药学学报

防治放射性肠炎的口服龙油制剂研究

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刘冬冬 ¹ , 魏萌 ¹ , 苑天宇 ¹ , 张蕾 ² , 张勇 ² , 金义光 ¹^,^*

药学学报 | 研究论文 2023,58(8): 2494-2502

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药学学报 |研究论文 2023 , 58 (8) : 2494 -2502

防治放射性肠炎的口服龙油制剂研究

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刘冬冬¹, 魏萌¹, 苑天宇¹, 张蕾², 张勇², 金义光¹^,^*

作者信息

1.军事科学院军事医学研究院辐射医学研究所, 北京 100850

2.安徽龙纪元生物科技有限公司, 安徽宿州 234000

通讯作者:

*金义光, Tel: 86-10-66931220, E-mail: jinyg@sina.com

Oral Long oil for prevention and treatment of radiation enteritis

Dong-dong LIU¹, Meng WEI¹, Tian-yu YUAN¹, Lei ZHANG², Yong ZHANG², Yi-guang JIN¹^,^*

Affiliations

1. Institute of Radiation Medicine, Academy of Military Medicine Sciences, Academy of Military Sciences, Beijing 100850, China

2. Anhui Longjiyuan Biotechnology Co., Ltd., Suzhou 234000, China

出版时间: 2023-08-12 doi: 10.16438/j.0513-4870.2022-1048

文章导航

摘要

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放射性肠炎(radiation enteritis, RE) 是腹盆腔恶性肿瘤患者放疗常见并发症, 严重影响生活质量, 临床无专门防治药物。龙油(Long oil, LO) 由海螵蛸、红花、核桃油、菜籽油中油脂成分组成, 临床用于创伤修复。本研究将口服LO用于RE防治并探讨机制。所有动物实验经军事科学院军事医学研究院辐射医学研究所伦理委员会批准且实验均按照相关指导原则和规定进行。小鼠腹部经13 Gy的γ射线照射, 成功建立RE模型。辐照前1 h给小鼠灌胃LO (8 mL·kg^-1), 与模型组比较, 辐照后第3.5日口服LO组小肠新生隐窝数量明显增多, 小肠绒毛更长; 第7日粪便肠道菌群丰度显著增加, 特别是Eubacterium、Lactobacillus等益生菌的数量; 第7日旷场实验显示口服LO组小鼠的运动总路程延长、不动时间变短、速度加快; 第14日口服LO组小鼠的小肠组织中的促炎因子包括肿瘤坏死因子-α和白介素-6水平显著降低, 接近正常水平。因此, 口服LO可减轻RE症状, 促进小肠损伤组织修复。荧光标记法证明口服LO组小鼠肠黏膜渗透性明显减小, 达到正常水平。口服LO可通过改善肠道微环境、减轻炎症反应、促进组织修复等作用, 保护肠黏膜, 防治RE。

关键词

龙油 / 肠道菌群 / 放射性肠炎 / 促炎因子 / 电离辐射

Abstract

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Radiation enteritis (RE) is a common syndrome in the radiotherapy of abdominal and pelvic malignant tumors, heavy influencing living quality, but no specific clinical regimens are available. Long oil (LO) is composed of the fat components from cuttlebone, safflower, walnut oil and rapeseed oil and has been clinically used for wound healing. In this study, oral LO was applied for the prevention and treatment of RE and the mechanisms were explored. Animal experiments were approved by the Ethics Committee of the Beijing Institute of Radiation Medicine, Academy of Military Medical Sciences, and the experiments were conducted in accordance with relevant guidelines and regulations. An RE mouse model was established after single whole abdominal γ-ray radiation of 13 Gy. LO (8 mL·kg^-1) was intragastrically administered to the mice 1 h pre-radiation. Compared to the models, the mice of the LO group had more regenerated intestinal crypts and longer villus on day 3.5, and remarkable increase in the abundance of gut microbiota on day 7, especially the amounts of probiotics including Eubacterium and Lactobacillus. Moreover, the mice of the LO group showed longer total movement distance, shorter immobility time, and higher speed than the model mice on day 7. On day 14, the mice of the LO group showed the high descending of proinflammatory factors including tumor necrosis factor-α and interleukin-6, close to the normal levels. Therefore, oral LO can alleviate the inflamed syndromes of RE and improve the repair of damaged intestinal tissues. Moreover, the mice of the LO group had highly low permeability of intestinal mucosa according to the fluorescence labeling experiment, which was close to the normal level. Oral LO can protect intestine mucosa and prevent RE by modification of the intestinal microenvironment, alleviation of the inflammatory response, and promotion of tissue repair.

