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Muscarinic acetylcholine receptor-mediated tight junction opening is involved in epiphora in late phase of submandibular gland transplantation

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Abstract

Submandibular gland (SMG) autotransplantation is an effective therapy for treating severe dry eye syndrome. However, epiphora occurs in more than 40% of patients 6 months after operation. We previously found that muscarinic acetylcholine receptor (mAChR) plays a crucial role in regulating SMG secretion partially through the modulation on tight junction (TJ)-based paracellular pathway. Therefore, the present study aimed to investigate the possible involvement of mAChR and TJ in a rabbit long-term model of SMG transplantation. We found that SMG secretion was significantly increased on postoperative days 90 and 180, which imitated epiphora observed in the patients with SMG transplantation. Although the mRNA expression and fluorescence intensity of M1 and M3 mAChR subtypes were reversed to control levels on postoperative days 30, 90, and 180, the content of β-arrestin2, but not β-arrestin1, was gradually decreased after transplantation, which suggests that mAChR may be hypersensitive in late phase of SMG transplantation. The width of acinar TJs was enlarged and fluorescence intensity of F-actin in peri-apicolateral membranes were remarkably increased on postoperative days 90 and 180. Topical treatment with atropine gel significantly reduced SMG secretion, TJ width, as well as F-actin intensity in peri-apicolateral membranes on postoperative days 180. Moreover, in a perfused rabbit SMG, carbachol increased salivary secretion, enlarged TJ width, and induced F-actin rearrangement, whereas these responses were inhibited by atropine pretreatment. Taken together, our findings suggest that the hypersensitive mAChR may contribute to epiphora in late phase of SMG transplantation through modulating TJ-based paracellular permeability.

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Acknowledgements

This study was supported by the National Natural Science Foundation of China 81470756 (NYY), 81300893 (XC), and 81400526 (GYY), and Beijing Natural Science Foundation 7154204 (NYY).

Author contributions

NYY performed the major experiments and wrote the manuscript. CD, JL, YZ and RLX were responsible for the isolation and perfusion of rabbit submandibular gland. LLW and GYY participated in data interpretation and manuscript improvement. XC designed the study, analyzed the data, and wrote the manuscript. All authors read and approved the final manuscript.

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Correspondence to Xin Cong.

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The authors declare that they have no competing interests.

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Yang, NY., Ding, C., Li, J. et al. Muscarinic acetylcholine receptor-mediated tight junction opening is involved in epiphora in late phase of submandibular gland transplantation. J Mol Hist 48, 99–111 (2017). https://doi.org/10.1007/s10735-016-9709-9

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  • DOI: https://doi.org/10.1007/s10735-016-9709-9

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