In order to identify biomarkers for early diagnosis and/or for therapeutic targets in the delayed health effects of ionizing radiation, we analyzed the subgroups of lymphocytes, serum protein levels and gene expression profiles in the peripheral blood of three 60Co γ-ray accidentally exposed persons during the three years after irradiation. Flow cytometry analyses and agarose gel electrophoresis were applied to investigate the subgroups of lymphocytes and the composition of serum proteins, respectively. Gene expression profiling was obtained using a whole genome gene expression chip assay. Both the percentage of CD4+ T lymphocytes and the ratio of Th to Ts were reduced compared with the normal control values. The percentage of albumin decreased whereas beta globulin increased. There were 285 up-regulated and 446 down-regulated genes in irradiated samples relative to the control samples. The expression of KDR, CEACAM8 and OSM was validated by RT-PCR. The majority of the differentially expressed genes encode proteins associated with the immune response, inflammation, oncogenesis, cell structure, oxidative stress, neuro-hormone regulation, reproduction, susceptibility to psychiatric disorders, or transcriptional regulation. We have identified a number of promising novel candidates that have potential for serving as biomarkers for delayed damage. Furthermore, the changes in the immunological indicator CD4+ T cells, and the ratio of CD4+ T to CD8+ T cells may be biomarkers for the prediction of delayed damage by ionizing radiation. The findings of our study are useful for forming a comprehensive understanding of the mechanisms underlying the delayed effects of ionizing radiation.
The skin, as the outermost barrier of the body, must provide the first line of defense against environmental free radical attack caused by, for example, exposure to UV radiation, ionizing radiation, chemical oxidants, and aerobic microorganisms. Therefore, the skin has developed a complex antioxidant network that includes enzymatic and non-enzymatic components. 1)Prolonged exposure of the skin to UV radiation results in inflammation including erythema and edema formation. 2)Premature aging, immune suppression and skin cancer are its possible late effects.3) Erythema formation is the result of local increases of blood flow, in the regulation of which nitric oxide (NO) has been known to play an important role. 4) In fact, UV radiation-mediated expression of inducible nitric oxide synthase (iNOS) was reported in the vessel endothelia of normal human skin and in cultured human dermal endothelial cells. 5) iNOS has been implicated in the pathogeneses of various inflammatory syndromes, including asthma, 6) transplant rejection, 7) inflammatory bowel disease, 8) rheumatoid arthritis, 9) septic shock 10) and parasitic infections.11) The expression of iNOS is also strongly implicated in psoriasis 12) and other inflammatory skin conditions including UV irradiation as stated above.5) Reactive oxygen species (ROS) have been connected with the pathogenesis of both inflammation syndromes 13) and UV-caused skin damage. 14) Similarly, the predominant event for ionizing irradiation of cell and tissue is the generation of ROS, for example, hydroxyl radicals and superoxide anion.15) In addition, the involvement of iNOSderived NO in acute radiation syndrome is suggested by an increase of iNOS gene expression or iNOS enzyme activity in the liver, 16) intestine, 17) colon and ileum 18) and brain. 19,20) NO has been detected in liver 21) and mammary tumorigenesis 22) after X-ray irradiation. However, there is no report on the direct measurement of the generation of NO and the expression of related enzymes, nitric oxide synthase, in ionizing radiation induced skin inflammatory reactions. In the present study we tried to measure NO production and NOS expression in mouse skin after high-dose X-ray irradiation. MATERIALS AND METHODSReagents Leupeptin, aprotinin, pepstatin, sodium orthovanadate and sodium fluoride were products of Sigma. AntiiNOS polyclonal antibody was a product of Santa Cruz Biotechnology Inc., Santa Cruz, U.S.A. (Catalog number: sc-650). The 5-20% resolving mini gels were purchased from BioRad Laboratories. Peroxidase linked anti-mouse and antirabbit secondary antibodies were products of Amersham Biosciences Co., Piscataway, U.S.A. (Catalog number: NA-934 and NA-931, respectively). Water was double distilled and treated with an ultra-pure water apparatus (Simpli Lab, Nihon Millipore K.K., Tokyo, Japan). Hematoxylin was from Vector Laboratories, Inc., Burlingame, CA, U.S.A. (Cat. No. H-4301) and 0.5% eosin Y ethanol solution was from Wako Inc., Japan. Aminoguanidine was purchased from Sigma. DNA ladder marker was the pro...
We previously showed that free radicals and oxidative stress are involved in radiation-induced skin reactions. Since vitamin E (VE) is a particularly important lipophilic antioxidant, VE-deficient mice were used to examine its effects on radiation-induced skin damage. The VE content of the skin was reduced to one fourth of levels of normal mice. Neither the time of onset nor the extent of the reactions quantified with a scoring system differed between normal and VE-deficient mice after local X-irradiation (50 Gy). Similarly, there was no difference in the levels of the ascorbyl radical between the groups, although they were higher in irradiated skin than non-irradiated skin. X-irradiation increased the amount of Bax protein in the skin of normal mice both in the latent and acute inflammatory stages, time- and dose-dependently. The increase was associated with an increase in cytochrome c in the cytosolic fraction, indicating that apoptosis was also promoted by the irradiation. The increase in Bax protein correlated well with the thickness of the skin. Although a deficiency in VE should lower resistance to free radicals in the mitochondrial membrane and thus enhance radiation-induced Bax expression and apoptosis, it actually attenuated the increase in Bax protein caused by irradiation.
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