免疫检查点抑制剂相关性肺炎小鼠模型的构建与评价

doi:10.12300/j.issn.1674-5817.2025.169

实验动物与比较医学 ›› 2026, Vol. 46 ›› Issue (4): 498-506.DOI: 10.12300/j.issn.1674-5817.2025.169

免疫检查点抑制剂相关性肺炎小鼠模型的构建与评价

龚志群, 饶希午, 张天弋, 吴荣琛, 叶明楠, 蒋春曦, 王苏美, 朱燕娟, 柴小姝()

广州中医药大学第二临床医学院, 广州 510000

收稿日期:2025-10-11 修回日期:2026-02-05 出版日期:2026-08-25 发布日期:2026-08-22
通讯作者: 柴小姝（1979—），女，博士，主任医师，研究方向：中医药防治恶性肿瘤。E-mail：chaixiaoshu@126.com。ORCID：0009-0004-4676-8135
作者简介:龚志群（1995—），女，硕士研究生，研究方向：中西医结合防治恶性肿瘤。E-mail：2320734340@qq.com
基金资助:
国家自然科学基金“益肺散结丸调控DOT1L介导的H3K79甲基化抑制STAT3/CD15轴抗肺癌免疫逃逸的机制”(82305340);广东省中医院国自然培育专项“加味苇茎汤抑制ICAM1/LFA-1介导的T细胞异常活化防治ICIs诱发免疫性相关肺炎的机制研究”(YN2024GZRPY039)

Construction and Evaluation of Mouse Models Simulating Immune Checkpoint Inhibitor-Associated Pneumonitis

GONG Zhiqun, RAO Xiwu, ZHANG Tianyi, WU Rongchen, YE Mingnan, JIANG Chunxi, WANG Sumei, ZHU Yanjuan, CHAI Xiaoshu()

The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou 510000, China

Received:2025-10-11 Revised:2026-02-05 Published:2026-08-25 Online:2026-08-22
Correspondence to: CHAI Xiaoshu (ORCID: 0009-0004-4676-8135), E-mail: chaixiaoshu@126.com

摘要/Abstract

摘要：

目的构建并评价模拟免疫检查点抑制剂相关肺炎（immune checkpoint inhibitor-associated pneumonitis，CIP）病理进程的小鼠模型，以解决该研究领域中标准化动物模型缺失的关键问题。方法将35只6周龄雄性SPF级C57BL/6J小鼠随机分为对照（Control）组（n=5）、博来霉素（BLM）组（n=15）及博来霉素+程序性死亡受体1（programmed death-1，PD-1）单克隆抗体（BLM+PD-1）组（n=15），通过腹腔注射相应药物进行干预，并系统观察小鼠的一般状态、体重变化、存活率及肺组织病理学改变。结果与BLM组相比，BLM+PD-1组小鼠肺纤维化程度显著加剧，表现为小鼠体重进行性下降，整体状态恶化更为明显。病理学观察结果显示，BLM组在造模第4周时，小鼠肺部炎症有所减轻；而BLM+PD-1组的肺部病变持续加重，在造模第28天时未见炎症缓解迹象。免疫组织化学染色的定量分析结果表明，在造模后第14天时，BLM+PD-1组肺组织中白细胞介素-17A（interleukin-17A，IL-17A）的阳性表达率达到34.28%，显著高于BLM组（24.02%，P<0.000 1），BLM+PD-1组平滑肌肌动蛋白α（α-smooth muscle actin，α-SMA）的阳性表达率为12.40%，约为BLM组（5.87%）的2倍；在造模后第28天时，BLM+PD-1组的α-SMA阳性表达率仍维持在7.72%，而BLM组已降至3.38%。结论在博来霉素可诱导小鼠肺纤维化的基础上，联合给予PD-1抑制剂可加速肺间质纤维化进程，较好地模拟了临床免疫治疗中免疫应答异常活化所致的肺组织损伤和纤维化病理进程，从而成功构建了从早期炎症反应进展至肺纤维化的CIP动态动物模型，弥补了当前领域内该病动物模型稀缺的关键短板，为后续该疾病的机制研究与治疗策略开发提供了实验工具。

关键词: 免疫检查点抑制剂, 免疫检查点抑制剂相关性肺炎, 小鼠模型, 博来霉素, 肺纤维化

Abstract:

