神经纤毛蛋白1负调控磷脂酰肌醇3-激酶/蛋白激酶B通路抑制肺成纤维细胞活化及其在小鼠肺纤维化中的作用研究

doi:10.12114/j.issn.1007-9572.2025.0204

中国全科医学 ›› 2026, Vol. 29 ›› Issue (26): 3788-3797.DOI: 10.12114/j.issn.1007-9572.2025.0204

神经纤毛蛋白1负调控磷脂酰肌醇3-激酶/蛋白激酶B通路抑制肺成纤维细胞活化及其在小鼠肺纤维化中的作用研究

程国仓¹^,², 贾元元¹, 赵停婷²^,³, 齐瑞鑫¹^,², 念苗苗¹^,², 陈娟¹^,²^,³^,^*()

1．750004　宁夏回族自治区银川市，宁夏医科大学总医院医学科学研究院临床病原微生物重点实验室
2．750004　宁夏回族自治区银川市，宁夏医科大学第一临床医学院
3．750004　宁夏回族自治区银川市，宁夏医科大学总医院呼吸与危重症医学科

收稿日期:2025-04-10 修回日期:2025-07-31 出版日期:2026-09-15 发布日期:2026-08-11
通讯作者: 陈娟
程国仓和贾元元为共同第一作者

作者贡献：
程国仓负责动物实验，数据采集，绘制图表和论文起草；贾元元负责细胞和分子生物学实验、数据分析和最终版本修订；赵停婷、齐瑞鑫、念苗苗负责临床血样收集和处理；陈娟负责文章的质量控制与审查，对文章整体负责。
基金资助:
国家自然科学基金资助项目(82460200); 宁夏自然科学基金资助项目(2022AAC03550); 中央引导地方科技发展专项(2024FRD05046); 宁夏重点研发计划项目(2023BEG02021)

Nrp1 Negatively Regulates PI3K/AKT Pathway to Inhibit the Activation of Lung Fibroblasts and Its Role in Mouse Pulmonary Fibrosis

CHENG Guocang¹^,², JIA Yuanyuan¹, ZHAO Tingting²^,³, QI Ruixin¹^,², NIAN Miaomiao¹^,², CHEN Juan¹^,²^,³^,^*()

1. Ningxia Key Laboratory of Clinical and Pathogenic Microorganisms, Institute of Medical Science, General Hospital of Ningxia Medical University, Yinchuan 750004, China
2. The First Clinical Medical College of Ningxia Medical University, Yinchuan 750004, China
3. Department of Respiratory and Critical Care Medicine, General Hospital of Ningxia Medical University, Yinchuan 750004, China

Received:2025-04-10 Revised:2025-07-31 Published:2026-09-15 Online:2026-08-11
Contact: CHEN Juan
About author:
CHENG Guocang and JIA Yuanyuan are co-first authors

