膜联蛋白A1在呼吸系统疾病中的研究进展

doi:10.12114/j.issn.1007-9572.2024.0154

摘要/Abstract

摘要： 膜联蛋白A1（ANXA1）是一种强大的抗炎蛋白，在呼吸系统疾病中的研究进展日益引起关注。研究表明，ANXA1可能通过调节炎症反应、清除氧化应激物质、影响细胞凋亡参与呼吸系统疾病的病理生理过程。但目前ANXA1参与上述疾病过程的研究缺乏有效的整合。本文通过归纳近年来相关文献，系统、全面地总结了ANXA1对慢性阻塞性肺疾病（以下简称慢阻肺）、哮喘、肺纤维化、肺缺血再灌注损伤和肺癌的影响，探讨了ANXA1参与上述疾病发生进展的作用机制。研究表明，ANXA1通过调控多种炎症信号通路，参与抑制白细胞的迁移、黏附及中性粒细胞凋亡，发挥抗炎作用，抑制哮喘气道高反应性，减轻慢阻肺肺部炎症、改善肺纤维化。此外，ANXA1还影响肿瘤细胞的增殖、转移和侵袭。本文能够为ANXA1在呼吸系统疾病的治疗提供一定的参考，为深入研究提供借鉴。

关键词: 呼吸道疾病, 膜联蛋白A1, 炎症, 纤维化, 哮喘, 慢性阻塞性肺疾病

Abstract:

Annexin A1 (ANXA1) is a potent anti-inflammatory protein, and research progress regarding its role in respiratory diseases has increasingly attracted attention. Research indicates that ANXA1 may participate in the pathophysiological process of respiratory diseases by regulating inflammatory response, clearing oxidative stress substances, and influencing cell apoptosis. However, there is currently a lack of effective integration in the research on ANXA1's involvement in the aforementioned disease processes. This article systematically and comprehensively summarizes the effects of ANXA1 on chronic obstructive pulmonary disease (COPD), asthma, pulmonary fibrosis, lung ischemia-reperfusion injury and lung cancer by reviewing relevant literature from recent years. It explores the mechanisms by which ANXA1 is involved in the occurrence and progression of these diseases. Research shows that ANXA1 exerts anti-inflammatory effects by regulating various inflammatory signaling pathways, participating in the inhibition of leukocyte migration, adhesion, and neutrophil apoptosis, suppressing airway hyperreactivity in asthma, alleviating pulmonary inflammation in COPD, and improving pulmonary fibrosis. In addition, ANXA1 also affects the proliferation, metastasis, and invasion of tumor cells. This article can provide a reference for the treatment of ANXA1 in respiratory diseases and serve as a guide for further in-depth research.

Key words: Respiratory tract diseases, Annexin A1, Inflammation, Fibrosis, Asthma, Chronic obstructive pulmonary disease

中图分类号:

R 725.6

谭会会,毛伟,杨子涵. 膜联蛋白A1在呼吸系统疾病中的研究进展[J]. 中国全科医学, 2025, 28(13): 1668-1673. DOI: 10.12114/j.issn.1007-9572.2024.0154.
TAN Huihui,MAO Wei,YANG Zihan. Research Progress of Annexin A1 in Respiratory Diseases[J]. Chinese General Practice, 2025, 28(13): 1668-1673. DOI: 10.12114/j.issn.1007-9572.2024.0154.

