重症哮喘气道上皮细胞损伤机制及潜在生物治疗靶点_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

姚庆美 , 陈玥 , 黎友伦 ,  王丹

重庆医科大学附属第一医院呼吸与危重症医学科（重庆 400016）;

Corresponding author：

王丹, Email: wangdan@hospital.cqmu.edu.cn

Keywords：

DOI：

10.7507/1671-6205.202208033

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Citation： 姚庆美, 陈玥, 黎友伦, 王丹. 重症哮喘气道上皮细胞损伤机制及潜在生物治疗靶点. Chinese Journal of Respiratory and Critical Care Medicine, 2022, 21(12): 899-903. doi: 10.7507/1671-6205.202208033 Copy

1.	GINA. Global Strategy for Asthma Management and Prevention-Updated 2022[EB/OL]. [2022-04-03] Available at: www. ginasthma. org.
2.	Enilari O, Sinha S. The global impact of asthma in adult populations. Ann Glob Health, 2019, 85(1): 2.
3.	Chung KF, Wenzel SE, Brozek JL, et al. International ERS/ATS Guidelines on Definition, Evaluation and Treatment of Severe Asthma. Eur Respir J, 2014, 43(2): 343-373.
4.	Bourdin A, Fabry-Vendrand C, Ostinelli J, et al. The burden of severe asthma in France: a case-control study using a medical claims database. J Allergy Clin Immunol Pract, 2019, 7(5): 1477-1487.
5.	Xiao C, Puddicombe SM, Field S, et al. Defective epithelial barrier function in asthma. J Allergy Clin Immunol, 2011, 128(3): 549-556,e1-12.
6.	Vieira Braga FA, Kar G, Berg M, et al. A cellular census of human lungs identifies novel cell states in health and in asthma. Nat Med, 2019, 25(7): 1153-1163.
7.	Frey A, Lunding LP, Ehlers JC, et al. More than just a barrier: the immune functions of the airway epithelium in asthma pathogenesis. Front Immunol, 2020, 11: 761.
8.	Buckley A, Turner JR. Cell biology of tight junction barrier regulation and mucosal disease. Cold Spring Harb Perspect Biol, 2018, 10(1): a029314.
9.	Lee PH, Kim BG, Lee SH, et al. Alteration in claudin-4 contributes to airway inflammation and responsiveness in asthma. Allergy Asthma Immunol Res, 2018, 10(1): 25-33.
10.	Yang YM, Jia M, Ou YW, et al. Mechanisms and biomarkers of airway epithelial cell damage in asthma: a review. Clin Respir J, 2021, 15(10): 1027-1045.
11.	Aghasafari P, George U, Pidaparti R. A review of inflammatory mechanism in airway diseases. Inflamm Res, 2019, 68(1): 59-74.
12.	Georas SN, Rezaee F. Epithelial barrier function: at the front line of asthma immunology and allergic airway inflammation. J Allergy Clin Immunol, 2014, 134: 509-520.
13.	Potaczek DP, Miethe S, Schindler V, et al. Role of airway epithelial cells in the development of different asthma phenotypes. Cell Signal, 2020, 69: 109523.
14.	Lachowicz-Scroggins ME, Yuan SP, Kerr SC, et al. Abnormalities in MUC5AC and MUC5B protein in airway mucus in asthma. Am J Respir Crit Care Med, 2016, 194(10): 1296-1299.
15.	Pardo-Saganta A, Law BM, Gonzalez-Celeiro M, et al. Ciliated cells of pseudostratified airway epithelium do not become mucous cells after ovalbumin challenge. Am J Respir Cell Mol Biol, 2013, 48(3): 364-373.
16.	Hellings PW, Steelant B. Epithelial barriers in allergy and asthma. J Allergy Clin Immunol, 2020, 145(6): 1499-1509.
17.	Kardas G, Kuna P, Panek M. Biological therapies of severe asthma and their possible effects on airway remodeling. Front Immunol, 2020, 11: 1134.
18.	Yagi R, Zhu JF, Paul WE. An updated view on transcription factor GATA3-mediated regulation of T_h1 and T_h2 cell differentiation. Int Immunol, 2011, 23(7): 415-420.
