白细胞介素-6在急性呼吸窘迫综合征中的生物学作用及治疗研究进展
Research Progress on the Biological Role and Treatment of Interleukin-6 in Acute Respiratory Distress Syndrome
DOI: 10.12677/acm.2024.1441031, PDF,   
作者: 李雨晴, 王导新*:重庆医科大学附属第二医院,呼吸与危重症医学科,重庆
关键词: 急性呼吸窘迫综合征白细胞介素-6信号通路Acute Respiratory Distress Syndrome Interleukin 6 Signalling Pathway
摘要: 急性呼吸窘迫综合征(ARDS)是一种严重急性肺损伤(ALI)的状态,其特征是短时间内弥漫性肺损伤、双侧肺水肿和顽固性低氧血症,目前尚无特异性治疗方法。白细胞介素-6 (IL-6)是一种能与自身受体结合形成复合物并通过信号传导发挥生物学作用的多功能细胞因子,在临床上与ARDS的发生、发展和预后密切相关。现有研究发现ARDS患者循环IL-6水平明显升高,并且与疾病严重程度呈正相关。在脂多糖诱导的急性肺损伤模型中,使用IL-6信号转导抑制剂显著减少了促炎细胞因子的释放。因此,靶向IL-6信号传导可能是治疗ARDS的有效方法。为了更深入理解IL-6在ARDS中的作用,该综述主要对IL-6的生物学特性、IL-6不同受体介导的信号转导机制以及目前靶向IL-6信号治疗的研究进展进行详细阐述,旨在为进一步以IL-6信号通路为靶点的ARDS药物研究提供理论依据。
Abstract: Acute respiratory distress syndrome (ARDS) is a state of severe acute lung injury (ALI) characterised by diffuse lung injury in a short period, bilateral pulmonary oedema and refractory hypoxaemia. There is currently no specific treatment for ARDS. Interleukin 6 (IL-6) is a multifunctional cytokine that binds to the receptors to form a complex and exerts biological effects through signaling pathway, which is clinically associated with the onset, development and prognosis of ARDS. Studies have shown that circulating levels of IL-6 are significantly elevated in ARDS patients and correlated with the severity of the disease. A reduction in the release of pro-inflammatory cytokines was observed by inhibiting IL-6 signalling in a lipopolysaccharide-induced acute lung injury model. Therefore, targeting the IL-6 signaling may be an effective approach for ARDS treatment. For a deeper understanding of the role of IL-6 in ARDS, the review elaborated on the biological properties of IL-6, the signalling mechanisms mediated by different receptors and current research progress in IL-6 signaling targeted therapy, which aims to provide a theoretical basis for further drug research targeting the IL-6 signalling pathway.
文章引用:李雨晴, 王导新. 白细胞介素-6在急性呼吸窘迫综合征中的生物学作用及治疗研究进展[J]. 临床医学进展, 2024, 14(4): 364-371. https://doi.org/10.12677/acm.2024.1441031

参考文献

[1] Matthay, M.A., Arabi, Y., Arroliga, A.C., et al. (2024) A New Global Definition of Acute Respiratory Distress Syndrome. American Journal of Respiratory and Critical Care Medicine, 209, 37-47. [Google Scholar] [CrossRef
[2] Meyer, N.J., Gattinoni, L. and Calfee, C.S. (2021) Acute Respiratory Distress Syndrome. The Lancet, 398, 622-637. [Google Scholar] [CrossRef
[3] Bellani, G., Laffey, J.G., Pham, T., et al. (2016) Epidemiology, Patterns of Care, and Mortality for Patients with Acute Respiratory Distress Syndrome in Intensive Care Units in 50 Countries. JAMA, 315, 788-800. [Google Scholar] [CrossRef] [PubMed]
[4] Bos, L.D.J. and Ware, L.B. (2022) Acute Respiratory Distress Syndrome: Causes, Pathophysiology, and Phenotypes. Lancet, 400, 1145-1156. [Google Scholar] [CrossRef
[5] McElvaney, O.J., Curley, G.F., Rose-John, S., et al. (2021) Interleukin-6: Obstacles to Targeting a Complex Cytokine in Critical Illness. The Lancet Respiratory Medicine, 9, 643-654. [Google Scholar] [CrossRef
[6] Meduri, G.U., Headley, S., Kohler, G., et al. (1995) Persistent Elevation of Inflammatory Cytokines Predicts a Poor Outcome in ARDS. Plasma IL-1 Beta and IL-6 Levels Are Consistent and Efficient Predictors of Outcome over Time. Chest, 107, 1062-1073. [Google Scholar] [CrossRef] [PubMed]
[7] Lin, W.C., Lin, C.F., Chen, C.L., et al. (2010) Prediction of Outcome in Patients with Acute Respiratory Distress Syndrome by Bronchoalveolar Lavage Inflammatory Mediators. Experimental Biology and Medicine, 235, 57-65. [Google Scholar] [CrossRef] [PubMed]