参考文献 30

[31]	BOUDHRAA Z，RONDEPIERRE F，OUCHCHANE L，et al. Annexin A1 in primary tumors promotes melanoma dissemination[J]. Clin Exp Metastasis，2014，31（7）：749-760.
[32]	RODRIGO J P，GARCIA-PEDRERO J M，FERNANDEZ M P，et al. Annexin A1 expression in nasopharyngeal carcinoma correlates with squamous differentiation[J]. Am J Rhinol，2005，19（5）：483-487.
[33]	XIAO D，ZENG T，ZHU W，et al. ANXA1 promotes tumor immune evasion by binding PARP1 and upregulating Stat3-induced expression of PD-L1 in multiple cancers[J]. Cancer Immunol Res，2023，11（10）：1367-1383.
[34]	LEE S H，LEE P H，KIM B G，et al. Annexin A1 in plasma from patients with bronchial asthma：its association with lung function[J]. BMC Pulm Med，2018，18（1）：1.
[35]	GRANELL R，CURTIN J A，HAIDER S，et al. A meta-analysis of genome-wide association studies of childhood wheezing phenotypes identifies ANXA1 as a susceptibility locus for persistent wheezing[J]. eLife，2023，12：e84315. DOI：10.7554/eLife.84315.
[36]	FERREIRA T P T，GUIMARÃES F V，SÁ Y A P J，et al. Annexin-A1-derived peptide Ac2-26 suppresses allergic airway inflammation and remodelling in mice[J]. Cells，2022，11（5）：759. DOI：10.3390/cells11050759.
[37]	LEBRON I S L，DA SILVA L F，PALETTA J T，et al. Modulation of the endogenous annexin A1 in a cigarette smoke cessation model：potential therapeutic target in reversing the damage caused by smoking?[J]. Pathol Res Pract，2019，215（10）：152614.
[38]	SANT'ANA M，SOUZA H R，POSSEBON L，et al. Effect of piperlongumine during exposure to cigarette smoke reduces inflammation and lung injury[J]. Pulm Pharmacol Ther，2020，61：101896. DOI：10.1016/j.pupt.2020.101896.
[39]	LAI T W，LI Y Y，MAI Z J，et al. Annexin A1 is elevated in patients with COPD and affects lung fibroblast function[J]. Int J Chron Obstruct Pulmon Dis，2018，13：473-486.
[40]	CAI J，CHEN X Y，LIU X Y，et al. AMPK：The key to ischemia-reperfusion injury[J]. J Cell Physiol，2022，237（11）：4079-4096. DOI：10.1002/jcp.30875.
[41]	CAPUZZIMATI M，HOUGH O，LIU M Y. Cell death and ischemia-reperfusion injury in lung transplantation[J]. J Heart Lung Transplant，2022，41（8）：1003-1013.
[42]	LIAO W I，WU S Y，WU G C，et al. Ac2-26，an annexin A1 peptide，attenuates ischemia-reperfusion-induced acute lung injury[J]. Int J Mol Sci，2017，18（8）：1771.
[43]	RUARO B，SALTON F，BRAGA L，et al. The history and mystery of alveolar epithelial type II cells：focus on their physiologic and pathologic role in lung[J]. Int J Mol Sci，2021，22（5）：2566.
[44]	ZHANG J J，ZHOU J R，YU Y F，et al. Sesamin induces the transdifferentiation of type II alveolar epithelial cells via AnnexinA1 and TRPV1[J]. Lung，2023，201（1）：65-77.
[45]	SHIHATA W A，PUTRA M R A，CHIN-DUSTING J P F. Is there a potential therapeutic role for caveolin-1 in fibrosis?[J]. Front Pharmacol，2017，8：567. DOI：10.3389/fphar.2017.00567.
[46]	YAN Z B，CHENG X R，WANG T，et al. Therapeutic potential for targeting Annexin A1 in fibrotic diseases[J]. Genes Dis，2022，9（6）：1493-1505. DOI：10.1016/j.gendis.2022.05.038.
[47]	KUROSU K，TAKIGUCHI Y，OKADA O，et al. Identification of annexin 1 as a novel autoantigen in acute exacerbation of idiopathic pulmonary fibrosis[J]. J Immunol，2008，181（1）：756-767.
[48]	DAMAZO A S，SAMPAIO A L，NAKATA C M，et al. Endogenous annexin A1 counter-regulates bleomycin-induced lung fibrosis[J]. BMC Immunol，2011，12：59.
[1]	THE LANCET. GBD 2017：a fragile world[J]. Lancet，2018，392（10159）：1683. DOI：10.1016/s0140-6736(18)32858-7.
[2]	COLLABORATORS G C R D. Prevalence and attributable health burden of chronic respiratory diseases，1990-2017：a systematic analysis for the global burden of disease study 2017[J]. Lancet Respir Med，2020，8（6）：585-596.