摘要/Abstract

摘要： 背景特发性肺纤维化（IPF）发病机制复杂、治疗手段有限、预后差，因此寻找安全有效的治疗靶点至关重要。目的探究神经纤毛蛋白1（Nrp1）通过磷脂酰肌醇3-激酶/蛋白激酶B（PI3K/AKT）信号对小鼠肺成纤维细胞（MPFs）活化的调控作用，以及重组蛋白Nrp1对小鼠肺纤维化（PF）的治疗作用及安全性。方法从基因表达数据库（GEO数据库）下载数据集GSE150910、GSE218997、GSE173523、GSE47460和GSE32537，分析PF小鼠模型和IPF患者肺组织中Nrp1表达以及Nrp1与IPF患者肺功能指标的相关性。选取2022—2024年在宁夏医科大学总医院呼吸与危重症医学科确诊的IPF患者45例，以及同期在本院健康管理中心体检的健康对照者29例，采用游离RNA（cfRNA）测序分析IPF患者和健康对照者血浆Nrp1表达水平及其诊断效能。将MPFs分为对照组、转化生长因子β1（TGF-β1）组、Nrp1过表达组和TGF-β1+Nrp1过表达组，TGF-β1诱导MPFs活化，过表达Nrp1检测其对PI3K/AKT通路和α-平滑肌肌动蛋白(α-SMA）、波形蛋白Vimentin（Vim）和纤连蛋白Fibronection（Fn）表达的影响。将30只雄性C57BL/6J小鼠随机分为对照组、博来霉素（BLM）组、BLM+Nrp1组，每组10只。构建小鼠PF模型后，BLM+Nrp1组连续20 d腹腔注射100 μg·kg-1·d-1的重组蛋白Nrp1。采用HE和Masson染色观察小鼠肺组织病理变化，评估小鼠肝肾功能指标，采用Western blotting和免疫组化检测肺组织中α-SMA、Vim和Fn表达，采用酶联免疫吸附试验（ELISA）测定血浆和支气管肺泡灌洗液（BALF）中Nrp1水平。结果数据集分析结果显示，与正常肺组织相比，PF小鼠和IPF患者肺组织中Nrp1表达降低（P<0.05），Nrp1表达与第1秒用力呼气量占预计值百分比（FEV1%pred）、用力肺活量占预计值百分比（FVC%pred）、一氧化碳弥散量占预计值百分比（DLCO%pred）呈正相关。IPF患者血浆Nrp1 mRNA表达水平低于健康对照者（P<0.05），血浆Nrp1诊断IPF的受试者工作特征曲线下面积为0.754（95%CI=0.634~0.874）。与TGF-β1组相比，TGF-β1+Nrp1过表达组中p-PI3K/PI3K、p-AKT/AKT表达降低，α-SMA、Vim和Fn表达降低（P<0.05）。腹腔注射重组蛋白Nrp1后，PF小鼠肺部病理特征改善，对照组、BLM组、BLM+Nrp1组血浆丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）、碱性磷酸酶（ALP）、血尿素氮（BUN）和肌酐（CREA）水平比较，差异均无统计学意义（P>0.05）。与BLM组比较，BLM+Nrp1组小鼠肺组织中α-SMA和Fn表达降低，血浆和BALF中Nrp1水平升高（P<0.05）。结论 IPF患者肺组织、血浆及BALF中Nrp1表达降低。Nrp1通过负向调控PI3K/AKT信号通路抑制小鼠肺成纤维细胞活化。腹腔注射重组Nrp1可以缓解小鼠肺纤维化，具有系统安全性。

关键词: 肺纤维化, 神经纤毛蛋白1, 肺成纤维细胞活化, 重组蛋白Nrp1

Abstract:

Background

Idiopathic pulmonary fibrosis (IPF) has a complex pathogenesis, limited treatment options and a poor prognosis. Therefore, it is crucial to identify the safe and effective therapeutic targets.

Objective

To investigate the regulatory effect of Nrp1 on the activation of mouse pulmonary fibroblasts (MPFs) through PI3K/AKT signaling pathway and the therapeutic effect and safety of recombinant Nrp1 protein on pulmonary fibrosis (PF) in mice.

Methods

GSE150910, GSE218997, GSE173523, GSE47460, and GSE32537 were downloaded from the GEO database to analyze the expression of Nrp1 in lung tissues of PF mouse models and IPF patients, as well as the correlation between Nrp1 expression and pulmonary function parameters in IPF patients. A total of 45 IPF patients diagnosed in the Department of Respiratory and Critical Care Medicine and 29 healthy controls who underwent physical examinations in the health management center in General Hospital of Ningxia Medical University from 2022 to 2024 were selected. Cell-free RNA (cfRNA) sequencing was used to analyze the expression levels of Nrp1 in the plasma of IPF patients and healthy controls and its diagnostic efficacy. MPFs were divided into the control group, TGF-β1 group, Nrp1 overexpression group and TGF-β1+Nrp1 overexpression group. TGF-β1 was used to induce the activation of MPFs, and the effects of Nrp1 overexpression on the PI3K/AKT pathway and the expression of α-SMA, Vim and Fn were detected. Thirty male C57BL/6J mice were randomly divided into the control group, BLM group and BLM+Nrp1 group, with 10 mice in each group. After establishing the mouse PF model, the BLM+Nrp1 group was intraperitoneally injected with 100 μg·kg^-1·d^-1 of recombinant Nrp1 protein for 20 consecutive days. HE and Masson staining were used to observe the pathological changes of mouse lung tissues, and liver and kidney function indicators were evaluated. Western blotting and immunohistochemistry were used to detect the expression of α-SMA, Vim and Fn in lung tissues. ELISA was used to measure the levels of Nrp1 in plasma and BALF.

