Thiol-Redox Metabolomic Profiling Implicates GSH Dysregulation in Early Experimental Graft versus Host Disease GVHDReportar como inadecuado

Thiol-Redox Metabolomic Profiling Implicates GSH Dysregulation in Early Experimental Graft versus Host Disease GVHD - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Graft-versus-host disease GVHD is a common complication of allogeneic bone marrow transplantation BMT. Upregulation of inflammatory cytokines precedes the clinical presentation of GVHD and predicts its severity. In this report, thiol-redox metabolomics was used to identify metabolic perturbations associated with early preclinical Day+4 and clinical Day+10 stages of GVHD by comparing effects in Syngeneic Syn; major histocompatibility complex- identical and allogeneic transplant recipients Allo BMT in experimental models. While most metabolic changes were similar in both groups, plasma glutathione GSH was significantly decreased, and GSH disulfide GSSG was increased after allogeneic compared to syngeneic recipient and non-transplant controls. The early oxidation of the plasma GSH-GSSG redox couple was also observed irrespective of radiation conditioning treatment and was accompanied by significant rise in hepatic protein oxidative damage and ROS generation. Despite a significant rise in oxidative stress, compensatory increase in hepatic GSH synthesis was absent following Allo BMT. Early shifts in hepatic oxidative stress and plasma GSH loss preceded a statistically significant rise in TNF-α. To identify metabolomic biomarkers of hepatic GVHD injury, plasma metabolite concentrations analyzed at Day+10 were correlated with hepatic organ injury. GSSG oxidized GSH and β-alanine, were positively correlated, and plasma GSH cysteinylglycine, and branched chain amino acids were inversely correlated with hepatic injury. Although changes in plasma concentrations of cysteine, cystathionine GSH precursors and cysteinylglycine a GSH catabolite were not significant by univariate analysis, principal component analysis PCA indicated that accumulation of these metabolites after Allo BMT contributed significantly to early GVHD in contrast to Syn BMT. In conclusion, thiol-redox metabolomic profiling implicates that early dysregulation of host hepatic GSH metabolism and oxidative stress in sub-clinical GVHD before elevated TNF-α levels is associated with GVHD pathogenesis. Future studies will probe the mechanisms for these changes and examine the potential of antioxidant intervention strategies to modulate GVHD.

Autor: Jung H. Suh , Bindu Kanathezhath, Swapna Shenvi, Hua Guo, Alicia Zhou, Anureet Tiwana, Frans Kuypers, Bruce N. Ames, Mark C. Walt



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