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.
Blackwell
T S
TS
Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2650, USA.
Christman
J W
JW
Hagan
T
T
Price
P
P
Edens
T
T
Morris
P E
PE
Wolff
S N
SN
Goodman
S A
SA
Christman
B W
BW
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