Key words

Long oil / gut microbiota / radiation enteritis / proinflammatory factor / ionizing radiation

引用本文

刘冬冬, 魏萌, 苑天宇, 张蕾, 张勇, 金义光. 防治放射性肠炎的口服龙油制剂研究. 药学学报, 2023 , 58 (8) : 2494 -2502 . DOI: 10.16438/j.0513-4870.2022-1048

Dong-dong LIU, Meng WEI, Tian-yu YUAN, Lei ZHANG, Yong ZHANG, Yi-guang JIN. Oral Long oil for prevention and treatment of radiation enteritis[J]. Acta Pharmaceutica Sinica, 2023 , 58 (8) : 2494 -2502 . DOI: 10.16438/j.0513-4870.2022-1048

正文

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放疗是肿瘤临床治疗常采用手段, 采用电离辐射照射肿瘤组织后促进肿瘤细胞凋亡和坏死。电离辐射包括α、β、γ、X射线、中子辐射等, 与机体作用后产生自由基、活性氧等造成组织细胞损伤。电离辐射的组织非选择性可造成正常组织损伤。放射性肠炎(radiation enteritis, RE) 是腹腔、腹膜后或盆腔部位肿瘤放疗后常见并发症^{[1, 2]}。急性放射性结肠炎的临床症状最早可在放疗开始后数小时或几天内出现, 但大多数患者在多次照射累积剂量达到30~40 Gy时才会出现症状。多数慢性放射性结直肠炎患者发生于放疗完成后6~24个月, 少数患者在数年甚至数十年之后才出现症状^[3]。

RE早期症状主要是射线对小肠或结直肠损伤后诱发的胃肠道反应, 包括恶心、呕吐、腹痛、腹泻等。大部分盆腔放疗患者伴有黏液血便或直肠出血, 全身营养状况较差, 出血时间较长的患者常合并贫血, 部分患者还可伴有低热。内脏放射性损伤累及小肠, 回肠黏膜受损时, 胆酸重吸收减少, 可引起腹泻^[4]。放射损伤可引起大量肠上皮细胞和血管内皮细胞凋亡, 肠黏膜发生炎性水肿、坏死、纤维化, 肠道上皮屏障被破坏^{[5, 6]}。RE临床常表现为里急后重、腹痛腹泻、便黏便血, 可进一步发展成肠瘘、肠穿孔等^[7]。RE治疗难, 迁延时间长, 防治结合是较好的选择。

目前RE没有专门防治药物。RE治疗药物包括非甾体类抗炎药、黏膜保护剂硫糖铝和激素等^[8-10], 但长期使用非甾体类抗炎药和激素类药物不良反应明显。细胞保护剂氨磷汀可用于放疗前正常组织细胞保护, 但氨磷汀是注射用药, 有严格给药时间限制, 并且不良反应明显, 限制了其临床使用^[11]。RE损伤部位主要是肠道黏膜上皮组织, 增加对肠黏膜的保护可能会减轻损伤程度。已有报道^[12]证明肠道菌群和电离辐射损伤有较密切关系, 改善肠道微生态环境可能对RE损伤有一定保护作用。

龙油(Long oil, LO) 是一种油脂混合物, 由海螵蛸、红花、核桃油、菜籽油中油脂成分组成, 临床用于创伤修复^[13]。本实验室将LO制备成纳米乳雾化液, 吸入后可减轻脂多糖造成的急性肺损伤^[14]。因为LO成分均可食用, 所以本研究采用动物模型灌胃LO进行防治RE研究, 考察其防护效果和作用机制。