[8] Hirano, T., Yasukawa, K., Harada, H., et al. (1986) Complementary DNA for a Novel Human Interleukin (BSF-2) That Induces B Lymphocytes to Produce Immunoglobulin. Nature, 324, 73-76. [Google Scholar] [CrossRef] [PubMed]
[9] Akdis, M., Aab, A., Altunbulakli, C., et al. (2016) Interleukins (From IL-1 to IL-38), Interferons, Transforming Growth Factor β, and TNF-α: Receptors, Functions, and Roles in Diseases. The Journal of Allergy and Clinical Immunology, 138, 984-1010. [Google Scholar] [CrossRef] [PubMed]
[10] Jones, S.A. and Jenkins, B.J. (2018) Recent Insights into Targeting the IL-6 Cytokine Family in Inflammatory Diseases and Cancer. Nature Reviews Immunology, 18, 773-789. [Google Scholar] [CrossRef] [PubMed]
[11] Yu, H., Lee, H., Herrmann, A., et al. (2014) Revisiting STAT3 Signalling in Cancer: New and Unexpected Biological Functions. Nature Reviews Cancer, 14, 736-746. [Google Scholar] [CrossRef] [PubMed]
[12] Maggio M., Guralnik J.M., Longo D.L., et al (2006) Interleukin-6 in Aging and Chronic Disease: A Magnificent Pathway. The Journals of Gerontology: Series A, Biological Sciences and Medical Sciences, 61, 575-584. [Google Scholar] [CrossRef] [PubMed]
[13] Garbers, C., Kuck, F., Aparicio-Siegmund, S., et al. (2013) Cellular Senescence or EGFR Signaling Induces Interleukin 6 (IL-6) Receptor Expression Controlled by Mammalian Target of Rapamycin (MTOR). Cell Cycle, 12, 3421-3432. [Google Scholar] [CrossRef] [PubMed]
[14] Choy, E.H., De Benedetti, F., Takeuchi, T., et al. (2020) Translating IL-6 Biology into Effective Treatments. Nature Reviews Rheumatology, 16, 335-345. [Google Scholar] [CrossRef] [PubMed]
[15] Schmidt-Arras, D. and Rose-John, S. (2021) Endosomes as Signaling Platforms for IL-6 Family Cytokine Receptors. Frontiers in Cell and Developmental Biology, 9, Article 688314. [Google Scholar] [CrossRef] [PubMed]
[16] Rose-John, S., Jenkins, B.J., Garbers, C., et al. (2023) Targeting IL-6 Trans-Signalling: Past, Present and Future Prospects. Nature ReviewsImmunology, 23, 666-681. [Google Scholar] [CrossRef] [PubMed]
[17] Heinrich, P.C., Behrmann, I., Haan, S., et al. (2003) Principles of Interleukin (IL)-6-Type Cytokine Signalling and Its Regulation. The Biochemical Journal, 374, 1-20. [Google Scholar] [CrossRef] [PubMed]
[18] Heink, S., Yogev, N., Garbers, C., et al. (2016) Trans-Presentation of IL-6 by Dendritic Cells Is Required for the Priming of Pathogenic TH17 Cells. Nature Immunology, 18, 74-85. [Google Scholar] [CrossRef] [PubMed]
[19] Elahi, R., Karami, P., Heidary, A.H., et al. (2022) An Updated Overview of Recent Advances, Challenges, and Clinical Considerations of IL-6 Signaling Blockade in Severe Coronavirus Disease 2019 (COVID-19). International Immunopharmacology, 105, Article ID: 108536. [Google Scholar] [CrossRef] [PubMed]
[20] Saki, N., Javan, M., Moghimian-Boroujeni, B., et al. (2023) Interesting Effects of Interleukins and Immune Cells on Acute Respiratory Distress Syndrome. Clinical and Experimental Medicine, 23, 2979-2996. [Google Scholar] [CrossRef] [PubMed]
[21] Qin, M. and Qiu, Z. (2019) Changes in TNF-α, IL-6, IL-10 and VEGF in Rats with ARDS and the Effects of Dexamethasone. Experimental and Therapeutic Medicine, 17, 383-387. [Google Scholar] [CrossRef] [PubMed]
[22] Terpstra, M.L., Aman, J., van Nieuw Amerongen, G.P., et al. (2014) Plasma Biomarkers for Acute Respiratory Distress Syndrome: A Systematic Review and Meta-Analysis. Critical Care Medicine, 42, 691-700.