19.	Kiwamoto T, Ishii Y, Morishima Y, et al. Transcription factors T-bet and GATA-3 regulate development of airway remodeling. Am J Respir Crit Care Med, 2006, 174(2): 142-151.
20.	Liang Z, Luo ZC, Chen J, et al. Bavachin inhibits IL-4 expression by downregulating STAT6 phosphorylation and GATA-3 expression and ameliorates asthma inflammation in an animal model. Immunobiology, 2022, 227(2): 152182.
21.	王丹, 杨丹, 王小虎, 等. 支气管哮喘发病中的固有免疫机制. 中华结核和呼吸杂志, 2018, 41(3): 228-231.
22.	Kuruvilla ME, Lee FE, Lee GB. Understanding asthma pheno-types, endotypes, and mechanisms of disease. Clin Rev Allergy Immunol, 2019, 56(2): 219-233.
23.	Liang YS, Yu BH, Chen JC, et al. Thymic stromal lymphopoietin epigenetically upregulates Fc receptor γ subunit-related receptors on antigen-presenting cells and induces T_H2/T_H17 polarization through dectin-2. J Allergy Clin Immunol, 2019, 144(4): 1025-1035, e7.
24.	Ray A, Kolls JK. Neutrophilic inflammation in asthma and association with disease severity. Trends Immunol, 2017, 38(12): 942-954.
25.	Gauvreau GM, Sehmi R, Ambrose CS, et al. Thymic stromal lymphopoietin: its role and potential as a therapeutic target in asthma. Expert Opin Ther Targets, 2020, 24(8): 777-792.
26.	Li Y, Wang W, Lv Z, et al. Elevated expression of IL-33 and TSLP in the airways of human asthmatics in vivo: a potential biomarker of severe refractory disease. J Immunol, 2018, 200(7): 2253-2262.
27.	Kouzaki H, Tojima I, Kita H, et al. Transcription of interleukin-25 and extracellular release of the protein is regulated by allergen proteases in airway epithelial cells. Am J Respir Cell Mol Biol, 2013, 49(5): 741-750.
28.	Hurst SD, Muchamuel T, Gorman DM, et al. New IL-17 family members promote Th1 or Th2 responses in the lung: in vivo function of the novel cytokine IL-25. J Immunol, 2002, 169(1): 443-453.
29.	Saikumar Jayalatha AK, Hesse L, Ketelaar ME, et al. The central role of IL-33/IL-1RL1 pathway in asthma: from pathogenesis to intervention. Pharmacol Ther, 2021, 225: 107847.
30.	Bahrami Mahneh S, Movahedi M, Aryan Z, et al. Serum IL-33 is elevated in children with asthma and is associated with disease severity. Int Arch Allergy Immunol, 2015, 168(3): 193-196.
31.	Xie Y, Abel PW, Casale TB, et al. T_H17 cells and corticosteroid insensitivity in severe asthma. J Allergy Clin Immunol, 2022, 149(2): 467-479.
32.	Ivanov II, McKenzie BS, Zhou L, et al. The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17⁺ T helper cells. Cell, 2006, 126(6): 1121-1133.
33.	Ramakrishnan RK, Al Heialy S, Hamid Q. Role of IL-17 in asthma pathogenesis and its implications for the clinic. Expert Rev Respir Med, 2019, 13(11): 1057-1068.
34.	Chang Y, Al-Alwan L, Risse PA, et al. Th17-associated cytokines promote human airway smooth muscle cell proliferation. FASEB J, 2012, 26(12): 5152-5160.
35.	Chien JW, Lin CY, Yang KD, et al. Increased IL-17A secreting CD4+ T cells, serum IL-17 levels and exhaled nitric oxide are correlated with childhood asthma severity. Clin Exp Allergy, 2013, 43(9): 1018-1026.
36.	Chen RC, Zhang QL, Chen SY, et al. IL-17F, rather than IL-17A, underlies airway inflammation in a steroid-insensitive toluene diisocyanate-induced asthma model. Eur Respir J, 2019, 53(4): 1801510.
37.	Chang Y, Al-Alwan L, Risse PA, et al. T_H17 cytokines induce human airway smooth muscle cell migration. J Allergy Clin Immunol, 2011, 127(4): 1046-1053,e1-e2.