Results

Compared with normal lung tissues, The expression of Nrp1 was decreased in the lung tissues of PF mouse and IPF patients (P<0.05), and the expression of Nrp1 was positively correlated with FEV₁%pred, FVC%pred and DLCO%pred. The mRNA expression of Nrp1 in plasma of IPF patients was significantly lower than that of healthy controls (P<0.05), and the area under the receiver operating characteristic curve of plasma Nrp1 for diagnosing IPF was 0.754 (95%CI=0.634-0.874). Compared with the TGF-β1 group, the ratios of p-PI3K/PI3K and p-AKT/AKT in the TGF-β1+Nrp1 overexpression group were decreased, and the expression of α-SMA, Vim and Fn was decreased (P<0.05). After intraperitoneal injection of recombinant Nrp1 protein, the pathological features of PF in mice were improved. There were no statistically significant differences in the levels of ALT, AST, ALP, BUN and CREA in plasma among the control group, BLM group and BLM+Nrp1 group (P>0.05). Compared with the BLM group, the expression of α-SMA and Fn in the lung tissues of the BLM + Nrp1 group was decreased, and the levels of Nrp1 in plasma and BALF were increased (P<0.05).

Conclusion

The expression of Nrp1 is decreased in the lung tissues, plasma and BALF of IPF patients. Nrp1 inhibits the activation of mouse pulmonary fibroblasts by negatively regulating the PI3K/AKT signaling pathway. Intraperitoneal injection of recombinant Nrp1 protein can alleviate pulmonary fibrosis in mice and exhibits systemic safety.

Key words: Pulmonary fibrosis, Neuropilin-1, Fibroblast activation, Recombinant Nrp1 protein

中图分类号:

R 563.13

程国仓,贾元元,赵停婷,等. 神经纤毛蛋白1负调控磷脂酰肌醇3-激酶/蛋白激酶B通路抑制肺成纤维细胞活化及其在小鼠肺纤维化中的作用研究[J]. 中国全科医学, 2026, 29(26): 3788-3797. DOI: 10.12114/j.issn.1007-9572.2025.0204.
CHENG Guocang,JIA Yuanyuan,ZHAO Tingting, et al. Nrp1 Negatively Regulates PI3K/AKT Pathway to Inhibit the Activation of Lung Fibroblasts and Its Role in Mouse Pulmonary Fibrosis[J]. Chinese General Practice, 2026, 29(26): 3788-3797. DOI: 10.12114/j.issn.1007-9572.2025.0204.

图/表 15

表1 引物序列

Table 1 Primer sequences

基因名称	基因ID	引物序列	产物长度（bp）
Nrp1	18186	F：CTCTCTCCACAAGGTTCATCAG	100
		R：GTAGGTGCTTCCACTTCACA
Fn	14268	F：GACTCATGGTGGCCACTAAATA	115
		R：CTTCTTGGAGGGCTAACATTCT
α-SMA	11475	F：TCAGGGAGTAATGGTTGGAATG	112
		R：GGTGATGATGCCGTGTTCTA
Vim	22352	F：CCCTGAACCTGAGAGAAACTAAC	93
		R：CTCTGGTCTCAACCGTCTTAATC
GAPDH	14433	F：GGTTGTCTCCTGCGACTTCA	183
		R：TGGTCCAGGGTTTCTTACTCC
β-actin	11461	F：TCATCCATGGCGAACTGGTG	92
		R：AAGGAAGGCTGGAAAAGAGC

图1 GEO数据集中Nrp1的基因表达及其与肺功能指标的相关性分析注：A为数据集GSE150910中，健康对照者和特发性肺纤维化患者肺组织中神经纤毛蛋白1（Nrp1）的基因表达水平；B和C为数据集GSE218997和GSE173523中，对照组和博来霉素组小鼠肺组织中Nrp1的基因表达水平；D和F为数据集GSE32537和GSE47460中，特发性肺纤维化患者支气管肺泡灌洗液（BALF）中Nrp1基因表达与一氧化碳弥散量占预计值百分比（DLCO%pred）的Spearman秩相关分析；E和G为数据集GSE32537和GSE47460中，特发性肺纤维化患者BALF中Nrp1基因表达与第1秒用力呼气容积占预计值百分比（FEV1%pred）的Spearman秩相关分析；H为数据集GSE47460中，特发性肺纤维化患者BALF中Nrp1基因表达与用力肺活量占预计值百分比（FVC%pred）的Spearman秩相关分析。

Figure 1 Analysis of Nrp1 gene expression and its correlation with pulmonary function parameters in GEO Datasets

表2 IPF患者与健康对照者基线资料比较

Table 2 Comparison of baseline characteristics between patients with idiopathic pulmonary fibrosis and healthy control

组别	例数	性别（男/女）	年龄[M（P₂₅，P₇₅），岁]	BMI（±s，kg/m²）	FVC（±s，L）	FVC%pred[M（P₂₅，P₇₅），%]	TLC（±s，L）	TLC%pred（±s，%）	DLCO%pred[M（P₂₅，P₇₅），%]
健康对照者	29	18/11	63（61，67）	25.1±3.1	3.60±0.70	111.50（88.45，120.25）	5.18±0.86	92.48±3.43	92.50（84.80，104.75）
特发性肺纤维化患者	45	27/18	66（62，70）	25.1±2.5	2.80±0.68	79.50（69.00，90.00）	4.48±0.86	71.81±11.70	53.00（44.00，64.00）
检验统计量值		0.032^a	539.000^b	0.072	3.737	86.000^b	1.536	3.481	8.000^b
P值		0.859	0.208	0.943	<0.001	<0.001	0.133	0.001	<0.001

图2 特发性肺纤维化患者与健康对照者血浆中Nrp1的表达及诊断效能注：A为细胞游离RNA（cfRNA）测序分析健康对照者与特发性肺纤维化患者外周血中Nrp1的基因表达水平；B为cfRNA测序分析健康对照者与特发性肺纤维化患者外周血中差异表达基因的火山图，红色点代表上调基因，蓝色点代表下调基因，灰色点代表无显著差异基因；C为Nrp1诊断特发性肺纤维化的受试者工作特征（ROC）曲线。

Figure 2 Nrp1 expression in plasma and its diagnostic performance in patients with idiopathic pulmonary fibrosis and healthy control

图3 对照组、TGF-β1组、Nrp1过表达组和TGF-β1+Nrp1过表达组α-SMA、Vim、Fn和Nrp1的蛋白表达注：A为Western blotting检测Nrp1过表达的效率；B为Western blotting检测对照组、TGF-β1组、Nrp1过表达组和TGF-β1+Nrp1过表达组α-平滑肌肌动蛋白（α-SMA）、波形蛋白Vimentin（Vim）、纤连蛋白Fibronection（Fn）和Nrp1的蛋白表达；TGF-β1=转化生长因子β1，GAPDH=甘油醛-3-磷酸脱氢酶；+表示使用TGF-β1，-表示未使用TGF-β1。

Figure 3 Protein expression levels of α-SMA, Vim, Fn and Nrp1 in the control group, TGF-β1 group, Nrp1 overexpression group and TGF-β1 + Nrp1 overexpression group

表3 对照组、TGF-β1组、Nrp1过表达组和TGF-β1+Nrp1过表达组α-SMA、Vim、Fn和Nrp1的mRNA表达水平比较（±s，n=3）

Table 3 Comparison of mRNA expression levels of α-SMA, Vim, Fn and Nrp1 in the control group, TGF-β1 group, Nrp1 overexpression group and TGF-β1+Nrp1 overexpression group

组别	α-SMA	Vim	Fn	Nrp1
对照组	1.000±0.016	1.000±0.065	1.000±0.020	1.000±0.050
TGF-β1组	1.378±0.105^a	1.003±0.026	2.508±0.061^a	0.294±0.010^a
Nrp1过表达组	0.801±0.067^a	0.844±0.041^a	0.592±0.009^a	2.132±0.015^a
TGF-β1+Nrp1过表达组	0.703±0.021^b	0.866±0.037^b	0.779±0.067^b	0.612±0.053^b
F值	65.63	10.88	1 057.00	1 360.00
P值	<0.000 1	0.003 4	<0.000 1	<0.000 1

表4 对照组、TGF-β1组、Nrp1过表达组和TGF-β1+Nrp1过表达组α-SMA、Vim、Fn和Nrp1蛋白表达水平比较（±s，n=3）

Table 4 Comparison of protein expression levels of α-SMA, Vim, Fn and Nrp1 in the control group, TGF-β1 group, Nrp1 overexpression group and TGF-β1+Nrp1 overexpression group

组别	α-SMA	Vim	Fn	Nrp1
对照组	1.000±0.035	1.000±0.019	1.000±0.022	1.000±0.030
TGF-β1组	1.396±0.014^a	1.101±0.023	1.546±0.039^a	0.744±0.042^a
Nrp1过表达组	0.136±0.029^a	0.553±0.035^a	0.185±0.006^a	1.368±0.023^a
TGF-β1+Nrp1过表达组	0.349±0.032^b	0.668±0.037^b	0.268±0.006^b	1.394±0.026^b
F值	1 225.00	236.70	2 364.00	300.60
P值	<0.000 1	<0.000 1	<0.000 1	<0.000 1

图4 对照组、TGF-β1组、Nrp1过表达组和TGF-β1+Nrp1过表达组p-PI3K、PI3K、p-AKT和AKT的蛋白表达注：p-PI3K=磷酸化磷脂酰肌醇3-激酶，PI3K=磷脂酰肌醇3-激酶，p-AKT=磷酸化蛋白激酶B，AKT=蛋白激酶B；+表示使用TGF-β1，-表示未使用TGF-β1。

Figure 4 Protein expression levels of p-PI3K, PI3K, p-AKT and AKT in the control group, TGF-β1 group, Nrp1 overexpression group and TGF-β1+Nrp1 overexpression group

表5 对照组、TGF-β1组、Nrp1过表达组和TGF-β1+Nrp1过表达组p-PI3K/PI3K、p-AKT/AKT水平比较（±s，n=3）

Table 5 Comparison of protein expression levels of p-PI3K/PI3K and p-AKT/AKT in the control group, TGF-β1 group, Nrp1 overexpression group and TGF-β1+Nrp1 overexpression group

组别	p-PI3K/PI3K	p-AKT/AKT
对照组	1.000±0.009	1.000±0.006
TGF-β1组	2.900±0.171^a	1.429±0.060^a
Nrp1过表达组	0.687±0.121^a	0.935±0.023
TGF-β1+Nrp1过表达组	0.820±0.013^b	0.915±0.036^b
F值	428.60	128.90
P值	<0.000 1	<0.000 1

图5 对照组、BLM组、BLM+Nrp1组小鼠肺组织的HE染色和Masson染色（×40）注：BLM=博来霉素。

Figure 5 HE and Masson staining of mouse lung tissues among the control group, BLM group and BLM + Nrp1 group

表6 对照组、BLM组、BLM+Nrp1组小鼠血浆中ALT、AST、ALP、BUN和CREA水平比较（n=4）

Table 6 Comparison of levels of ALT, AST, ALP, BUN and CREA in the plasma of mice among the control group, BLM group and BLM+Nrp1 group

组别	ALT（±s，U/L）	AST（±s，U/L）	ALP（±s，U/L）	BUN[M（P₂₅，P₇₅），mmol/L]	CREA（±s，μmol/L）	BUN/CREA（±s）
对照组	33.350±5.639	93.150±7.490	81.500±34.857	9.000（8.475，9.800）	13.925±1.992	0.677±0.132
BLM组	23.275±5.010	105.820±19.032	89.750±42.680	7.800（7.450，7.825）	14.075±2.824	0.553±0.148
BLM+Nrp1组	39.400±25.549	105.650±14.389	96.250±25.171	8.450（7.500，9.250）	13.475±0.801	0.619±0.133
F（Z）值	1.122	1.014	0.179	2.100^a	0.093	0.808
P值	0.367	0.401	0.839	0.085	0.912	0.476

图6 免疫组化检测对照组、BLM组、BLM+Nrp1组小鼠肺脏中α-SMA、Nrp1蛋白的表达（×40）

Figure 6 Protein expression of α-SMA and Nrp1 in the lung tissue of mice among the control group, BLM group and BLM + Nrp1 group by immunohistochemistry

图7 Western blotting检测对照组、BLM组、BLM+Nrp1组小鼠肺组织Nrp1、α-SMA、Vim和Fn的蛋白表达注：β-actin=β肌动蛋白。

Figure 7 Protein expression of Nrp1, α-SMA, Vim and Fn in the lung tissue of mice among the control group, BLM group and BLM+Nrp1 group by Western blotting

表7 对照组、BLM组、BLM+Nrp1组小鼠肺脏中α-SMA、Vim、Fn、Nrp1蛋白表达水平比较（±s，n=3）

Table 7 Comparison of protein expression levels of α-SMA, Vim, Fn and Nrp1 in the lung tissue of mice among the control group, BLM group and BLM+Nrp1 group

组别	α-SMA	Vim	Fn	Nrp1
对照组	1.000±0.181	1.000±0.250	1.000±0.597	1.000±0.209
BLM组	1.875±0.268^a	2.602±0.051^a	12.650±0.893^a	0.363±0.067^a
BLM+Nrp1组	1.404±0.440	2.317±0.215	6.365±3.043^b	0.564±0.379
F值	5.371	435.5	29.22	5.572
P值	0.046	<0.0001	0.008	0.043

表8 对照组、BLM组、BLM+Nrp1组小鼠BALF和血浆中Nrp1蛋白水平比较（±s）

Table 8 Comparison of Nrp1 protein levels in BALF and plasma of mice among the control group，BLM group and BLM+Nrp1 group

组别	只数	BALF	血浆
对照组	4	482.588±41.030	442.518±34.359
BLM组	4	292.586±38.597^a	205.975±97.804^a
BLM+Nrp1组	4	591.949±79.132^b	501.745±147.847^b
F值		9.450	27.37
P值		0.0061	0.0001

