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Thiol/redox metabolomic profiling implicates GSH dysregulation in early experimental graft versus host disease (GVHD).

Suh JH, Kanathezhath B, Shenvi S, Guo H, Zhou A, Tiwana A, Kuypers F, Ames BN, Walters MC - PLoS ONE (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Children's Hospital Oakland Research Institute, Oakland, California, United States of America.

ABSTRACT
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.

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Significant correlations between hepatic GVHD scores and changes in plasma metabolite concentrations at Day +10.GVHD was induced without conditioning in paternal in the F1 hybrid (C57BL/6 → B6DBA2F1) model. Pearson correlation coefficient analysis was used to calculate the correlation between plasma metabolite concentrations and hepatic GVHD histopathological severity scoring obtained at Day+10. *Denotes metabolites that showed significant correlations to hepatic GVHD severity scores. Abbreviations: Leu – Leucine, Ile - Isoleucine, T. cysgly-Total cysteinylglycine, GSH-Free GSH, T.GSH- Total GSH, Gly-Glycine, Arg-Arginine, Met-Methionine, Ser-Serine, Cit-Citrulline, T.Cys-Total cysteine, MetSO-Methionine sulfoxide, T. Hcy-Total homocysteine, Cysgly-Cysteinylglycine, Sar-Sarcosine, Thr-Threonine, His-Histidine, Tyr-Tyrosine, Glu-Glutamate, CySS-Cystine, Orn-Ornithine, Lys-Lysine, Cys Redox-Cysteine redox potential (mV), Cys-Cysteine, 3MH-3-Methylhistidine, Asp-Aspartate, Phe-Phenylanine, Trp-Tryptophan, Asn-Asparagine, Ala-Alanine, Pro-Proline, Erg-Ergothioneine, B.Ala-β-Alanine, GSH Redox –GSH/GSSG redox potential (mV), AdoHcy - S-adenosylhomocysteine, GSSG - GSH disulfide.
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pone-0088868-g004: Significant correlations between hepatic GVHD scores and changes in plasma metabolite concentrations at Day +10.GVHD was induced without conditioning in paternal in the F1 hybrid (C57BL/6 → B6DBA2F1) model. Pearson correlation coefficient analysis was used to calculate the correlation between plasma metabolite concentrations and hepatic GVHD histopathological severity scoring obtained at Day+10. *Denotes metabolites that showed significant correlations to hepatic GVHD severity scores. Abbreviations: Leu – Leucine, Ile - Isoleucine, T. cysgly-Total cysteinylglycine, GSH-Free GSH, T.GSH- Total GSH, Gly-Glycine, Arg-Arginine, Met-Methionine, Ser-Serine, Cit-Citrulline, T.Cys-Total cysteine, MetSO-Methionine sulfoxide, T. Hcy-Total homocysteine, Cysgly-Cysteinylglycine, Sar-Sarcosine, Thr-Threonine, His-Histidine, Tyr-Tyrosine, Glu-Glutamate, CySS-Cystine, Orn-Ornithine, Lys-Lysine, Cys Redox-Cysteine redox potential (mV), Cys-Cysteine, 3MH-3-Methylhistidine, Asp-Aspartate, Phe-Phenylanine, Trp-Tryptophan, Asn-Asparagine, Ala-Alanine, Pro-Proline, Erg-Ergothioneine, B.Ala-β-Alanine, GSH Redox –GSH/GSSG redox potential (mV), AdoHcy - S-adenosylhomocysteine, GSSG - GSH disulfide.

Mentions: The correlation between plasma GSH and hepatic GVHD severity was determined using the paternal to F1 hybrid model (Table 1, model 2). This model was chosen because inter-animal variations in GSH and hepatic GVHD were greater than in model 1, and thus this model provided an opportunity to examine potential correlations between plasma metabolites and the severity of GVHD in the liver. As shown (Figure 4), histopathological scores and plasma GSSG were strongly and positively correlated (r2 = 0.65; p = 0.002). Significant positive correlations were also were observed in the GSH/GSSG redox potential (more positive = more oxidized). Significant inverse correlations were also observed between liver histopathological damage and plasma total cysteinylglycine (T. Cysgly; GSH catabolite), GSH, and total GSH (T. GSH), suggesting that concurrent plasma GSH/GSSG oxidation state reflects the extent of GVHD injury in the liver.


