The purpose of this study was to evaluate the possible involvement of nitric oxide and its toxic metabolite -peroxynitrite -in the pathogenesis of recurrent tonsillitis. Tonsil specimens with recurrent inflammation were obtained from patients who required tonsillectomies as surgical treatment for their conditions. The relatively normal tonsils were obtained from patients who underwent uvulo-palato-pharyngoplasty for habitual snoring or obstructive sleep apnea. The sites of inducible nitric oxide synthase (iNOS) expression in the tonsil specimens were examined with an immunohistochemical technique. The possible production of peroxynitrite was evaluated by immunolabeling of 3-nitrotyrosine (3-NT) as its biological footprint. Each section was given a score of 0 to 4 according to the labeling intensity seen, with the highest number representing the highest labeling intensity. We found that tonsils with recurrent inflammation had iNOS expression mainly in the mucosal epithelium, subepithelial regions and vascular endothelium. The parenchyma of the tonsils, where T-and B-cell clones are located, showed little iNOS immunoreactivity. The accumulation of 3-NT had a similar distribution pattern to that of iNOS expression. However, the normal tonsils showed limited iNOS expression on mucosal epithelium and rare 3-NT accumulation. Recurrently inflamed tonsils had significantly higher labeling scores for both iNOS and 3-NT compared to normal tonsils. Further, a higher iNOS score correlated with a higher 3-NT accumulation. These data suggest that iNOS expression and the formation of peroxynitrite may have an important role in the pathogenesis of recurrent tonsillitis.
Lee Y-L, Lin S-K, Hou K-L, Kok S-H, Lai EH-H, Wang H-W, Chang JZ-C, Yang H, Hong C-Y. Sirtuin 6 attenuates periapical lesion propagation by modulating hypoxia-induced chemokine (C-C motif) ligand 2 production in osteoblasts. International Endodontic Journal, 51, e74-e86,
2018.Aim To investigate the attenuating effect of sirtuin 6 (SIRT6) on hypoxia-induced production of chemokine (C-C motif) ligand 2 (CCL2) by osteoblasts and the relevance of this action on the pathogenesis of periapical lesions. Methodology Sirtuin 6 was overexpressed in MC3T3-E1 murine osteoblasts by lentivirus-mediated gene transfer. The relationship between the antiglycolytic/antioxidative activities of SIRT6 and its effect on hypoxia-induced CCL2 production were examined. Pathogenetic relevance of the actions of SIRT6 was assessed in a rat model of induced apical periodontitis. The data were analysed statistically using Student's t-test or one-way analysis of variance (ANOVA) and then a Tukey's multiple comparison test. Results In cultured murine osteoblasts, 24-h hypoxic treatment significantly enhanced the generation of reactive oxygen species (P = 0.003), expression of lactate dehydrogenase A (LDHA) and production of lactate (P = 0.007). A reciprocal effect between hypoxia-induced redox imbalance and hypoxiaenhanced glycolysis was noted which in turn augmented the secretion of CCL2. Through its antiglycolytic and antioxidative effects, SIRT6 blocked the vicious cycle to suppress CCL2 production. In normal periapical tissues of rats, strong expression of SIRT6 and low levels of LDHA and 8-OHdG (a marker of oxidative DNA damage) were found in osteoblasts. In induced apical periodontitis, osteoblastic expression of SIRT6 was significantly suppressed (P = 0.001) which was associated with significantly elevated levels of LDHA (P = 0.003) and 8-OHdG (P = 0.004) and significantly enhanced recruitment of macrophages (P = 0.004). Conclusions Sirtuin 6 has a therapeutic effect on periapical lesions through suppression of CCL2 synthesis. The anti-inflammatory action of SIRT6 is closely related to its regulatory activities in cellular metabolism and redox homoeostasis.
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