参考文献 25

[1]	Wan R Y, Wang L, Duan Y D, et al. ADRB2 inhibition combined with antioxidant treatment alleviates lung fibrosis by attenuating TGFβ/SMAD signaling in lung fibroblasts[J]. Cell Death Discov, 2023, 9(1): 407.
[2]	Zabihi M, Shahriari Felordi M, Lingampally A, et al. Understanding myofibroblast origin in the fibrotic lung[J]. Chin Med J Pulm Crit Care Med, 2024, 2(3): 142-150. DOI: 10.1016/j.pccm.2024.08.003.
[3]	Vásquez-Pacheco E, Marega M, Lingampally A, et al. Highlighting fibroblast plasticity in lung fibrosis: the WI-38 cell line as a model for investigating the myofibroblast and lipofibroblast switch[J]. Theranostics, 2024, 14(9): 3603-3622. DOI: 10.7150/thno.93519.
[4]	Glass D S, Grossfeld D, Renna H A, et al. Idiopathic pulmonary fibrosis: current and future treatment[J]. Clin Respir J, 2022, 16(2): 84-96. DOI: 10.1111/crj.13466.
[5]	Ma J, Li G, Wang H, et al. Comprehensive review of potential drugs with anti-pulmonary fibrosis properties[J]. Biomed Pharmacother, 2024, 173: 116282. DOI: 10.1016/j.biopha.2024.116282.
[6]	Barratt S L, Mulholland S, Al Jbour K, et al. South-west of England's experience of the safety and tolerability pirfenidone and nintedanib for the treatment of idiopathic pulmonary fibrosis(IPF)[J]. Front Pharmacol, 2018, 9: 1480. DOI: 10.3389/fphar.2018.01480.
[7]	Gulati S, Luckhardt T R. Updated evaluation of the safety, efficacy and tolerability of pirfenidone in the treatment of idiopathic pulmonary fibrosis[J]. Drug Healthc Patient Saf, 2020, 12: 85-94.
[8]	Broz M, Kolarič A, Jukič M, et al. Neuropilin(NRPs)related pathological conditions and their modulators[J]. Int J Mol Sci, 2022, 23(15): 8402. DOI: 10.3390/ijms23158402.
[9]	Valdembri D, Regano D, Maione F, et al. Class 3 semaphorins in cardiovascular development[J]. Cell Adh Migr, 2016, 10(6): 641-651.
[10]	Kazemi M, Carrer A, Moimas S, et al. VEGF121 and VEGF165 differentially promote vessel maturation and tumor growth in mice and humans[J]. Cancer Gene Ther, 2016, 23(5): 125-132.
[11]	Zhao J Q, Bai J, Peng F L, et al. USP9X-mediated NRP1 deubiquitination promotes liver fibrosis by activating hepatic stellate cells[J]. Cell Death Dis, 2023, 14(1): 40.
[12]	Yi J X, Gao H, Wei X F, et al. The transcription factor GATA3 positively regulates NRP1 to promote radiation-induced pulmonary fibrosis[J]. Int J Biol Macromol, 2024, 262(Pt 2): 130052.
[13]	佘炜, 魏江, 董丹丹, 等. NRP1调控M2型巨噬细胞极化介导电离辐射肺纤维化的作用研究[J]. 中国免疫学杂志, 2023, 39(2): 252-256. DOI: 10.3969/j.issn.1000-484X.2023.02.005.
[14]	Yombo D J K, Ghandikota S, Vemulapalli C P, et al. SEMA3B inhibits TGFβ-induced extracellular matrix protein production and its reduced levels are associated with a decline in lung function in IPF[J]. Am J Physiol Cell Physiol, 2024, 326(6): C1659-C1668.
[15]	Zhang J J, Qiu J X, Zhou W Y, et al. Neuropilin-1 mediates lung tissue-specific control of ILC2 function in type 2 immunity[J]. Nat Immunol, 2022, 23(2): 237-250.
[16]	Evyapan G, Senturk N C, Celik I S. Correction: ornidazole inhibits the angiogenesis and migration abilities of non-small cell lung cancer(NSCLC)via downregulation of VEGFA/VEGFR2/NRP-1 and PI3K/AKT/mTOR pathways[J]. Cell Biochem Biophys, 2025, 83(1): 1325. DOI: 10.1007/s12013-024-01501-8.
[17]	Wang L, Feng Y M, Xie X Y, et al. Neuropilin-1 aggravates liver cirrhosis by promoting angiogenesis via VEGFR2-dependent PI3K/Akt pathway in hepatic sinusoidal endothelial cells[J]. EBioMedicine, 2019, 43: 525-536. DOI: 10.1016/j.ebiom.2019.04.050.
[18]	Raghu G, Remy-Jardin M, Myers J L, et al. Diagnosis of idiopathic pulmonary fibrosis. an official ATS/ERS/JRS/ALAT clinical practice guideline[J]. Am J Respir Crit Care Med, 2018, 198(5): e44-e68.
[19]	Farkas L, Horowitz J C, Mora A L. How a fibroblast ages: a role for bone morphogenetic protein 4 in protecting lung fibroblasts from senescence in pulmonary fibrosis[J]. Eur Respir J, 2022, 60(6): 2201702. DOI: 10.1183/13993003.01702-2022.
[20]	Ng B, Dong J R, D'Agostino G, et al. Interleukin-11 is a therapeutic target in idiopathic pulmonary fibrosis[J]. Sci Transl Med, 2019, 11(511): eaaw1237. DOI: 10.1126/scitranslmed.aaw1237.
[21]	梅倩茹. 抑制剂XI-011靶向MDM4治疗特发性肺纤维化[D]. 武汉: 华中科技大学, 2024.
[22]	董卓. NRP1基因特异性敲除对放射性肺纤维化进程的影响及其作用机制[D]. 长春: 吉林大学, 2020.
[23]	Fu J W, He J Y, Zhang L M, et al. Comprehensive analysis and immunohistochemistry localization of NRP1 expression in pancancer and normal individual tissues in relation to SARS-CoV-2 susceptibility[J]. Exp Ther Med, 2023, 27(2): 52.
[24]	Wang H T, Sun K, Peng H, et al. Emerging roles of noncoding RNAs in idiopathic pulmonary fibrosis[J]. Cell Death Discov, 2024, 10(1): 443. DOI: 10.1038/s41420-024-02170-5.
[25]	Liu C, Somasundaram A, Manne S, et al. Neuropilin-1 is a T cell memory checkpoint limiting long-term antitumor immunity[J]. Nat Immunol, 2020, 21(9): 1010-1021.

