity to Fas-induced oxidative stress and a decreased level of Bcl-xL. In contrast, HIP/PAP transgenic mice were resistant to Fas, with HIP/PAP serving as a sulfhydryl buffer to slow down decreases in glutathione and Bcl-xL. In Reg2-/- mice, liver regeneration was markedly impaired, with 29% mortality and delay of the S-phase and the activation of ERK1/2 and AKT. Activation of STAT3 began on time at 3 hours but persisted strongly up to 72 hours despite significant accumulation of SOCS3. Thus, Reg2 deficiency induced exaggerated IL-6/STAT-3 activation and mito-inhibition. Because the Reg2 gene was activated between 6 and 24 hours after hepatectomy in wild-type mice, Reg2 could mediate the TNF-alpha/IL-6 priming signaling by exerting a negative feed-back on STAT3/IL-6 activation to allow the hepatocytes to progress through the cell cycle. In conclusion, Reg2 deficiency enhanced liver sensitivity to Fas-induced oxidative stress and delayed liver regeneration with persistent TNF-alpha/IL6/STAT3 signaling. In contrast, overexpression of human HIP/PAP promoted liver resistance to Fas and accelerated liver regeneration with early activation/deactivation of STAT3. Reg2/HIP/PAP is therefore a critical mitogenic and antiapoptotic factor for the liver.
Assuntos
Regeneração Hepática/fisiologia , Proteínas/fisiologia , Receptor fas/fisiologia , Animais , Anticorpos Monoclonais , Antígenos de Neoplasias/fisiologia , Biomarcadores Tumorais/fisiologia , Doença Hepática Induzida por Substâncias e Drogas , DNA/biossíntese , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Hepatectomia , Humanos , Hidrazinas , Interleucina-6/fisiologia , Lectinas Tipo C/fisiologia , Camundongos , Camundongos Transgênicos , Proteína Oncogênica v-akt/fisiologia , Proteínas Associadas a Pancreatite , Pirazinas , Quinolinas , Transdução de Sinais/fisiologia , Fator de Necrose Tumoral alfa/fisiologiaRESUMO
BACKGROUND: There is increasing evidence for the presence of oxidative stress and vitamin C deficiency in dialysis patients. Limited data, however, are available regarding the effects of vitamin C supplementation on oxidative stress and inflammation markers in such patients. METHODS: We ran a prospective, randomized, open-label trial to assess the effects of oral vitamin C supplementation (250 mg three times per week) for 2 months on well-defined oxidative and inflammatory markers in 33 chronic haemodialysis (HD) patients. RESULTS: Normalization of plasma total vitamin C and ascorbate levels by oral vitamin C supplementation did not modify plasma levels of carbonyls, C-reactive protein and albumin, or erythrocyte concentrations of reduced and oxidized glutathione. CONCLUSION: Short-term oral vitamin C supplementation did not modify well-defined oxidative/antioxidative stress and inflammation markers in HD patients. Whether a higher oral dose or the intravenous route can modify these markers remains to be determined.