[23] Swaroopa, D., Bhaskar, K., Mahathi, et al. (2016) Association of Serum Interleukin-6, Interleukin-8, and Acute Physiology and Chronic Health Evaluation II Score with Clinical Outcome in Patients with Acute Respiratory Distress Syndrome. Indian Journal of Critical Care Medicine, 20, 518-525. [Google Scholar] [CrossRef] [PubMed]
[24] Chen, X., Zhao, B., Qu, Y., et al. (2020) Detectable Serum Severe Acute Respiratory Syndrome Coronavirus 2 Viral Load (RNAemia) Is Closely Correlated with Drastically Elevated Interleukin 6 Level in Critically Ill Patients with Coronavirus Disease 2019. Clinical Infectious Diseases, 71, 1937-1942. [Google Scholar] [CrossRef] [PubMed]
[25] Herold, T., Jurinovic, V., Arnreich, C., et al. (2020) Elevated Levels of IL-6 and CRP Predict the Need for Mechanical Ventilation in COVID-19. The Journal of Allergy and Clinical Immunology, 146, 128-136.E4. [Google Scholar] [CrossRef] [PubMed]
[26] Famous, K.R., Delucchi, K., Ware, L.B., et al. (2017) Acute Respiratory Distress Syndrome Subphenotypes Respond Differently to Randomized Fluid Management Strategy. American Journal of Respiratory and Critical Care Medicine, 195, 331-338. [Google Scholar] [CrossRef
[27] Calfee, C.S., Delucchi, K.L., Sinha, P., et al. (2018) Acute Respiratory Distress Syndrome Subphenotypes and Differential Response to Simvastatin: Secondary Analysis of a Randomised Controlled Trial. The Lancet Respiratory Medicine, 6, 691-698.
[28] Sinha, P., Furfaro, D., Cummings, M.J., et al. (2021) Latent Class Analysis Reveals COVID-19—Related Acute Respiratory Distress Syndrome Subgroups with Differential Responses to Corticosteroids. American Journal of Respiratory and Critical Care Medicine, 204, 1274-1285. [Google Scholar] [CrossRef
[29] Beitler, J.R., Thompson, B.T., Baron, R.M., et al. (2022) Advancing Precision Medicine for Acute Respiratory Distress Syndrome. The Lancet Respiratory Medicine, 10, 107-120. [Google Scholar] [CrossRef
[30] Recovery Collaborative Group (2021) Tocilizumab in Patients Admitted to Hospital with COVID-19 (RECOVERY): A Randomised, Controlled, Open-Label, Platform Trial. Lancet, 397, 1637-1645. [Google Scholar] [CrossRef
[31] Brunner, H.I., Ruperto, N., Zuber, Z., et al. (2015) Efficacy and Safety of Tocilizumab in Patients with Polyarticular-Course Juvenile Idiopathic Arthritis: Results from a Phase 3, Randomised, Double-Blind Withdrawal Trial. Annals of the Rheumatic Diseases, 74, 1110-1117. [Google Scholar] [CrossRef] [PubMed]
[32] Garbers, C., Heink, S., Korn, T., et al. (2018) Interleukin-6: Designing Specific Therapeutics for a Complex Cytokine. Nature Reviews Drug Discovery, 17, 395-412. [Google Scholar] [CrossRef] [PubMed]
[33] Aletaha, D., Kerschbaumer, A., Kastrati, K., et al. (2023) Consensus Statement on Blocking Interleukin-6 Receptor and Interleukin-6 in Inflammatory Conditions: An Update. Annals of the Rheumatic Diseases, 82, 773-787. [Google Scholar] [CrossRef] [PubMed]