Thiol/redox metabolomic profiling implicates GSH dysregulation in early experimental graft versus host disease (GVHD).

Suh JH, Kanathezhath B, Shenvi S, Guo H, Zhou A, Tiwana A, Kuypers F, Ames BN, Walters MC - PLoS ONE (2014)

Significant correlations between hepatic GVHD scores and changes in plasma metabolite concentrations at Day +10.GVHD was induced without conditioning in paternal in the F1 hybrid (C57BL/6 → B6DBA2F1) model. Pearson correlation coefficient analysis was used to calculate the correlation between plasma metabolite concentrations and hepatic GVHD histopathological severity scoring obtained at Day+10. *Denotes metabolites that showed significant correlations to hepatic GVHD severity scores. Abbreviations: Leu – Leucine, Ile - Isoleucine, T. cysgly-Total cysteinylglycine, GSH-Free GSH, T.GSH- Total GSH, Gly-Glycine, Arg-Arginine, Met-Methionine, Ser-Serine, Cit-Citrulline, T.Cys-Total cysteine, MetSO-Methionine sulfoxide, T. Hcy-Total homocysteine, Cysgly-Cysteinylglycine, Sar-Sarcosine, Thr-Threonine, His-Histidine, Tyr-Tyrosine, Glu-Glutamate, CySS-Cystine, Orn-Ornithine, Lys-Lysine, Cys Redox-Cysteine redox potential (mV), Cys-Cysteine, 3MH-3-Methylhistidine, Asp-Aspartate, Phe-Phenylanine, Trp-Tryptophan, Asn-Asparagine, Ala-Alanine, Pro-Proline, Erg-Ergothioneine, B.Ala-β-Alanine, GSH Redox –GSH/GSSG redox potential (mV), AdoHcy - S-adenosylhomocysteine, GSSG - GSH disulfide.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3928313&req=5

pone-0088868-g004: Significant correlations between hepatic GVHD scores and changes in plasma metabolite concentrations at Day +10.GVHD was induced without conditioning in paternal in the F1 hybrid (C57BL/6 → B6DBA2F1) model. Pearson correlation coefficient analysis was used to calculate the correlation between plasma metabolite concentrations and hepatic GVHD histopathological severity scoring obtained at Day+10. *Denotes metabolites that showed significant correlations to hepatic GVHD severity scores. Abbreviations: Leu – Leucine, Ile - Isoleucine, T. cysgly-Total cysteinylglycine, GSH-Free GSH, T.GSH- Total GSH, Gly-Glycine, Arg-Arginine, Met-Methionine, Ser-Serine, Cit-Citrulline, T.Cys-Total cysteine, MetSO-Methionine sulfoxide, T. Hcy-Total homocysteine, Cysgly-Cysteinylglycine, Sar-Sarcosine, Thr-Threonine, His-Histidine, Tyr-Tyrosine, Glu-Glutamate, CySS-Cystine, Orn-Ornithine, Lys-Lysine, Cys Redox-Cysteine redox potential (mV), Cys-Cysteine, 3MH-3-Methylhistidine, Asp-Aspartate, Phe-Phenylanine, Trp-Tryptophan, Asn-Asparagine, Ala-Alanine, Pro-Proline, Erg-Ergothioneine, B.Ala-β-Alanine, GSH Redox –GSH/GSSG redox potential (mV), AdoHcy - S-adenosylhomocysteine, GSSG - GSH disulfide.
Mentions: The correlation between plasma GSH and hepatic GVHD severity was determined using the paternal to F1 hybrid model (Table 1, model 2). This model was chosen because inter-animal variations in GSH and hepatic GVHD were greater than in model 1, and thus this model provided an opportunity to examine potential correlations between plasma metabolites and the severity of GVHD in the liver. As shown (Figure 4), histopathological scores and plasma GSSG were strongly and positively correlated (r2 = 0.65; p = 0.002). Significant positive correlations were also were observed in the GSH/GSSG redox potential (more positive = more oxidized). Significant inverse correlations were also observed between liver histopathological damage and plasma total cysteinylglycine (T. Cysgly; GSH catabolite), GSH, and total GSH (T. GSH), suggesting that concurrent plasma GSH/GSSG oxidation state reflects the extent of GVHD injury in the liver.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Children's Hospital Oakland Research Institute, Oakland, California, United States of America.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus