基于“火郁发之”理论探讨宣郁清热法治疗免疫检查点抑制剂相关心脏毒性

Exploring the treatment of immune checkpoint inhibitors-induced cardiotoxicity with the method of relieving constraint and clearing heat based on “the dispersing method for fire stagnation”

摘要

免疫检查点抑制剂（immune checkpoint inhibitors， ICIs）相关心脏毒性是肿瘤患者高致死率的免疫相关不良事件，中医治疗有独特优势。《黄帝内经》病机十九条中有五条论述火邪病机，均为“火郁”状态。 ICIs 相关心脏毒性与“火”密切相关，其主要临床表现均与炎症相关，以“火郁”理论认识 ICIs 相关心脏毒性非常契合。 ICIs 相关心脏毒性的病机包括：卫气有余，壮火燔灼；诸邪酿毒，伏火耗元；心脾肾虚，阴火扰动。 宣郁清热辨治 ICIs 相关心脏毒性，主要表现在：以栀子豉汤类方宣透壮火；以升降散类方宣清伏火；以升阳散火汤类方清补阴火。

Abstract

Immune checkpoint inhibitors (ICIs) associated cardiac toxicity is a highly lethal immune related adverse event in cancer patients, and Traditional Chinese Medicine treatment has unique advantages. Five out of the Nineteen Items of Pathogenesis from the Huangdi Neijing (Inner Canon of Yellow Emperor) discuss the pathogenic mechanisms of fire, all of which are in a state of fire stagnation. The cardiac toxicity associated with ICIs is closely related to fire, and its main clinical manifestations are all related to inflammation. Understanding ICIs related cardiac toxicity through the theory of fire stagnation is very consistent. The pathogenesis of ICIs related cardiac toxicity includes: excess defense qi, and strong fire becomes intense and burning; various pathogenic factors generate toxins, and latent fire consumes original qi; heart, spleen and kidney deficiency, and disturbance of yin fire. The main manifestations of treating ICIs related cardiac toxicity through “the method of dispersing for fire stagnation” are as follows: In the stage of excess fire, Zhizichi Decoction (Gardenia and Fermented Soybean Decoction) and its analogues are used to disperse. In the stage of latent fire, the formula of Shengjiang Powder (Ascending and Descending Powder), with possible modifications, is used to disperse and clear. In the stage of yin fire, Shengyang Sanhuo Decoction (Yang-Ascending and Fire-Dispersing Decoction) and its analogous prescriptions are used for clearing and tonifying.

关键词

火郁发之 / 宣郁清热 / 免疫检查点抑制剂 / 心脏毒性

Key words

the dispersing method for fire stagnation / relieving constraint and clearing heat / immune checkpoint inhibitors / cardiotoxicity

参考文献

[1] LI C, BHATTI S A, YING J . Immune checkpoint inhibitors—associated cardiotoxicity[J]. Cancers, 2022, 14(5): 1145.

[2] VASBINDER A, CHEN Y, PROCUREUR A, et al. Biomarker trends, incidence, and outcomes of immune checkpoint inhibitor—induced myocarditis[J]. JACC CardioOncol, 2022, 4(5): 689-700.

[3] SALEM J E, MANOUCHEHRI A, MOEY M, et al. Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study[J]. Lancet Oncol, 2018, 19(12): 1579-1589.

[4] 许生, 谭颖颖, 黄笛, 等 . 论“火郁发之”在《伤寒论》治法中的体现[J]. 中国中医基础医学杂志, 2020, 26(9): 1234-1236.

[5] 闫家馨, 张纾难, 贾明月, 等 . “火郁发之”在《伤寒论》寒热错杂方证中的应用[J]. 中国中医急症, 2023, 32(2): 245-248.

[6] 吴有性 . 温疫论[M]. 2版. 何永, 校注. 北京: 中国医药科技出版社, 2019: 56.

[7] 江瓘 . 名医类案正续编[M]. 太原: 山西科学技术出版社, 2013: 459.

[8] 赵献可 . 医贯[M]. 晏婷婷, 校注. 北京: 中国中医药出版社, 2009: 54.

[9] 何梦瑶 . 《医碥》全本校注与研究[M]. 广州: 广东科技出版社, 2018: 46.

[10] 陈沙沙, 张明泉, 张鹏飞, 等 . 国医大师李士懋教授运用“火郁发之”治疗妇科病经验撷英[J]. 时珍国医国药, 2025, 36(5): 950-952.

[11] 张宇, 杨岚, 曹宇翔, 等 . 国医大师熊继柏基于“火郁发之”运用普济消毒饮经验[J]. 吉林中医药, 2025, 45(1): 46-50.

[12] 刘卜瑞, 李小平, 郝建梅, 等 . 国医大师杨震从“郁热相火”论治皮肤病经验[J]. 陕西中医, 2022, 43(9): 1269-1271.

[13] 陈泓志, 梁伟林, 顾瞻, 等 . 程序性细胞死亡蛋白—1及其配体抑制剂免疫相关不良反应的中医病因病机及治法[J]. 世界中医药, 2021, 16(9): 1386—1390, 1399.

[14] 周思瑶, 沈洋, 杨婕, 等 . 从热毒伤阴探讨免疫检查点抑制剂相关肺炎中医病机及治疗[J]. 现代中医临床, 2025, 32(1): 85-88.

[15] 张介宾 . 张景岳医学全书[M]. 北京: 中国中医药出版社, 1999: 1845.

[16] ZHU H, GALDOS F X, LEE D, et al. Identification of pathogenic immune cell subsets associated with checkpoint inhibitor—induced myocarditis[J]. Circulation, 2022, 146(4): 316-335.

[17] 戴天章 . 重订广温热论[M]. 福州: 福建科学技术出版社, 2010.

[18] SINGH N, BABY D, RAJGURU J, et al. Inflammation and cancer[J]. Ann Afr Med, 2019, 18(3): 121.

[19] 张胜月, 刘红梅 . 活血化瘀中药调控肿瘤血管正常化研究进展[J]. 陕西中医, 2026, 47(4): 573-576, F0003.

[20] 颜博, 张然, 袁智勇, 等 . 免疫治疗导致的心脏毒性相关研究进展[J]. 癌症, 2023, 42(9): 473-483.

[21] 张国霞, 苏鑫, 商洪才, 等 . 从“毒损心络”探析肿瘤心脏病的中医病机[J]. 中医杂志, 2022, 63(14): 1394-1396.

[22] QUAGLIARIELLO V, PASSAIELLO M, REA D, et al. Evidences of CTLA—4 and PD—1 blocking agents—induced cardiotoxicity in cellular and preclinical models[J]. J Pers Med, 2020, 10(4): 179.

[23] XIA W, ZOU C, CHEN H, et al. Immune checkpoint inhibitor induces cardiac injury through polarizing macrophages via modulating microRNA—34a/Kruppel—like factor 4 signaling[J]. Cell Death Dis, 2020, 11(7): 575.

[24] AWADALLA M, MAHMOOD S S, GROARKE J D, et al. Global longitudinal strain and cardiac events in patients with immune checkpoint inhibitor—related myocarditis[J]. J Am Coll Cardiol, 2020, 75(5): 467-478.

[25] HASSON S P, SALWEN B, SIVAN A, et al. Re—introducing immunotherapy in patients surviving immune checkpoint inhibitors—mediated myocarditis[J]. Clin Res Cardiol, 2021, 110(1): 50-60.

[26] 张锡驹 . 伤寒论直解[M]. 北京: 中国中医药出版社, 2015: 166.

[27] 倪朱谟 . 本草汇言[M]. 郑金生, 甄雪燕, 杨梅香, 校点. 北京: 中医古籍出版社, 2005: 395.

