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 c ontribute to organ injury after bone marrow transplantation (BMT). Keratino cyte growth factor (KGF) ameliorates graft-versus-host disease (GVHD)-assoc iated organ injury in murine BMT models. Methods. B10.BR mice received total body irradiation (TBI; day -1) +/- cycl ophosphamide (Cy; 120 mg/kg/day i.p., days -3 and -2), then were transplant ed on day 0 with C57BL/6 bone marrow + spleen cells as a source of GVHD-cau sing T cells. KGF (5 mg/kg/day subcutaneously [s.c.]) or saline was given o n 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 (E-h) calculated. Organ malondialdehyde (MDA) was determined on day 5 as an inde x of ROS-mediated lipid peroxidation. Results. In lung, TBI+BMT oxidized GSH E-h and increased MDA. Cy further ox idized lung GSH E-h In liver, neither BMT regimen altered GSH redox status or MDA. KGF prevented the decrease in lung GSH after TBI+Cy and decreased l ung MDA after both TBI and TBI + Cy. KGF increased liver GSH levels and GSH E-h after TBI and GSH E-h 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 GS H redox status is maintained under these experimental conditions. KGF treat ment attenuates the Cy-induced decrease in lung GSH, decreases post-BMT lun g lipid peroxidation, and improves liver GSH redox indices. KGF may have a therapeutic role to prevent or attenuate GSH depletion and ROS-mediated org an injury in BMT.