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标题: 粒细胞集落刺激因子在哮喘中作用 [打印本页]

作者: wjh 时间: 2020-12-16 11:33
标题: 粒细胞集落刺激因子在哮喘中作用
本帖最后由 wjh 于 2020-12-16 11:36 编辑

朱敏姚欣

南京医科大学第一附属医院（江苏省人民医院） 210029

粒细胞集落刺激因子（G-CSF）是一种含有174个氨基酸的糖蛋白，可由多种细胞类型产生，包括单核细胞、成纤维细胞、内皮细胞、巨噬细胞和骨髓基质细胞等1。G-CSF最初被定义为造血生长因子，最早在1983年被提纯鉴定，并发现其可以直接作用于靶祖细胞，刺激骨髓中大量粒细胞祖细胞的初始增殖2-4。通过诱导祖细胞嗜中性粒细胞的发育和促进骨髓中性粒细胞的释放，G-CSF被认为是稳态粒细胞生成的关键调节剂5。G-CSF通常在循环中以低浓度存在，很难检测到，但在感染和炎症情况下，其水平显著升高6-8。

G-CSF受体及信号转导

G-CSF受体主要在早期髓样祖细胞，成熟的粒细胞，单核细胞/巨噬细胞上表达，在内皮细胞、T和B淋巴细胞上也有描述9-12。G-CSF通过其同源受体（GCSFR）通过多种信号转导途径促进细胞增殖分化和存活: G-CSF受体的近端细胞质结构域包含box 1和box 2基序，激活JAK转自磷酸化，进而导致STAT3和STAT5磷酸化，促进增殖和分化相关基因的表达；远端细胞质结构域包含可磷酸化的关键酪氨酸残基，并作为Src同源结构域2（SH2）蛋白质的对接位点，从而激活例如RAS–MAPK和PI3K–AKT信号转导途径13。

G-CSF在哮喘中的作用

中性粒细胞是哮喘的关键炎症细胞之一，通过释放弹性蛋白酶、金属蛋白酶、趋化因子等在哮喘发病机制中发挥重要作用，气道中性粒细胞增多与哮喘的严重程度相关，也与哮喘类固醇激素抵抗有关14。许多研究表明，G-CSF通过调节中性粒细胞生成在各种急慢性炎症中发挥重要调节作用5-8, 15。G-CSF通过扩大和增强吞噬作用16和调节炎症细胞因子/趋化因子的产生17，对先天免疫应答，特别是对单核细胞/巨噬细胞系统具有广泛的影响。而越来越多的证据显示，G-CSF在适应性免疫中也发挥着深远的调节作用。G-CSF介导伴随TH2细胞分化的抗炎反应，并在APC / T细胞相互作用的两极促进耐受性细胞群，在免疫耐受和调节中发挥重要作用18。NN Jarjour等人发现在哮喘急性发作期，G-CSF浓度升高19。肺apoA-I可通过G-CSF依赖性机制负调控OVA诱导的哮喘嗜中性气道炎症20。此外，G-CSF可能通过直接作用于气道2型固有淋巴样细胞（ILC2s）促进细胞因子产生，从而增加HDM的过敏性致敏；通过促进骨髓单核祖细胞群扩增，增加外周单核细胞衍生的树突状细胞池从而增强抗原呈递21。最近的研究表明，G-CSF与小鼠哮喘模型和人类嗜中性粒细胞性哮喘患者气道中的嗜中性粒细胞增多显著相关，G-CSF通过上调骨髓生成促进气道中性粒细胞增多，G-CSF和上游细胞因子是中性粒细胞哮喘潜在的诊断和治疗靶点22。

参考文献
1. Hareng L, Hartung T. Induction and regulation of endogenous granulocyte colony-stimulating factor formation. Biological chemistry 2002;383(10):1501-1517.
2. Nicola NA, Metcalf D, Matsumoto M, Johnson GR. Purification of a factor inducing differentiation in murine myelomonocytic leukemia cells. Identification as granulocyte colony-stimulating factor. The Journal of biological chemistry 1983;258(14):9017-9023.
3. Metcalf D, Nicola NA. Proliferative effects of purified granulocyte colony-stimulating factor (G-CSF) on normal mouse hemopoietic cells. Journal of cellular physiology 1983;116(2):198-206.
4. Whetton AD, Dexter TM. Myeloid haemopoietic growth factors. Biochimica et biophysica acta 1989;989(2):111-132.
5. Eyles JL, Hickey MJ, Norman MU, Croker BA, Roberts AW, Drake SF, et al. A key role for G-CSF-induced neutrophil production and trafficking during inflammatory arthritis. Blood 2008;112(13):5193-5201.
6. Hamilton JA. Colony-stimulating factors in inflammation and autoimmunity. Nature reviews Immunology 2008;8(7):533-544.
7. Eyles JL, Roberts AW, Metcalf D, Wicks IP. Granulocyte colony-stimulating factor and neutrophils--forgotten mediators of inflammatory disease. Nature clinical practice Rheumatology 2006;2(9):500-510.
8. Cornish AL, Campbell IK, McKenzie BS, Chatfield S, Wicks IP. G-CSF and GM-CSF as therapeutic targets in rheumatoid arthritis. Nature reviews Rheumatology 2009;5(10):554-559.
9. Demetri GD, Griffin JD. Granulocyte colony-stimulating factor and its receptor. Blood 1991;78(11):2791-2808.
10. Morikawa K, Morikawa S, Nakamura M, Miyawaki T. Characterization of granulocyte colony-stimulating factor receptor expressed on human lymphocytes. British journal of haematology 2002;118(1):296-304.
11. Sloand EM, Kim S, Maciejewski JP, Van Rhee F, Chaudhuri A, Barrett J, et al. Pharmacologic doses of granulocyte colony-stimulating factor affect cytokine production by lymphocytes in vitro and in vivo. Blood 2000;95(7):2269-2274.
12. Franzke A, Piao W, Lauber J, Gatzlaff P, Könecke C, Hansen W, et al. G-CSF as immune regulator in T cells expressing the G-CSF receptor: implications for transplantation and autoimmune diseases. Blood 2003;102(2):734-739.
13. Mehta HM, Glaubach T, Corey SJ. Systems approach to phagocyte production and activation: neutrophils and monocytes. Advances in experimental medicine and biology 2014;844:99-113.
14. Ray A, Kolls JK. Neutrophilic Inflammation in Asthma and Association with Disease Severity. Trends in immunology 2017;38(12):942-954.
15. Feghali CA, Wright TM. Cytokines in acute and chronic inflammation. Frontiers in bioscience : a journal and virtual library 1997;2:d12-26.
16. Bober LA, Grace MJ, Pugliese-Sivo C, Rojas-Triana A, Sullivan LM, Narula SK. The effects of colony stimulating factors on human monocyte cell function. International journal of immunopharmacology 1995;17(5):385-392.
17. Xu S, Höglund M, Hakansson L, Venge P. Granulocyte colony-stimulating factor (G-CSF) induces the production of cytokines in vivo. British journal of haematology 2000;108(4):848-853.
18. Franzke A. The role of G-CSF in adaptive immunity. Cytokine & growth factor reviews 2006;17(4):235-244.
19. Jarjour NN, Gern JE, Kelly EA, Swenson CA, Dick CR, Busse WW. The effect of an experimental rhinovirus 16 infection on bronchial lavage neutrophils. The Journal of allergy and clinical immunology 2000;105(6 Pt 1):1169-1177.
20. Dai C, Yao X, Keeran KJ, Zywicke GJ, Qu X, Yu ZX, et al. Apolipoprotein A-I attenuates ovalbumin-induced neutrophilic airway inflammation via a granulocyte colony-stimulating factor-dependent mechanism. American journal of respiratory cell and molecular biology 2012;47(2):186-195.
21. Patel DF, Peiró T, Bruno N, Vuononvirta J, Akthar S, Puttur F, et al. Neutrophils restrain allergic airway inflammation by limiting ILC2 function and monocyte-dendritic cell antigen presentation. Science immunology 2019;4(41).
22. Kim YM, Kim H, Lee S, Kim S, Lee JU, Choi Y, et al. Airway G-CSF identifies neutrophilic inflammation and contributes to asthma progression. The European respiratory journal 2020;55(2).

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