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基于钙调磷酸酶抑制剂的多药物免疫抑制方案及其转换为雷帕霉素对大鼠唾液腺形态、细胞凋亡和增殖的长期影响。

The long-term effects of multidrug immunosuppressive protocols based on calcineurin inhibitors and conversion to rapamycin on the morphology, apoptosis, and proliferation of rat salivary glands.

机构信息

Department of Histology and Developmental Biology, Faculty of Health Sciences, Pomeranian Medical University, Żołnierska 48, 71-210, Szczecin, Poland.

Department of Gastroenterological Surgery and Transplantation, Central Hospital of Ministry of Internal Affairs and Administration, Wołoska 137, 02-507, Warsaw, Poland.

出版信息

Pharmacol Rep. 2023 Oct;75(5):1240-1253. doi: 10.1007/s43440-023-00521-0. Epub 2023 Sep 2.

DOI:10.1007/s43440-023-00521-0
PMID:37658979
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10539461/
Abstract

BACKGROUND

The effect of multidrug immunosuppressive protocols on the salivary glands is still unknown. This study aimed to determine the influence of immunosuppressive regimens based on calcineurin inhibitors (CNIs) and conversion to rapamycin on the morphology, apoptosis, and proliferation of rat salivary glands.

METHODS

Male rats received cyclosporin A (CsA), tacrolimus (FK-506), mycophenolate mofetil (MMF), rapamycin (Rapa), and prednisone (Pre) according to three-drug protocols: CMP (CsA, MMF, and Pre), CMP/R (CsA, MMF, and Pre with conversion to Rapa), TMP (FK-506, MMF, and Pre), and TMP/R (FK-506, MMF, and Pre with conversion to Rapa). Morphological and immunohistochemical and quantitative analyses of the salivary glands were performed.

RESULTS

Structural changes in salivary glands were observed in all experimental groups, especially in the submandibular gland. In the salivary glands, the percentages of collagen fibers and TUNEL-, Ki67- and PCNA-positive cells were higher in the experimental groups vs. the control but were lower in the CMP/R and TMP/R groups vs. the CMP and TMP groups, with the exception of collagen fibers in the parotid gland in the TMP/R group vs. the TMP group.

CONCLUSIONS

Long-term administration of CNIs in triple regimens and after conversion to rapamycin monotherapy, causes morphological changes in the salivary glands of rats. Immunosuppressive treatment based on CNIs is associated with an increase in collagen accumulation. The effects of the conversion of treatment with CNIs to rapamycin in immunosuppressive protocols in rat salivary glands lead to decreased fibrosis, apoptosis, and proliferation. These changes may possibly prevent abnormalities resulting from the application of CNIs.

摘要

背景

多药物免疫抑制方案对唾液腺的影响尚不清楚。本研究旨在确定基于钙调神经磷酸酶抑制剂（CNI）的免疫抑制方案和转换为雷帕霉素对大鼠唾液腺形态、细胞凋亡和增殖的影响。

方法

雄性大鼠接受环孢素 A（CsA）、他克莫司（FK-506）、霉酚酸酯（MMF）、雷帕霉素（Rapa）和泼尼松（Pre），根据三药方案：CMP（CsA、MMF 和 Pre）、CMP/R（CsA、MMF 和 Pre 转换为 Rapa）、TMP（FK-506、MMF 和 Pre）和 TMP/R（FK-506、MMF 和 Pre 转换为 Rapa）。对唾液腺进行形态学和免疫组织化学及定量分析。

结果

所有实验组的唾液腺均出现结构变化，尤其是颌下腺。在唾液腺中，实验组胶原纤维、TUNEL、Ki67 和 PCNA 阳性细胞的百分比高于对照组，但 CMP/R 和 TMP/R 组低于 CMP 和 TMP 组，除了 TMP/R 组的颌下腺的胶原纤维外。

结论

长期给予三联方案中的 CNI 及转换为雷帕霉素单药治疗，导致大鼠唾液腺发生形态学变化。基于 CNI 的免疫抑制治疗与胶原积累增加有关。CNI 治疗转换为雷帕霉素在大鼠唾液腺免疫抑制方案中的作用导致纤维化、细胞凋亡和增殖减少。这些变化可能有助于预防 CNI 应用引起的异常。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e7d/10539461/63bfac037b60/43440_2023_521_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e7d/10539461/ec1a9311cb6b/43440_2023_521_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e7d/10539461/2667fbbe9034/43440_2023_521_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e7d/10539461/2e6ba9c6873c/43440_2023_521_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e7d/10539461/2064d834ffc5/43440_2023_521_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e7d/10539461/63bfac037b60/43440_2023_521_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e7d/10539461/ec1a9311cb6b/43440_2023_521_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e7d/10539461/2667fbbe9034/43440_2023_521_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e7d/10539461/2e6ba9c6873c/43440_2023_521_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e7d/10539461/2064d834ffc5/43440_2023_521_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e7d/10539461/63bfac037b60/43440_2023_521_Fig5_HTML.jpg

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