材料与方法

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药物与试剂 龙油(批号: 20190917, 合肥龙纪元生物科技有限公司); 异硫氰酸荧光素-葡聚糖(FITC-dextran, Sigma试剂公司); 二胺氧化酶(diamine oxidase, DAO) 活性检测试剂盒、小鼠肿瘤坏死因子-α (tumor necrosis factor-α, TNF-α) 检测试剂盒、小鼠白细胞介素-6 (interleukin-6, IL-6) 检测试剂盒及小鼠IL-22检测试剂盒(上海酶联生物科技有限公司); 用水均为去离子水, 用纯水仪制备。

仪器 ⁶⁰Co γ辐射装置(军事医学研究院辐射医学研究所); 倒置荧光显微镜(BDS200-FL, 重庆奥特光学仪器有限责任公司); EnSpire多功能酶标仪(SN23000371, 美国铂金埃尔默有限公司); 高速组织研磨仪(型号: KI-Ⅱ, 武汉谷歌生物科技有限公司); 血液细胞分析仪(型号: DF52 Vet, 深圳市帝迈生物技术有限公司); 纯水仪(型号: Heal Force Super NW, 上海康雷仪器有限公司); 旷场实验平台(DB018, 北京智多宝生物科技有限责任公司); 动物行为学视频分析系统主控器(DigBehv, 上海吉量软件科技公司)。

动物 C57BL/6J小鼠, SPF级, 雄性, 体质量(22 ± 2) g, 购于北京维通利华实验动物技术有限公司, 许可证号: SCXK (京) 2021-0006。实验期间自由给予水和食物。动物实验经军事科学院军事医学研究院辐射医学研究所伦理委员会批准, 且实验均按相关指导原则和规定进行。

放射性肠炎动物模型建立及给药方案 将小鼠随机分为3组: 正常组、模型组、LO组, 每组12只。在全腹部照射前3日和当日照射前1 h, 模型组小鼠灌胃0.2 mL生理盐水, LO组小鼠灌胃0.2 mL LO原料, 10 min后小鼠麻醉固定后局部屏蔽进行腹部辐照, 采用⁶⁰Co γ射线腹部单次照射, 剂量为13 Gy, 剂量率为60.12 cGy·min^-1, 建立RE动物模型, 并于照后连续3日灌胃。正常组不做任何处理。

血液细胞分析 小鼠辐照后第0、1、7、14日分别尾静脉取血20 μL, 与0.48 mL细胞稀释液混匀, 用血细胞分析仪测定白细胞、红细胞及血小板数量。

肠黏膜渗透性实验 小鼠辐照后第14日, 提前禁食12 h, 灌胃0.2 mL FITC-dextran (60 mg·100 g^-1), 4 h后摘眼球取血, 1 000 r·min^-1离心15 min取得血清。取100 μL血清, 在激发波长490 nm和发射波长520 nm下用酶标仪测定血清中的荧光强度。

DAO活性检测 在小鼠照射后第14日, 摘眼球取血, 1 000 r·min^-1离心15 min取得血清, 用DAO试剂盒测定活性。

小肠病理检查 分别于小鼠辐照后第1、3.5、7日麻醉处死小鼠, 取距胃部下端5 cm处的小肠组织, 放入4%多聚甲醛溶液中固定24 h, 苏木精-伊红(hematoxylin and eosin, H&E) 染色后在显微镜下观察组织病理形态。

旷场实验 在小鼠辐照后第7日开展旷场实验。旷场箱体大小为50 cm × 50 cm × 50 cm, 测试时将小鼠置于旷场中心, 摄像头记录小鼠5 min内的自由活动轨迹。实验结束后清理动物排泄物, 用消毒液擦拭箱体底部, 待气味消失后再进行下一组实验, 避免残留气味影响后续实验。

IL-22、TNF-α、IL-6含量测定 在小鼠辐照后第14日, 取距胃部下端5 cm处的小肠组织, 加入4 ℃的9倍质量生理盐水, 用高速组织研磨仪研磨, 研磨液在10 000 ×g、4 ℃高速离心15 min, 取上清用试剂盒分别测定IL-22、TNF-α和IL-6。

肠道菌群检测 在小鼠辐照后第7日, 用灭菌后的1.5 mL离心管接取小鼠新鲜粪便, 收集后立即液氮冷冻, 并贮存于-80 ℃待分析。委托安升达公司进行菌群的16s rDNA测序, 利用R语言等软件进行数据分析。