Objective To construct and evaluate a mouse model that simulates the pathological progression of immune checkpoint inhibitor-associated pneumonitis (CIP), in order to address the critical issue of the lack of standardized animal models in this research field. Methods Thirty-five SPF-grade 6-week-old male C57BL/6J mice were randomly assigned to a control group (n=5), a bleomycin (BLM) group (n=15), and a BLM+programmed death-1 (PD-1) monoclonal antibody (BLM+PD-1) group (n=15). Corresponding drugs were administered via intraperitoneal injection for intervention. The general condition, body weight changes, survival rate, and pulmonary histopathological alterations were systematically monitored. Results Compared with the BLM group, the BLM+PD-1 group exhibited significantly more severe pulmonary fibrosis, characterized by progressive body weight loss and more severe deterioration of general conditions. Histopathological examination showed that pulmonary inflammation was alleviated 4 weeks post-modeling in the BLM group. In contrast, pulmonary lesions continued to worsen in the BLM+PD-1 group, with no evidence of resolution of inflammation 28 days post-modeling. Quantitative immunohistochemical analysis revealed that the positive expression rate of interleukin-17A (IL-17A) in lung tissues reached 34.28% in the BLM+PD-1 group 14 days post-modeling, which was markedly higher than that in the BLM group (24.02%, P < 0.000 1). The positive expression rate of α-smooth muscle actin (α-SMA) was 12.40% in the BLM+PD-1 group 14 days post-modeling, nearly twice the level in the BLM group (5.87%). 28 days post-modeling, the positive expression rate of α-SMA remained at 7.72% in the BLM+PD-1 group, while it declined to 3.38% in the BLM group. Conclusion The addition of a PD-1 inhibitor to bleomycin treatment accelerates the progression of pulmonary interstitial fibrosis and effectively recapitulates the pathological process of lung injury and fibrosis driven by aberrant immune activation during clinical immunotherapy. Accordingly, this study successfully establishes a dynamic CIP animal model recapitulating the progression from early inflammatory response to pulmonary fibrosis. This model addresses the critical shortage of animal models for this condition and offers an experimental platform for further mechanistic studies and the development of therapeutic strategies.

Key words: Immune checkpoint inhibitors, Immune checkpoint inhibitor-associated pneumonitis, Mouse model, Bleomycin, Pulmonary fibrosis

中图分类号:

R-332

龚志群,饶希午,张天弋,等. 免疫检查点抑制剂相关性肺炎小鼠模型的构建与评价[J]. 实验动物与比较医学, 2026, 46(4): 498-506. DOI: 10.12300/j.issn.1674-5817.2025.169.

GONG Zhiqun,RAO Xiwu,ZHANG Tianyi,et al. Construction and Evaluation of Mouse Models Simulating Immune Checkpoint Inhibitor-Associated Pneumonitis[J]. Laboratory Animal and Comparative Medicine, 2026, 46(4): 498-506. DOI: 10.12300/j.issn.1674-5817.2025.169.

图/表 3

注：A，小鼠的生存曲线；B，小鼠在造模后第7、14、21、28天的体重变化。Control组，造模第1、5、8、11、15天腹腔注射100 μL 0.9%氯化钠注射液；BLM组，造模第1、5、8、11、15天腹腔注射100 μL博来霉素（5 mg/mL）；BLM+PD-1组，造模第1、5、8、11、15天腹腔注射100 μL博来霉素（5 mg/mL）和100 μL PD-1单克隆抗体（2 mg/mL）。与Control组相比，^nsP>0.05，^*P＜0.05。
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图1 小鼠的生存曲线及体重变化
注：A，小鼠的生存曲线；B，小鼠在造模后第7、14、21、28天的体重变化。Control组，造模第1、5、8、11、15天腹腔注射100 μL 0.9%氯化钠注射液；BLM组，造模第1、5、8、11、15天腹腔注射100 μL博来霉素（5 mg/mL）；BLM+PD-1组，造模第1、5、8、11、15天腹腔注射100 μL博来霉素（5 mg/mL）和100 μL PD-1单克隆抗体（2 mg/mL）。与Control组相比，^nsP>0.05，^*P＜0.05。

Figure 1 Survival curves and body weight changes of mice
Note： A， Survival curves of mice； B， Body weight changes of mice on days 7， 14， 21， and 28 post-modeling. Mice in the Control group received intraperitoneal injections of 100 μL of normal saline on days 1， 5， 8， 11， and 15 post-modeling. The BLM group was injected intraperitoneally with 100 μL of bleomycin （5 mg/mL） at the same time points. Mice in the BLM+PD-1 group received intraperitoneal co-administration of 100 μL of bleomycin （5 mg/mL） and 100 μL of anti-PD-1 monoclonal antibody （2 mg/mL） on the same schedule. Compared with the Control group， ^nsP > 0.05，^*P ＜ 0.05.