[3]	ABOUMSALLEM J P，SHI C X，DE WIT S，et al. Multi-omics analyses identify molecular signatures with prognostic values in different heart failure aetiologies[J]. J Mol Cell Cardiol，2023，175：13-28. DOI：10.1016/j.yjmcc.2022.12.001.
[4]	ZHANG L L，SHAO L B，LI J J，et al. Annexin A1-loaded alginate hydrogel promotes cardiac repair via modulation of macrophage phenotypes after myocardial infarction[J]. ACS Biomater Sci Eng，2024，10（5）：3232-3241.
[5]	ADEL F W，RIKHI A，WAN S H，et al. Annexin A1 is a potential novel biomarker of congestion in acute heart failure[J]. J Card Fail，2020，26（8）：727-732. DOI：10.1016/j.cardfail.2020.05.012.
[6]	NI C P，GAO S，ZHENG Y L，et al. Annexin A1 attenuates neutrophil migration and IL-6 expression through Fpr2 in a mouse model of Streptococcus suis-induced meningitis[J]. Infect Immun，2021，89（3）：e00680-20.
[7]	CHEN J M，OGGERO S，CECCONELLO C，et al. The Annexin-A1 mimetic RTP-026 promotes acute cardioprotection through modulation of immune cell activation[J]. Pharmacol Res，2023，198：107005. DOI：10.1016/j.phrs.2023.107005.
[8]	GERKE V，MOSS S E. Annexins：from structure to function[J]. Physiol Rev，2002，82（2）：331-371.
[9]	DE COUPADE C，SOLITO E，LEVINE J D. Dexamethasone enhances interaction of endogenous annexin 1 with L-selectin and triggers shedding of L-selectin in the monocytic cell line U-937[J]. Br J Pharmacol，2003，140（1）：133-145.
[10]	DE SOUZA FERREIRA L P，DA SILVA R A，GIL C D，et al. Annexin A1，A2，A5，and A6 involvement in human pathologies[J]. Proteins，2023，91（9）：1191-1204. DOI：10.1002/prot.26512.
[49]	TRENTIN P G，FERREIRA T P T，ARANTES A C S，et al. Annexin A1 mimetic peptide controls the inflammatory and fibrotic effects of silica particles in mice[J]. Br J Pharmacol，2015，172（12）：3058-3071. DOI：10.1111/bph.13109.
[50]	JIA Y，MORAND E F，SONG W Q，et al. Regulation of lung fibroblast activation by annexin A1[J]. J Cell Physiol，2013，228（2）：476-484. DOI：10.1002/jcp.24156.
[51]	BRAY F，FERLAY J，SOERJOMATARAM I，et al. Global cancer statistics 2018：GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin，2018，68（6）：394-424. DOI：10.3322/caac.21492.
[52]	RONG B X，CAI X G，LIU H，et al. Increased level of annexin A1 in bronchoalveolar lavage fluid as a potential diagnostic indicator for lung cancer[J]. Int J Biol Markers，2017，32（1）：e132-140.
[53]	ELAKAD O，LI Y C，GIESER N，et al. Role of annexin A1 in squamous cell lung cancer progression[J]. Dis Markers，2021，2021：5520832. DOI：10.1155/2021/5520832.
[54]	DENG C M，LIU X H，ZHANG C Q，et al. ANXA1-GSK3β interaction and its involvement in NSCLC metastasis[J]. Acta Biochim Biophys Sin，2021，53（7）：912-924.
[55]	GUAN X Y，FANG Y，LONG J，et al. Annexin 1-nuclear factor-κB-microRNA-26a regulatory pathway in the metastasis of non-small cell lung cancer[J]. Thorac Cancer，2019，10（4）：665-675. DOI：10.1111/1759-7714.12982.
[56]	FANG Y，GUAN X Y，CAI T H，et al. Knockdown of ANXA1 suppresses the biological behavior of human NSCLC cells in vitro[J]. Mol Med Rep，2016，13（5）：3858-3866.
[57]	YU Z Z，LIU Y Y，ZHU W，et al. ANXA1-derived peptide for targeting PD-L1 degradation inhibits tumor immune evasion in multiple cancers[J]. J Immunother Cancer，2023，11（3）：e006345. DOI：10.1136/jitc-2022-006345.
[11]	XIAO D，ZENG T，ZHU W，et al. ANXA1 promotes tumor immune evasion by binding PARP1 and upregulating Stat3-induced expression of PD-L1 in multiple cancers[J]. Cancer Immunol Res，2023，11（10）：1367-1383.