统计学分析 采用SPSS 16.0软件通过单因素方差分析对数据进行统计学分析。数据以均数±标准差(x±s) 表示; 比较组间差异, P < 0.05表示具有显著性差异。

结果

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1 龙油对辐照小鼠生存率和体质量的影响

小肠上皮细胞增殖能力强, 小剂量辐照造成的肠损伤可快速恢复, 但辐照剂量较大时, 组织损伤过于严重, 肠黏膜难以修复, 甚至出现死亡。经13 Gy ⁶⁰Co γ射线全腹部辐照后, 模型组小鼠体质量明显下降, 辐照后第14日也未能恢复至初始体质量; 而LO组小鼠辐照后, 在开始阶段的第3~4日体质量下降, 但第5日开始上升, 第14日恢复至正常水平(图 1A)。大剂量电离辐射常造成死亡, 因此死亡率是评估药物防护效果的重要指标。全腹部辐照后第3日, 模型组小鼠死亡2只, 而LO组仅死亡1只; 模型组小鼠于第4、5日都出现死亡, 而LO组小鼠均存活, 两组生存率分别为66.67%和91.66% (图 1B)。因此, 小鼠在辐照前后口服LO可显著增加小鼠体质量和生存率, 具有较好的抗辐射作用。

2 龙油促进辐照小鼠血细胞恢复

RE主要发生于局部腹部照射, 与全身照射相近, 同样会引起外周血变化, 其中白细胞的数量变化最为明显。全腹部照射后, LO组小鼠外周血白细胞数急剧下降, 但到辐照后第7日时, LO组白细胞明显增加, 与模型组相比有显著差异(图 2A, P < 0.001); LO组小鼠外周血红细胞数始终保持较高水平, 与正常组水平保持一致, 与模型组相比有统计学差异(图 2B, P < 0.001); 各组小鼠外周血血小板数量变化不大, 组间无统计学差异(图 2C)。因此, 口服LO具有较好的抗辐射作用, 可有效减轻辐射对造血系统的损伤, 促进辐照后血细胞快速恢复, 进而治疗RE。

3 龙油减轻辐射小肠损伤

小肠绒毛和隐窝是肠上皮组织的重要组成, 有重要的吸收、免疫功能^[15]。肠干细胞位于隐窝底部, 电离辐射会严重损伤干细胞, 影响肠黏膜修复^[16]。辐照后第1日, 模型组小肠隐窝明显皱缩(图 3A); 辐照后第3.5日, 模型组绒毛排列混乱, 长度明显减小, 大量隐窝丢失, 且出现空泡; 辐照后第7日, 模型组隐窝异常增殖, 排列不规则。LO组在辐照后的整个过程中肠绒毛长度与正常组无明显差异, 而新生隐窝数量明显多于模型组(图 3A), 绒毛下端2/3处可见大量排列整齐的上皮细胞, 与模型组相比有显著性差异(图 3B, P < 0.01; 图 3C, P < 0.001)。因此, 口服LO可明显减轻辐射肠损伤, 在恢复后期能显著促进肠隐窝和小肠绒毛的恢复。

4 龙油增强肠黏膜屏障功能

肠上皮细胞紧密连接属于肠黏膜屏障的重要结构, 辐射可破坏小鼠肠细胞紧密连接, 肠黏膜屏障功能受损, 肠渗透性增加^[17]。用肠渗透性实验可评价辐照后小肠黏膜屏障的恢复。LO组小鼠外周血中FITC-dextran的含量低, 与正常组无明显差异; 而模型组肠黏膜屏障受损严重, 大量FITC-dextran进入血液, 与LO组及正常组相比具有明显差异(图 4A, P < 0.001)。DAO是一种代谢多胺类物质的酶, 广泛存在于成熟的小肠绒毛上皮细胞中, 但在增殖能力强的肠上皮细胞中活性低, 因此可通过DAO活性评估肠上皮屏障完整性和受损程度^[18]。辐照后肠上皮细胞损伤严重, DAO通过肠黏膜屏障进入血液, 血清中DAO含量增加; 而LO组血清中DAO活性低于模型组(图 4B)。因此, 口服LO能有效保护辐照小鼠的肠上皮, 改善肠上皮细胞紧密连接, 增强肠黏膜屏障功能。

