JAPANESE JOURNAL OF ORAL & MAXILLOFACIAL SURGERY

Vol. 55 No. 1       2009

ISSN: 0021-5163      UBIC: 151-J

ABSTRACT

Oxidative damage to the gland was measured by 8-OHdG and HEL using the Sjögren's syndrome (SS) saliva. In addition, LDH and mitochondrial (m) -GOT, both general markers for cell damage, were also analyzed. Increased levels of 8-OHdG and HEL were found in the saliva from SS patients, but not in those from patients with other salivary gland dysfunction or those of healthy individuals. Levels of LDH and m-GOT were significantly correlated with 8-OHdG and HEL levels respectively. Furthermore, the increased levels of 8-OHdG and HEL were also correlated in the SS saliva. These findings suggested the involvement of oxidative stress in glandular tissue destruction in SS. It was indicated that the detection of 8-OHdG and HEL in the saliva may become a useful tool for the diagnosis of SS. Epstein-Barr virus (EBV) reactivation is thought as a causative factor for SS. However, the physiological stimuli responsible for the EBV activation in the patients have not been characterized. 2, 3, 7, 8-tetracholorodibenzo (p) dioxin, (TCDD) and certain polycyclic aromatic hydrocarbons are widespread environmental pollutants that are designated human carinogenes, immunomodulator and virus activator. We used the firefly luciferase plasmids connected with promoters of BZLF1, indispensable and sufficient for viral reactivation, and CYP1A1, target gene for aryl hydrocarbon receptor (AhR). We have found that xenobiotics bound AhR upregulated the BZLF1 promoter activity in salivary epithelial cells, HSY. This result suggested that dioxins might activate EBV reactivation in epithelial cells. Next, to confirm the effect of dioxins for the pathogenesis of SS, we analyzed promoter activity of CYP1A1 in saliva from SS (n = 10) and control individuals (n = l0). The average CYP1A1 activity induced by SS saliva (3.56-fold) was higher than by control saliva (1.61-fold). Moreover, a significant correlation was observed between the level of CYP1A1 and BZLF1 promoter activities, and the amount of EBV DNA in each saliva sample of SS patients was parallel to the BZLF1 promoter activity. These results suggest that xenobiotics activated AhR in SS saliva might enhance the EBV reactivation in salivary epithelial cells. Stem cell based-therapy is a promising treatment for patients suffering from severe dry mouth. We identified side population cells (SP cells), which are highly enriched for stem cell activity, in salivary glands to apply them for the cell therapy of hypofunction in the damaged glands. Submandibular gland cells from the fractions of side population cells (SP cells) and main population cells (MP cells) were sorted on a flow cytometry into tubes. We also analyzed differential gene expressions between SP and MP cells by cDNA microarray. In addition, to examine whether SP cell transplantation can recover the function of the glands, we isolated SP cells from submandibular glands of transgenic mice expressing green fluorescent protein (GFP) and transplanted them into mice with hypofunction in the glands induced by irradiation. By cDNA microarray, we could identify a SP cell-specific gene in salivary glands. Furthermore, SP cell transplantation enabled recovery from the hypofunction in the irradiated glands, although the transplanted cells were only sparsely distributed in the glands of the recipient mice, suggesting that soluble factors secreted from SP cells are possibly involved in the rescue of secretory function. Our data suggests that SP cell transplantation is available for the recovery of secretory function in damaged glands. Key words: Sjögren's syndrome, oxidative stress, Epstein-Barr virus, dioxin, regenerative medicine.

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