神经纤毛蛋白1负调控磷脂酰肌醇3-激酶/蛋白激酶B通路抑制肺成纤维细胞活化及其在小鼠肺纤维化中的作用研究

Nrp1 Negatively Regulates PI3K/AKT Pathway to Inhibit the Activation of Lung Fibroblasts and Its Role in Mouse Pulmonary Fibrosis

RichHTML

PDF

可视化

摘要/Abstract

引用本文

使用本文

图/表 15

参考文献 25

相关文章 11

编辑推荐

Metrics

留言

[1]	毛瑞晓, 冯贞贞, 刘文瑞, 王佳佳, 李建生. 近30年特发性肺纤维化中医证候时空演变规律分析[J]. 中国全科医学, 2026, 29(19): 2678-2687.
[2]	张明悦, 侯艳. 呼出气、肺泡气一氧化氮在间质性肺疾病中的研究进展[J]. 中国全科医学, 2026, 29(18): 2571-2576.
[3]	杨其芬, 赵惠亮, 郭永胜, 渠景连. Jagged1/Notch1信号通路对特发性肺纤维化过程中内皮间质转化的影响研究[J]. 中国全科医学, 2025, 28(25): 3151-3160.
[4]	黄丽惠, 舒娟, 陶会会, 包海荣. 新型冠状病毒诱发的炎症后肺纤维化治疗新进展[J]. 中国全科医学, 2024, 27(32): 4085-4092.
[5]	徐莉莉, 洪赟晢, 李智慧, 于宁霞, 邸家琪, 杨曙光, 林青青, 余学庆. 特发性肺纤维化预后标志物的研究进展[J]. 中国全科医学, 2023, 26(03): 372-379.
[6]	蔡博，陈娴秋，杨文兰，杨光红，黄劲，全华，冯永红. 性别-年龄-肺功能分期与复合生理指数对特发性肺纤维化患者死亡风险的预测价值比较研究[J]. 中国全科医学, 2021, 24(35): 4485-4491.
[7]	曾茂君，申婕，曾志辉，赵明一，旷寿金. 儿童特发性肺含铁血黄素沉着症三例误诊及诊断思路分析[J]. 中国全科医学, 2019, 22(14): 1751-1754.
[8]	谢洋1，2，赵虎雷2，王佳佳2，王明航1，2. 特发性肺纤维化患者报告结局测评工具文献研究[J]. 中国全科医学, 2018, 21(5): 604-610.
[9]	刘锐，何嘉，梁梓扬，刘秀芳，侯体保，伍娟娟. 麦门冬汤对肺纤维化模型大鼠肺组织转化生长因子β1和基质金属蛋白酶9及基质金属蛋白酶组织抑制剂1表达的影响研究[J]. 中国全科医学, 2018, 21(29): 3590-3596.
[10]	彭守春, 李学任. 特发性肺纤维化患者临床和肺生理指标的变化及其与预后关联性的研究[J]. 中国全科医学, 2016, 19(35): 4338-4345.
[11]	孙辉，李建生，谢洋. 重视特发性肺纤维化的并发症[J]. 中国全科医学, 2015, 18(26): 3248-3252.