5 龙油减轻肠组织炎症

在RE恢复过程中, 免疫功能平衡有重要作用, 其中IL-6、TNF-α是促炎因子, 而IL-22是抗炎因子^{[19, 20]}。IL-22还可通过增强抗菌肽表达, 促进肠上皮细胞再生, 促进肠屏障功能恢复^{[21, 22]}。LO组小鼠肠组织IL-22水平显著高于模型组(图 5A, P < 0.001), 而促炎因子TNF-α、IL-6水平明显低于模型组(图 5B, P < 0.01; 图 5C, P < 0.001), 且与正常组无统计学差异。因此, 口服LO可促进肠细胞分泌抗炎因子, 同时减少促炎因子表达, 减轻辐照小鼠肠组织炎症, 促进损伤组织恢复。

6 龙油可调节肠道菌群

电离辐射除影响人体细胞外, 也影响肠道微生物^[23]。辐照往往导致肠道菌群紊乱, 大量肠益生菌死亡, 降低肠道微生物群在物种操作单元(OTU) 水平上的丰富度和多样性^[24]。正常组小鼠特有的肠道微生物有384种, LO组有187种, 而模型组仅有72种, 且益生菌种类和数量大大减少(图 6A)。根据OTU水平分析主要微生物群落, 可得到Shannon、Simpson指数及Chao 1指数^{[25, 26]}。统计学分析表明, LO组小鼠的菌群丰富度和多样性高于模型组, 与正常组小鼠微生物群落相近(图 6B)。LefSe (linear discriminant analysis effect size) 分析揭示不同分类水平的丰度分布情况。模型组小鼠的肠道微生物群中LDA (linear discriminant analysis) 得分高于3的特征分类在f_Helicobacteraceae、c_Campylobacteria和g_Parabacteriodes显示出最高的相对丰度。正常组小鼠肠道微生物中g_Muribaculaceae等益生菌的丰度明显高于模型组, 有助于减弱致病菌定殖, 保持日常生命活动健康状态。辐照后的小鼠肠道微生物中的幽门螺杆菌、大肠弯曲杆菌等革兰阴性菌和其他致病菌及条件致病菌增加, 但通过LO处理的小鼠肠道微生物中f_Eubacterium等益生菌的丰度出现明显增加(图 6C)。因此, LO可增加肠道微生物群落的丰富度和多样性, 增加益生菌丰度, 减弱辐射引起的肠黏膜损伤。

使用Spearman相关分析对辐照后第7日的所有样本丰度最高的20个属进行聚类分析, 并以热图的形式呈现(图 7A、B)。电离辐射引起肠道菌群组成的改变。模型组小鼠肠道菌群与健康组比较发生明显变化, 而LO组小鼠肠道微生物的组成变化较小。LO组小鼠肠道内益生菌Muribaculaceae与Lactobacillus相对丰度和健康组无明显差异, 而远高于模型组(图 7C, P < 0.01; 图 7D, P < 0.05); 而益生菌[Eubacterium]_coprostanoligenes的相对丰度明显增加, 并远高于模型组和健康组(图 7E, P < 0.01)。这些益生菌可产生短链脂肪酸等活性分子, 保护肠道黏膜, 调节免疫功能, 促进肠黏膜的恢复^[27-30]。模型组中条件致病菌和致病菌比例显著上升, 以拟杆菌科为代表的革兰阴性杆菌所占比例显著增加, 以毛螺菌科、瘤胃球菌科为代表的革兰阳性球菌丰度明显降低, 肠道菌群紊乱, 严重影响炎症因子的表达与肠黏膜修复。

7 龙油促进辐照小鼠体力恢复

旷场实验反映动物的运动能力和探索精神, 可用于评价辐照动物的运动能力恢复情况^[31]。与正常组相比, 模型组小鼠在旷场实验中的总路程显著降低(图 8A, P < 0.01), 运动较少, 多沿箱体边缘活动, 行动能力减弱, 而LO组小鼠表现活跃, 在不动时间、平均速度方面与模型组均有统计学差异(图 8B, P < 0.01; 图 8C, P < 0.01), 并恢复至正常水平。因此, 口服LO可通过减轻辐射损伤, 增强辐照小鼠的运动能力。

