Aellos Fabiana, Ramos Amarissa, Civit-Balta Alba, Grauer Joseph A, Cuevas Pedro L, Rao Samyak, Yuan Xue, Liu Bo, Helms Jill A
Department of Surgery, Stanford University School of Medicine, Stanford, California, USA.
Facultat de Biologia, Universitat de Barcelona (UB), Barcelona, Spain.
J Periodontal Res. 2025 Jan 12. doi: 10.1111/jre.13375.
To investigate additional factors contributing to the pathophysiology of chemotherapy-induced oral mucositis and periodontitis beyond the systemic immune suppression caused by the chemotherapeutic agent 5-Fluorouracil (5-FU).
5-Fluorouracil was topically delivered to the non-keratinized, rapidly proliferating junctional epithelium (JE) surrounding the dentition, and acts as an immunologic and functional barrier to bacterial ingression. Various techniques, including EdU incorporation, quantitative immunohistochemistry (qIHC), histology, enzymatic activity assays, and micro-computed tomographic (μCT) imaging, were employed to analyze the JE at multiple time points following topical 5-FU treatment. Systemic 5-FU delivery was used for comparison, and all 5-FU treated tissues were compared to vehicle-treated controls.
We first showed that systemic 5-FU blocked mitotic activity that rapidly led to JE atrophy. This atrophy was accompanied by suppression of the immune system. We then demonstrated that topical 5-FU delivery effectively inhibited cell proliferation in the JE. Quantitative immunohistochemical (qIHC) analyses further demonstrated a progressive breakdown in JE barrier functions following topical 5-FU. CBC analyses confirmed that topical 5-FU did not alter the innate immune system but did suppress the local immune response of the JE. The longer-term consequences of this disruption in JE barrier functions were significant alveolar bone loss and an increase in porosity. Together, these results document the essential requirement for rapid JE cell proliferation to maintain homeostasis of the periodontium.
The reduction of cell division in the JE due to 5-FU treatment directly compromises both its structural integrity and immune surveillance capabilities, contributing to the destruction of periodontal hard tissues.
研究除化疗药物5-氟尿嘧啶（5-FU）引起的全身免疫抑制之外，导致化疗诱导的口腔黏膜炎和牙周炎病理生理学的其他因素。
将5-氟尿嘧啶局部递送至牙列周围非角化、快速增殖的结合上皮（JE），其作为细菌侵入的免疫和功能屏障。采用多种技术，包括EdU掺入、定量免疫组织化学（qIHC）、组织学、酶活性测定和微型计算机断层扫描（μCT）成像，在局部5-FU治疗后的多个时间点分析JE。使用全身给予5-FU作为对照，并将所有5-FU处理的组织与载体处理的对照进行比较。
我们首先表明，全身给予5-FU会阻断有丝分裂活性，迅速导致JE萎缩。这种萎缩伴随着免疫系统的抑制。然后我们证明，局部给予5-FU可有效抑制JE中的细胞增殖。定量免疫组织化学（qIHC）分析进一步证明，局部给予5-FU后JE屏障功能逐渐破坏。全血细胞计数分析证实，局部给予5-FU不会改变先天免疫系统，但会抑制JE的局部免疫反应。JE屏障功能破坏的长期后果是明显的牙槽骨丢失和孔隙率增加。总之，这些结果证明了JE细胞快速增殖对维持牙周组织稳态的基本要求。
5-FU治疗导致JE中细胞分裂减少，直接损害其结构完整性和免疫监视能力，导致牙周硬组织破坏。
