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Objectives: To investigate the effects of radiation on paracellular pathway of rat submandibular glands (SMGs) and the mechanism of increasing secretion following treatment with pilocarpine. Materials and Methods: In situ irradiation models of SMGs in Wistar rats were conducted, and the glands were exposed to X‐radiation at a single dose of 20 Gy. Pilocarpine was intraperitoneally injected 60 min prior to radiation and continuous 6 days postirradiation for a total of 7 days. Salivary secretion, histological changes, pro‐inflammatory cytokines, alterations in tight junctions (TJs), and functional membrane proteins aquaporin‐5 (AQP5) and claudin‐4 mediated by the muscarinic acetylcholine M3 subtype receptor were determined at 1 and 12 weeks after irradiation. Results: Salivary secretion of the irradiated glands was reduced at 1 and 12 weeks. As well, acinar cell numbers, TJ width, and the levels of M3 receptor and AQP5 were decreased. In contrast, tumor necrosis factor‐α, interleukin 6, interleukin 1α, and the expression of the TJ protein claudin‐4 were significantly increased in irradiated SMGs. Notably, all the alterations were attenuated by pilocarpine treatment. Conclusions: Pilocarpine could improve the secretory function of irradiated rat SMGs via reducing inflammation, ameliorating the structural injury of TJs, and attenuating the up‐regulation of claudin‐4 expression. [ABSTRACT FROM AUTHOR]

To investigate the effects of radiation on rat submandibular glands and the possible protective effects of ischemic preconditioning, the submandibular glands of Wistar rats were subjected to in situ radiation after ischemic preconditioning. The glands were exposed to X‐radiation at a single dose of 20 Gy. Ischemic preconditioning was achieved by three min of ischemia and three min of reperfusion, repeated three times before irradiation. Salivary secretion, histological changes, alterations in tight junctions, and the levels of oxidative stress, pro‐inflammatory cytokines, and water secretion proteins mediated by the muscarinic acetylcholine M3 subtype receptor were determined at 1 and 12 weeks post‐irradiation. In glands subjected to irradiation only, the secretion, superoxide dismutase activity, tight junction width, acinar cell number, and M3 receptor and aquaporin‐5 levels were lower at 1 and 12 weeks than seen in the ischemically preconditioned irradiated glands. In contrast, tumor necrosis factor‐α, malondialdehyde, myeloperoxidase activity, and the expression of the tight junction protein claudin‐4 were significantly higher in the irradiated only glands. Our study revealed that radiation caused a series of injury‐stress responses, especially damage to the water secretion pathway mediated by the M3 receptor that ultimately led to hyposecretion, which might play an important role in the dysfunction of the irradiated only glands. Ischemic preconditioning reduced the radiation‐induced injury to submandibular glands and ameliorated salivary hyposecretion. [ABSTRACT FROM AUTHOR]