[12]	CUI Y F，YANG S Y. Overexpression of Annexin A1 protects against benzo [a] Pyrene-induced bronchial epithelium injury[J]. Mol Med Rep，2018，18（1）：349-357.
[13]	NG F S P，WONG K Y，GUAN S P，et al. Annexin-1-deficient mice exhibit spontaneous airway hyperresponsiveness and exacerbated allergen-specific antibody responses in a mouse model of asthma[J]. Clin Exp Allergy，2011，41（12）：1793-1803.
[14]	LI Y Z，WANG Y Y，HUANG L，et al. Annexin A protein family in atherosclerosis[J]. Clin Chim Acta，2022，531：406-417.
[15]	ZHANG H H，ZHANG Z，GUO T T，et al. Annexin A protein family：Focusing on the occurrence，progression and treatment of cancer[J]. Front Cell Dev Biol，2023，11：1141331.
[16]	SUGIMOTO M A，VAGO J P，TEIXEIRA M M，et al. Annexin A1 and the resolution of inflammation：modulation of neutrophil recruitment，apoptosis，and clearance[J]. J Immunol Res，2016，2016：8239258. DOI：10.1155/2016/8239258.
[17]	PURVIS G S D，SOLITO E，THIEMERMANN C. Annexin-A1：therapeutic potential in microvascular disease[J]. Front Immunol，2019，10：938. DOI：10.3389/fimmu.2019.00938.
[18]	SHEN X，ZHANG S，GUO Z，et al. The crosstalk of ABCA1 and ANXA1：a potential mechanism for protection against atherosclerosis[J]. Mol Med，2020，26（1）：84.
[19]	ROSENGARTH A，GERKE V，LUECKE H. X-ray structure of full-length annexin 1 and implications for membrane aggregation[J]. J Mol Biol，2001，306（3）：489-498.
[20]	BOUDHRAA Z，BOUCHON B，VIALLARD C，et al. Annexin A1 localization and its relevance to cancer[J]. Clin Sci，2016，130（4）：205-220. DOI：10.1042/CS20150415.
[21]	ARCONE R，ARPAIA G，RUOPPOLO M，et al. Structural characterization of a biologically active human lipocortin 1 expressed in Escherichia coli[J]. Eur J Biochem，1993，211（1/2）：347-355. DOI：10.1111/j.1432-1033.1993.tb19904.x.
[22]	PERRETTI M，D’ACQUISTO F. Annexin A1 and glucocorticoids as effectors of the resolution of inflammation[J]. Nat Rev Immunol，2009，9（1）：62-70. DOI：10.1038/nri2470.
[23]	PARENTE L，SOLITO E. Annexin 1：more than an anti-phospholipase protein[J]. Inflamm Res，2004，53（4）：125-132.
[24]	FILEP J G. Biasing the lipoxin A4/formyl peptide receptor 2 pushes inflammatory resolution[J]. Proc Natl Acad Sci USA，2013，110（45）：18033-18034. DOI：10.1073/pnas.1317798110.
[25]	ZHENG Y L，LI Y，LI S，et al. Annexin A1（Ac2-26）-dependent Fpr2 receptor alleviates sepsis-induced acute kidney injury by inhibiting inflammation and apoptosis in vivo and in vitro[J]. Inflamm Res，2023，72（2）：347-362.
[26]	HAN P F，CHE X D，LI H Z，et al. Annexin A1 involved in the regulation of inflammation and cell signaling pathways[J]. Chin J Traumatol，2020，23（2）：96-101. DOI：10.1016/j.cjtee.2020.02.002.
[27]	BUSS N A P S，GAVINS F N E，COVER P O，et al. Targeting the annexin 1-formyl peptide receptor 2/ALX pathway affords protection against bacterial LPS-induced pathologic changes in the murine adrenal cortex[J]. FASEB J，2015，29（7）：2930-2942.
[28]	SOLITO E，KAMAL A，RUSSO-MARIE F，et al. A novel calcium-dependent proapoptotic effect of annexin 1 on human neutrophils[J]. FASEB J，2003，17（11）：1544-1546.
[29]	SCANNELL M，FLANAGAN M B，DESTEFANI A，et al. Annexin-1 and peptide derivatives are released by apoptotic cells and stimulate phagocytosis of apoptotic neutrophils by macrophages[J]. J Immunol，2007，178（7）：4595-4605.
[30]	VECCHI L，ALVES PEREIRA ZÓIA M，GOSS SANTOS T，et al. Inhibition of the AnxA1/FPR1 autocrine axis reduces MDA-MB-231 breast cancer cell growth and aggressiveness in vitro and in vivo[J]. Biochim Biophys Acta Mol Cell Res，2018，1865（9）：1368-1382. DOI：10.1016/j.bbamcr.2018.06.010.