讨论

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RE是腹腔、腹膜后或盆腔部位肿瘤放疗后常见并发症, 包括急性RE和慢性RE, 如无有效治疗, 迁延可达十余年, 给肿瘤生存患者叠加带来极大痛苦, 严重影响生活质量。RE一旦发生, 治疗棘手、时间长, 因此预防RE的发生或减轻放射损伤的程度显得尤为重要^[32]。细胞保护剂氨磷汀已上市多年, 用于放化疗防护, 动物和临床研究也非常多, 但国内肿瘤放疗患者使用率低, 除对放射性组织损伤如RE重视不够外, 还与氨磷汀毒性和严格使用时间限制有关^[33]。找到安全有效的药物成为防治RE的关键。

LO是从多种药用动植物中提取的油脂类混合物, 含有亚油酸、亚麻酸等抗炎、抗氧化活性物质, 临床已大量用于皮肤创伤治疗和修复, 对细菌感染创伤也有效。亚油酸是一种功能性的多不饱和脂肪酸, 可通过抑制炎症因子的表达促进伤口愈合^[34]。本实验室已证明LO纳米乳雾化液吸入后可减轻脂多糖引起的急性肺损伤^[14]。因为RE主要表现为肠黏膜损伤, 且在肠道环境下发生严重感染和炎症反应, 所以本研究尝试将LO口服后用于肠黏膜损伤防护。

急性RE的主要病理特征是肠黏膜局部水肿和炎症反应, 临床表现为急性腹泻、里急后重和肛门疼痛^[35]。慢性RE的主要病理特征包括肠壁小血管的缺血和肠壁纤维化, 临床表现为便血、肠道狭窄和肠瘘等^[36]。针对RE的病理特征, 本研究重点考察了口服LO对肠黏膜炎症、肠道菌群、死亡率的影响。

TNF-α是一种多功能促炎细胞因子, 使肠上皮细胞屏障功能及形态结构发生改变, 增加肠黏膜与血管壁通透性, 破坏肠黏膜完整性, 是评价RE最重要的促炎因子之一^[37]。IL-6是一种急性炎症介质, 由各种类型细胞释放, 通过增强肠上皮细胞分泌电解质, 导致内皮细胞肿胀和通透性增加, 中性粒细胞浸润至炎症部位, 是评价肠组织损伤的重要指标^[38]。IL-22是一种抗炎因子, 可通过增强抗菌肽表达, 促进肠上皮细胞再生, 激活肠道免疫, 促进肠屏障功能恢复^[39]。本研究证明, RE小鼠的促炎细胞因子TNF-α、IL-6表达显著增加, IL-22抗炎细胞因子表达减少, 肠组织损伤严重, 大量肠上皮细胞被破坏。口服LO可有效降低辐照小鼠肠组织中TNF-α和IL-6水平, 增强IL-22表达, 促进肠黏膜修复。因此, LO是一种可口服的有较好抗肠道炎症的药物。

肠道微生态环境特别是肠道菌群对肠黏膜结构和功能有重要影响^[40]。腹部辐照后可引起肠道菌群紊乱, 益生菌大量减少, 致病菌增加, 引起局部感染, 进一步加重肠黏膜损伤^[41]。调节肠道菌群、增加益生菌数量和减少致病菌可通过释放更多短链脂肪酸等机制有效减轻辐射肠黏膜损伤^[42]。Eubacterium等益生菌丰度增加, 可有效改善肠道微生态环境, 维持肠道健康状态^[43]。Campylobacteria等致病菌可导致严重肠炎, 引起腹泻^[44]。本研究证明口服LO可显著增加Eubacterium、Lactobacillus等益生菌丰度, 减少Campylobacteria等致病菌丰度, 原因可能是LO作为一种黏稠的油脂类混合物, 肠道内可被益生菌代谢, 增加肠道微生物群落的丰富度和多样性, 起到益生元作用。

