Oxidative stress and NF-kappaB activation: correlation in patients following allogeneic bone marrow transplantation.
Although in vitro data has linked reactive oxygen species (ROS) to activation of nuclear factor kappaB (NF-kappaB), little data exist regarding this relationship in human disease. We hypothesized that bone marrow transplantation (BMT) would impart a degree of oxidative stress that might lead to in vivo activation of the redox-sensitive transcription factor NF-kappaB. Because NF-kappaB regulates transcription of many proinflammatory mediators, we reasoned that activation of NF-kappaB might contribute to the development of transplant-related complications. To evaluate NF-kappaB activation in humans, we measured NF-kappaB binding activity in nuclear extracts of bronchoalveolar lavage (BAL) cells obtained before and after allogeneic bone marrow transplantation (BMT) in 7 patients. Changes in BAL cell NF-kappaB binding activity were compared with changes in urinary F2-isoprostane concentration, an indicator of in vivo free radical-catalyzed lipid peroxidation. Although the extent of in vivo lipid peroxidation has substantial interindividual variability over time, we found a strong correlation between the pre/post-BMT ratio of urinary isoprostane concentrations and pre/post-BMT ratio of NF-kappaB binding activity in BAL cells, R = 0.96, p = 0.0005). This correlation is selective, because no relationship was found between the transcription factor CREB and urinary F2-isoprostane excretion. Although limited by the small number of patients studied, our data link oxidant stress to NF-kappaB activation in human alveolar macrophages following BMT. It is possible that such interactions may contribute to the clinical course after BMT by affecting transcription of proinflammatory genes.
Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2650, USA.
T S
TS
Blackwell
J W
JW
Christman
T
T
Hagan
P
P
Price
T
T
Edens
P E
PE
Morris
S N
SN
Wolff
S A
SA
Goodman
B W
BW
Christman
D000328:Adult; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology; D016026:Bone Marrow Transplantation / Q000009:adverse effects*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D017362:Cyclic AMP Response Element-Binding Protein / Q000032:analysis; D015237:Dinoprost / Q000031:analogs & derivatives / Q000652:urine; D028441:F2-Isoprostanes; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D019337:Hematologic Neoplasms / Q000378:metabolism / Q000628:therapy; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000235:genetics; D015227:Lipid Peroxidation; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species; D014158:Transcription, Genetic; D019172:Transplantation Conditioning / Q000009:adverse effects; D014184:Transplantation, Homologous
D000970:Antineoplastic Agents; D017362:Cyclic AMP Response Element-Binding Protein; D028441:F2-Isoprostanes; D016328:NF-kappa B; D017382:Reactive Oxygen Species; C075750:8-epi-prostaglandin F2alpha; D015237:Dinoprost