Regulation of glutathione redox status in lung and liver by conditioning regimens and keratinocyte growth factor in murine allogeneic bone marrow transplantation.
BACKGROUND
Reactive oxygen species (ROS) and glutathione (GSH) depletion contribute to organ injury after bone marrow transplantation (BMT). Keratinocyte growth factor (KGF) ameliorates graft-versus-host disease (GVHD)-associated organ injury in murine BMT models.


METHODS
B10.BR mice received total body irradiation (TBI; day -1) +/- cyclophosphamide (Cy; 120 mg/kg/day i.p., days -3 and -2), then were transplanted on day 0 with C57BL/6 bone marrow + spleen cells as a source of GVHD-causing T cells. KGF (5 mg/kg/day subcutaneously [s.c.]) or saline was given on days -6, -5, and -4. Lung and liver GSH and oxidized GSH disulfide (GSSG) levels were measured on days 0 and 5 and glutathione redox potential (Eh) calculated. Organ malondialdehyde (MDA) was determined on day 5 as an index of ROS-mediated lipid peroxidation.


RESULTS
In lung, TBI+BMT oxidized GSH Eh and increased MDA. Cy further oxidized lung GSH Eh. In liver, neither BMT regimen altered GSH redox status or MDA. KGF prevented the decrease in lung GSH after TBI+Cy and decreased lung MDA after both TBI and TBI+Cy. KGF increased liver GSH levels and GSH Eh after TBI and GSH Eh after TBI+Cy.


CONCLUSIONS
In murine allogeneic BMT, TBI oxidizes the lung GSH redox pool and Cy exacerbates this response by 5 days post-BMT. In contrast, liver GSH redox status is maintained under these experimental conditions. KGF treatment attenuates the Cy-induced decrease in lung GSH, decreases post-BMT lung lipid peroxidation, and improves liver GSH redox indices. KGF may have a therapeutic role to prevent or attenuate GSH depletion and ROS-mediated organ injury in BMT.
Ziegler
T R
TR
Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA. tzieg01@emory.edu
Panoskaltsus-Mortari
A
A
Gu
L H
LH
Jonas
C R
CR
Farrell
C L
CL
Lacey
D L
DL
Jones
D P
DP
Blazar
B R
BR
D000818:Animals; D016026:Bone Marrow Transplantation; D003520:Cyclophosphamide / Q000494:pharmacology; D005260:Female; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008168:Lung / Q000378:metabolism*; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009928:Organ Specificity; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D014916:Whole-Body Irradiation
C496454:Fgf7 protein, mouse; D017382:Reactive Oxygen Species; D051523:Fibroblast Growth Factor 7; D008315:Malondialdehyde; D005346:Fibroblast Growth Factors; D003520:Cyclophosphamide; D005978:Glutathione