注：Control组，造模第1、5、8、11、15天腹腔注射100 μL 0.9%氯化钠注射液；BLM组，造模第1、5、8、11、15天腹腔注射100 μL博来霉素（5 mg/mL）；BLM+PD-1组，造模第1、5、8、11、15天腹腔注射100 μL博来霉素（5 mg/mL）和PD-1单克隆抗体100 μL（2 mg/mL）。n=3；黑色箭头（→）指示纤维化病灶、肺泡间隔增厚的区域；标尺=20 μm。
">

图2 小鼠肺组织的HE染色结果
注：Control组，造模第1、5、8、11、15天腹腔注射100 μL 0.9%氯化钠注射液；BLM组，造模第1、5、8、11、15天腹腔注射100 μL博来霉素（5 mg/mL）；BLM+PD-1组，造模第1、5、8、11、15天腹腔注射100 μL博来霉素（5 mg/mL）和PD-1单克隆抗体100 μL（2 mg/mL）。n=3；黑色箭头（→）指示纤维化病灶、肺泡间隔增厚的区域；标尺=20 μm。

Figure 2 HE staining results of lung tissues in mice
Note：Mice in the control group received intraperitoneal injections of 100 μL of normal saline on days 1， 5， 8， 11， and 15 post-modeling. The BLM group was injected intraperitoneally with 100 μL of bleomycin （5 mg/mL） at the same time points. Mice in the BLM+PD-1 group received intraperitoneal co-administration of 100 μL of bleomycin （5 mg/mL） and 100 μL of anti-PD-1 monoclonal antibody （2 mg/mL） on the same schedule. n=3； Black arrows （→） indicate areas of fibrotic lesions and alveolar septal thickening. Scale bar=20 μm.

注：Control组、BLM组和BLM+PD-1组小鼠在造模后第14、21、28天，肺组织中IL-17A和α-SMA的免疫组织化学染色情况（A～B）和相应的阳性面积占比（C～D）。Control组，造模第1、5、8、11、15天腹腔注射100 μL 0.9%氯化钠注射液；BLM组，造模第1、5、8、11、15天腹腔注射100 μL博来霉素（5 mg/mL）；BLM+PD-1组，造模第1、5、8、11、15天分别腹腔注射100 μL博来霉素（5 mg/mL）和PD-1单克隆抗体100 μL（2 mg/mL）。IL-17A，白细胞介素17A；α-SMA，平滑肌肌动蛋白α。n=3；与Control组相比，^****P＜0.000 1。
">

图3 各组小鼠肺组织中IL-17A和α-SMA的免疫组织化学染色结果
注：Control组、BLM组和BLM+PD-1组小鼠在造模后第14、21、28天，肺组织中IL-17A和α-SMA的免疫组织化学染色情况（A～B）和相应的阳性面积占比（C～D）。Control组，造模第1、5、8、11、15天腹腔注射100 μL 0.9%氯化钠注射液；BLM组，造模第1、5、8、11、15天腹腔注射100 μL博来霉素（5 mg/mL）；BLM+PD-1组，造模第1、5、8、11、15天分别腹腔注射100 μL博来霉素（5 mg/mL）和PD-1单克隆抗体100 μL（2 mg/mL）。IL-17A，白细胞介素17A；α-SMA，平滑肌肌动蛋白α。n=3；与Control组相比，^****P＜0.000 1。

Figure 3 Immunohistochemical staining results of IL-17A and α-SMA in lung tissues of mice in each group
Note： Immunohistochemical staining of IL-17A and α-SMA in lung tissues of mice from control group， BLM group and BLM+PD-1 group on days 14， 21 and 28 post-modeling（A–B）， and the corresponding percentages of positive area（C–D）. Mice in the Control group received intraperitoneal （i.p.） injections of 100 μL of normal saline on days 1， 5， 8， 11， and 15 post-modeling. The BLM group was given i.p. injections of 100 μL of bleomycin （5 mg/mL） on the same schedule. The BLM+PD-1 group received i.p. co-injections of 100 μL of bleomycin （5 mg/mL） and 100 μL of anti-PD-1 monoclonal antibody （2 mg/mL） on days 1， 5， 8， 11， and 15 post-modeling. IL-17A， interleukin-17A； α-SMA， α- smooth muscle actin. n=3； Compared with Control group， ^****P < 0.000 1.

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免疫检查点抑制剂相关性肺炎小鼠模型的构建与评价

Construction and Evaluation of Mouse Models Simulating Immune Checkpoint Inhibitor-Associated Pneumonitis

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