油脂类物质涂覆在皮肤和黏膜表面后可产生封闭效果, 有助于防治损伤发生和促进损伤修复^[45]。LO性质较黏稠, 外用时易涂覆在创伤表面, 起到封闭、抗炎、促愈合作用。口服LO到达RE小鼠受损肠黏膜表面后, 可产生封闭效果, 防止致病菌局部感染, 促进肠黏膜屏障的修复。肠黏膜屏障功能评价表明, 口服LO有效改善肠上皮细胞紧密连接, 增强肠黏膜屏障功能, 减少肠黏膜渗透性。

肠黏膜生理屏障的正常化是肠黏膜损伤修复的重要指征^[46]。FITC-dextran作为高分子物质, 无法通过完整肠黏膜生理屏障, 但肠黏膜受损后, 可进入体内。在血液中测得FITC-dextran可作为肠黏膜生理屏障完整性的评价指标^[47]。肠组织细胞中存在大量DAO, 组织损伤后可释放到血液中, 因此测得血液中的DAO可作为肠道黏膜结构和功能完整性的重要指标^[48]。本研究通过肠组织病理切片证明RE小鼠肠组织被严重破坏, 血液中的FITC-dextran和DAO水平很高。口服LO后, 肠黏膜上皮新生隐窝数量增多, 小肠绒毛长度恢复至正常水平, 促进营养吸收和体质量恢复, 血液中的FITC-dextran和DAO水平与正常组接近, 肠黏膜生理屏障得到有效保护和重建。

大剂量电离辐射包括局部照射可严重损伤动物造血系统和敏感组织器官如肠黏膜^{[49, 50]}。本研究证明13 Gy的γ射线全腹部照射小鼠后, 白细胞数量显著减少, 体质量下降, 活动量大大减少, 第3日开始出现死亡, 后续连续出现死亡。口服LO的辐照小鼠白细胞数量下降缓慢, 随着小鼠肠道功能的恢复, 进食量与进水量增加, 体质量从第4日开始增加, 第3日出现死亡后, 剩余动物全部存活; 而模型组体质量恢复缓慢, 存活率远低于LO组。其他辐射损伤治疗研究中也报道了相同趋势^{[51, 52]}。口服LO增加肠道内益生菌相对丰度, 后者产生短链脂肪酸等活性分子, 而短链脂肪酸可促进造血系统恢复^[24]。特别是在第7日, 旷场实验证明口服LO的小鼠活动量大大增加, 与正常组无差异; 而模型组存活小鼠状态仍然很差, 活动量很低。

RE是临床难治疾病, 现无有效防治方法。本研究基于RE的致病原因和病理特征, 通过口服LO有效增加益生菌种类和相对丰富度, 改善肠道微生态环境, 显著降低促炎细胞因子表达, 增加抗炎因子表达, 促进肠黏膜生理屏障和肠道功能恢复, 降低死亡率, 改善动物生存状态, 表现出良好的辐射防护效果。LO服用方便, 安全性好, 可长期服用。口服LO可能的临床用药方案是照射前3天或更早口服龙油, 每日1次, 照射后继续服用3日。本研究首次证明口服天然混合油脂类药物LO的防治RE效果和机制, 为临床RE的防治提供了安全有效的天然活性成分口服制剂。

作者贡献: 刘冬冬负责实验设计、实验操作、数据分析和文章撰写; 魏萌负责实验设计、结果分析和文章修改; 苑天宇参与实验并进行文章修改; 张蕾和张勇参与部分实验设计; 金义光负责课题设计、实验指导、数据分析、文章写作与修改。

利益冲突: 所有作者声明不存在利益冲突。

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北京市自然科学基金-海淀原始创新联合基金资助项目(L212060)

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2023年第58卷第8期

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doi: 10.16438/j.0513-4870.2022-1048

接收时间：2022-09-09
首发时间：2025-11-21
出版时间：2023-08-12

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收稿日期：2022-09-09
修回日期：2022-11-03

基金

北京市自然科学基金-海淀原始创新联合基金资助项目(L212060)

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1.军事科学院军事医学研究院辐射医学研究所, 北京 100850

2.安徽龙纪元生物科技有限公司, 安徽宿州 234000

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*金义光, Tel: 86-10-66931220, E-mail: jinyg@sina.com

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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