[34] Sarıoğlu, N., Sunay, F.B., Yay, A., et al. (2021) Antiinflammatory Effects of Adalimumab, Tocilizumab, and Steroid on Lipopolysaccharide-Induced Lung Injury. Turkish Journal of Medical Sciences, 51, 2741-2751. [Google Scholar] [CrossRef] [PubMed]
[35] Boyce, E.G., Rogan, E.L., Vyas, D., et al. (2018) Sarilumab: Review of a Second IL-6 Receptor Antagonist Indicated for the Treatment of Rheumatoid Arthritis. The Annals of Pharmacotherapy, 52, 780-791. [Google Scholar] [CrossRef] [PubMed]
[36] Deisseroth, A., Ko, C.W., Nie, L., et al. (2015) FDA Approval: Siltuximab for the Treatment of Patients with Multicentric Castleman Disease. Clinical Cancer Research, 21, 950-954. [Google Scholar] [CrossRef
[37] Villaescusa, L., Zaragozá, F., Gayo-Abeleira, I., et al. (2022) A New Approach to the Management of COVID-19. Antagonists of IL-6: Siltuximab. Advances in Therapy, 39, 1126-1148. [Google Scholar] [CrossRef] [PubMed]
[38] Zia, K., Nur-E-Alam, M., Ahmad, A., et al. (2024) Taming the Cytokine Storm: Small Molecule Inhibitors Targeting IL-6/IL-6α Receptor. Molecular Diversity. https://Link.Springer.Com/Article/10.1007/S11030-023-10805-5#Sec17 [Google Scholar] [CrossRef] [PubMed]
[39] Zhang, S., Chen, B., Wang, B., et al. (2023) Effect of Induction Therapy with Olamkicept vs Placebo on Clinical Response in Patients with Active Ulcerative Colitis: A Randomized Clinical Trial. JAMA, 329, 725-734. [Google Scholar] [CrossRef] [PubMed]
[40] Xu, F., Wang, S., Wang, Y., et al. (2023) Inhibition of Gp130 Alleviates LPS-Induced Lung Injury by Attenuating Apoptosis and Inflammation through JAK1/STAT3 Signaling Pathway. Inflammation Research, 72, 493-507. [Google Scholar] [CrossRef] [PubMed]
[41] Rose-John, S. (2017) The Soluble Interleukin 6 Receptor: Advanced Therapeutic Options in Inflammation. Clinical Pharmacology and Therapeutics, 102, 591-598. [Google Scholar] [CrossRef] [PubMed]
[42] Saad, M.I. and Jenkins, B.J. (2024) The Protease ADAM17 at the Crossroads of Disease: Revisiting Its Significance in Inflammation, Cancer, and beyond. The FEBS Journal, 291, 10-24. [Google Scholar] [CrossRef] [PubMed]
[43] Schumacher, N. and Rose-John, S. (2019) ADAM17 Activity and IL-6 Trans-Signaling in Inflammation and Cancer. Cancers, 11, Article 1736. [Google Scholar] [CrossRef] [PubMed]
[44] Zunke, F. and Rose-John, S. (2017) the Shedding Protease ADAM17: Physiology and Pathophysiology. Biochimica et Biophysica Acta (BBA)—Molecular Cell Research, 1864, 2059-2070. [Google Scholar] [CrossRef] [PubMed]
[45] Wong, E., Cohen, T., Romi, E., et al. (2016) Harnessing the Natural Inhibitory Domain to Control TNFα Converting Enzyme (TACE) Activity in Vivo. Scientific Reports, 6, Article No. 35598. [Google Scholar] [CrossRef] [PubMed]
[46] Dreymueller, D., Martin, C., Kogel, T., et al. (2012) Lung Endothelial ADAM17 Regulates the Acute Inflammatory Response to Lipopolysaccharide. EMBO Molecular Medicine, 4, 412-423. [Google Scholar] [CrossRef] [PubMed]
[47] Lartey, N.L., Valle-Reyes, S., Vargas-Robles, H., et al. (2022) ADAM17/MMP Inhibition Prevents Neutrophilia and Lung Injury in a Mouse Model of COVID-19. Journal of Leukocyte Biology, 111, 1147-1158. [Google Scholar] [CrossRef