[28] 李时珍 . 本草纲目[M]. 北京: 北京燕山出版社, 2007: 330.

[29] 吴永刚, 蒋守涛, 徐玉莲 . 加味栀子豉汤对冠状动脉粥样硬化性心绞痛失眠患者心肌保护作用和睡眠质量的影响[J]. 包头医学院学报, 2020, 36(7): 107-109.

[30] LIN W H, KUO H H, HO L H, et al. Gardenia jasminoides extracts and Gallic acid inhibit lipopolysaccharide—induced inflammation by suppression of JNK2/1 signaling pathways in BV—2 cells[J]. Iran J Basic Med Sci, 2015, 18(6): 555-562.

[31] 刘大朋, 李影, 孙作乾, 等 . 栀子多糖调控miR—141—3p对LPS诱导的心肌细胞炎症反应及凋亡的影响[J]. 中国免疫学杂志, 2022, 38(18): 2226-2230.

[32] 陈榕, 何梓炫, 颜烨, 等 . 栀子及其主要成分的药理及毒性作用研究进展[J]. 中草药, 2023, 54(18): 6092-6105.

[33] 罗刚, 黄彩兰, 王桂红, 等 . 升降散加味对脓毒症毒热内盛证患者炎症因子的影响研究[J]. 浙江中医杂志, 2025, 60(10): 871-872.

[34] 黄风玲, 杨辰华, 朱翠翠, 等 . 基于网络药理学和动物实验探讨加味升降散治疗糖尿病肾脏病的分子机制[J]. 中医药导报, 2024, 30(6): 10-16, 33.

[35] 李佳欣, 周丽雅, 张益蒴, 等 . 加味升降散调节PINK1/Parkin信号通路激活糖尿病肾病线粒体自噬的机制[J]. 中国实验方剂学杂志, 2025, 31(12): 121-128.

[36] 王博, 朱振刚 . 升降散及其中药组成治疗特发性肺纤维化机制的探讨[J]. 实用中医内科杂志, 2024, 38(10): 60-63.

[37] 张尧, 高飞, 宋瑞婧, 等 . 基于TLR4/NF—κB、Raf/MEK通路探讨加味升降散抑制糖尿病大鼠肾脏炎症和纤维化的作用机制[J]. 中药药理与临床, 2022, 38(5): 20-27.

[38] 李东垣 . 脾胃论[M]. 侯堃, 校. 北京: 中国科学技术出版社, 2024: 17.

[39] 叶桂 . 临证指南医案[M]. 沈庆法, 点评. 北京: 中国医药科技出版社, 2020: 142.

[40] 李玲玲 . 升阳散火汤治疗慢性疲劳综合征的作用机制[D]. 北京: 北京中医药大学, 2021.

[41] 王珏, 沈悦忠, 赖明阳, 等 . 升阳散火汤加味联合维生素B2治疗恶性肿瘤靶向药物所致口腔溃疡临床研究[J]. 新中医, 2023, 55(21): 1-7.

[42] 柴效科, 周海存, 杨涛, 等 . 免疫检查点抑制剂联合化疗治疗三阴性乳腺癌疗效和安全性的Meta分析[J]. 中国循证医学杂志, 2025, 25(1): 81-87.

[43] 王延玲, 李晶, 孙静, 等 . 免疫检查点抑制剂治疗广泛期小细胞肺癌的疗效及发生甲状腺功能紊乱风险的Meta分析[J]. 黑龙江医学, 2025, 49(2): 131-135.

[44] 陈威, 陈嘉怡, 李铃, 等 . 免疫检查点抑制剂治疗转移性结直肠癌疗效与安全性的Meta分析[J]. 中国药房, 2023, 34(4): 482-486.

基金资助

中国中医科学院西苑医院提升中医药临床循证证据级别研究专项(XYZX0201-19)

第五批全国中医临床优秀人才研修项目(国中医药人教函〔2022〕1号)