血管收縮劑對於放射線皮膚炎的影響

Abstract

背景與研究目的 在過去的二十年中，台灣的乳癌發病率從每十萬人 36.5 例上升到 90.36 例。放射治療在乳癌治療中非常有效，但它也可能導致嚴重的皮膚炎。這種併發症可能會阻礙康復，甚至需要進一步的手術。儘管探索了類固醇和其他治療方法來緩解這些影響，但仍面臨重大挑戰。放射性皮膚炎被認為與氧化壓力造成的損傷有關。血管收縮劑可能會提供保護，減少由發炎和活性氧物質引起的皮膚炎，這已在小鼠試驗中得到證實。我們的研究旨在確定局部血管收縮劑是否能有效預防放射性皮膚炎，並探討與皮膚損傷相關的細胞代謝和調節因子。

實驗方法 針對 α-1A、α-2 和 β2 等受體的多種局部血管收縮劑，我們根據使用方便性和組織氧氣檢測，對這些血管收縮劑進行了改良。在對小鼠背部皮膚進行 40 Gy 照射之前，於背部施用了一劑血管收縮劑，接下來六周內持續監測小鼠背部皮膚變化。進一步利用組織學檢查，觀察皮膚的結構變化，包括每層皮膚厚度的變化、皮膚附屬物的數量；此外，透過 K1、K5 和 loricrin 的免疫螢光染色來確認表皮分層的狀態。

結果 塗抹後，相較於對照組，局部血管收縮劑在誘導皮膚血管收縮方面顯示出顯著效果。對照組的潰瘍在第 18 天開始出現，並在第 21 天至第 30 天之間惡化，然後趨 於穩定。到 46 天研究期結束時，未經治療的小鼠背部出現了不同程度的潰瘍，範圍從 5%到 15%。相比之下，治療組從第 16 天開始顯示出極少的潰瘍（少於 2%），大多數在隨後達到完全的傷口癒合。組織學評估顯示，未治療組的表皮和真皮厚度顯著增加，並伴有淋巴細胞浸潤。此外，對照組的毛囊數量減少，而治療組的毛囊數量保持穩定。loricrin、K1 和 K5 的免疫組織化學染色顯示，對照組存在多層表皮結構，這種病理現象在治療組中未見，這突顯了血管收縮劑對放射性皮膚炎的保護效果。

結論 由血管收縮劑引起的缺氧有效地保護了皮膚免受輻射損傷。

Introduction Over the past two decades, Taiwan's breast cancer incidence has surged from 36.5 to 90.36 per 100,000. Radiation therapy is effectively in breast cancer treatment, but it could also lead to severe dermatitis. This complication can hinder recovery and may require further surgeries. Despite the exploration of steroids and other treatments to alleviate these effects, significant challenges persist. Radiation dermatitis was believed to related injury by oxidative stress. Vasoconstrictors may offer protection against dermatitis, influenced by inflammation and reactive oxygen species, as evidenced by pilot rat studies. Our research aims to determine whether topical vasoconstrictors are an effective preventive management against radiation dermatitis and to explore the cellular metabolism and regulatory factors associated with skin injuries.

Methods Topical adrenergic vasoconstrictors targeting α-1A, α-2, and β2 receptors were prepared and optimized based on applicability and tissue oxygen mapping for this experiment. A single dose was administered topically just before a 40 Gy irradiation was applied to the mice's back skin. We continuously monitored the skin changes over six weeks. Further histological examinations were conducted to observe structural changes in the skins, including variations in the thickness of each skin layer, the number of skin appendages, and immune reactions. Additionally, immunofluorescence staining using K1, K5, and loricrin helped identify detailed cell proliferation and survival conditions in each epidermal sublayer.

Results Following application, topical vasoconstrictors demonstrated marked efficacy in inducing skin vasoconstriction compared to the control group. Initiation of ulceration in the control group was observed on day 18, with a subsequent exacerbation from day 21 to day 30 before stabilizing. By the conclusion of the 46-day study period, untreated mice exhibited ulcerations, varying in severity from 5% to 15% of the back area. In contrast, treatment groups displayed minimal ulceration (less than 2%) starting from day 16, with the majority achieving complete wound resolution subsequently.Histological evaluations indicated a significant increase in epidermal and dermal thickness and lymphocyte infiltration in the untreated groups. Moreover, a reduction in hair follicle count was observed in the control group, whereas hair follicle numbers remained stable in the treated groups. Immunohistochemical staining for loricrin, K1, and K5 revealed a multi-layered epidermal structure in the control groups—a pathology not evident in the treated groups, underscoring the protective effect of the vasoconstrictors against structural skin damage induced by conditions simulated in the study.

Conclusion Hypoxia induced by vasoconstrictors effectively protected the skin from radiation damage.