肥大細胞於放射線引發之口腔潰瘍小鼠模式中之影響

Abstract

口腔黏膜炎是一種由化療或放療引起常見的副作用。在頭頸癌患者的治療中，放射線治療被廣泛地使用。由於放射線治療後口腔粘膜炎的高發病率，常造成患者沉重的經濟負擔，並因此開發一種有效的治療方法是迫切需要的。在這項研究中，我們展示了一個動物模型，可以穩定地在針對舌頭照射25Gy 的放射線之後產生口腔黏膜炎。照射後一個星期，體重會有明顯的下降，並且在大約相同的時間可以看到舌頭上產生紅斑。除此之外由組織學證實上皮的厚度變薄，以及上皮細胞的增殖受到阻礙。潰瘍形成於照射後10 天，會發生嗜中性細胞的浸潤。粘膜下層組織中的肥大細胞也增加，證明嗜中性細胞及肥大細胞可能參與在口腔黏膜炎的進程中。藉由肥大細胞缺陷的小鼠，我們觀察在口腔黏膜炎動物模式中，與肥大細胞缺陷的小鼠比較時，野生型小鼠有較大的潰瘍和較薄的上皮。因此有肥大細胞的參與可能會造成較為嚴重的口腔黏膜炎。然而促炎性細胞激素的表現量，在肥大細胞缺陷的小鼠舌頭內的表現量也較高，顯示較為嚴重的炎症反應可能不是造成較口腔黏膜炎嚴重性的原因。此外，在背側的上皮細胞顯示了一個特定的恢復模式，在舌頭尖端的上皮細胞較其他部位早開始增殖。這個區域特定的恢復情形可能來自於不同微環境之間的差異，但其中的機制仍不清楚。總結，此篇研究提供放射線導致口腔黏膜炎啟始和復原期之黏膜外觀、潰瘍及角質細胞增生病理變化，根據發炎前驅物和口腔黏膜炎嚴重程度在肥大細胞缺陷及野生型小鼠不一致的結果顯示發炎反應可能不是決定放射線引發口腔黏膜炎之決定因子。

Oral mucositis is a common side-effect caused either by chemo- or radiotherapy. In the head-and-neck cancer patients, radiotherapy is widely used as the primary therapeutic approach or adjunctive therapy post-operationally. During radiotherapy, the oral mucositis is a heavy economic burden to the patient, but preventive or effective treatment is still in need. In this study, we developed a mouse model of oral mucositis after 25Gy irradiation delivered restrictively to the tongue. One week after irradiation, the mouse body weight dropped significantly and the erythema on tongue emerged . The thickness of epithelium is reduced and the proliferation of the epithelial cells is hindered. The ulceration began 10 days after irradiation with infiltration of neutrophils. The tissue-resident mast cells also increase at the submucosa, suggesting their roles in the progression of oral mucositis. In the mast cells-deficient mice, epithelial damage or ulceration area was reduced comparing with the wild type mice, suggesting that mast cells may be harmful to the epithelium during radiation-induced inflammation. However, the level of pro-inflammatory cytokines was significantly higher in the mutant mice suggesting that epithelial damage may be induced by other inflammatory mediators. In addition, the recovery of the epithelial cells exhibited a site-specific pattern with the epithelial cells locate at the tip start to recover earlier than other regions of the dorsal side. This site-specific recovery might result from the differences between microenvironment yet the mechanism remains unclear.