38.	Lamb D, De Sousa D, Quast K, et al. RORγt inhibitors block both IL-17 and IL-22 conferring a potential advantage over anti-IL-17 alone to treat severe asthma. Respir Res, 2021, 22(1): 158.
39.	Takahashi K, Hirose K, Kawashima S, et al. IL-22 attenuates IL-25 production by lung epithelial cells and inhibits antigen-induced eosinophilic airway inflammation. J Allergy Clin Immunol, 2011, 128(5): 1067-1076. e6.
40.	Hirose K, Ito T, Nakajima H. Roles of IL-22 in allergic airway inflammation in mice and humans. Int Immunol, 2018, 30(9): 413-418.
41.	Pelaia C, Crimi C, Vatrella A, et al. Molecular targets for biological therapies of severe asthma. Front Immunol, 2020, 11: 603312.
42.	Pelaia C, Pelaia G, Crimi C, et al. Tezepelumab: a potential new biological therapy for severe refractory asthma. Int J Mol Sci, 2021, 22(9): 4369.
43.	Verstraete K, Peelman F, Braun H, et al. Structure and antagonism of the receptor complex mediated by human TSLP in allergy and asthma. Nat Commun, 2017, 8: 14937.
44.	Corren J, Parnes JR, Wang LW, et al. Tezepelumab in adults with uncontrolled asthma. N Engl J Med, 2017, 377(10): 936-946.
45.	Menzies-Gow A, Corren J, Bourdin A, et al. Tezepelumab in adults and adolescents with severe, uncontrolled asthma. N Engl J Med, 2021, 384(19): 1800-1809.
46.	Nian SJ, Zhu JG, Yu H, et al. Development and identification of a fully human single-chain variable fragment 29 against TSLP. Biotechnol Appl Biochem, 2019, 66(4): 510-516.
47.	Mitchell PD, O’Byrne PM. Epithelial-derived cytokines in asthma. Chest, 2017, 151(6): 1338-1344.
48.	Chen YL, Gutowska-Owsiak D, Hardman CS, et al. Proof-of-concept clinical trial of etokimab shows a key role for IL-33 in atopic dermatitis pathogenesis. Sci Transl Med, 2019, 11(515): eaax2945.
49.	Chinthrajah S, Cao S, Liu C, et al. Phase 2a randomized, placebo-controlled study of anti-IL-33 in peanut allergy. JCI Insight, 2019, 4(22): e131347.
50.	Wechsler ME, Ruddy MK, Pavord ID, et al. Efficacy and safety of itepekimab in patients with moderate-to-severe asthma. N Engl J Med, 2021, 385(18): 1656-1668.
51.	Wang YB, Zhang ST, Li HY, et al. Small-molecule modulators of toll-like receptors. Acc Chem Res, 2020, 53(5): 1046-1055.
52.	Aryan Z, Rezaei N. Toll-like receptors as targets for allergen immunotherapy. Curr Opin Allergy Clin Immunol, 2015, 15(6): 568-574.
53.	Pfaar O, Barth C, Jaschke C, et al. Sublingual allergen-specific immunotherapy adjuvanted with monophosphoryl lipid A: a phase I/IIa study. Int Arch Allergy Immunol, 2011, 154(4): 336-344.
54.	Musarra A, Bignardi D, Troise C, et al. Long-lasting effect of a monophosphoryl lipid-adjuvanted immunotherapy to parietaria. A controlled field study. Eur Ann Allergy Clin Immunol, 2010, 42: 115-119.
55.	Beeh KM, Kanniess F, Wagner F, et al. The novel TLR-9 agonist QbG10 shows clinical efficacy in persistent allergic asthma. J Allergy Clin Immunol, 2013, 131(3): 866-874.
56.	Gauvreau GM, Hessel EM, Boulet LP, et al. Immunostimulatory sequences regulate interferon-inducible genes but not allergic airway responses. Am J Respir Crit Care Med, 2006, 174(1): 15-20.

1. GINA. Global Strategy for Asthma Management and Prevention-Updated 2022[EB/OL]. [2022-04-03] Available at: www. ginasthma. org.
2. Enilari O, Sinha S. The global impact of asthma in adult populations. Ann Glob Health, 2019, 85(1): 2.
3. Chung KF, Wenzel SE, Brozek JL, et al. International ERS/ATS Guidelines on Definition, Evaluation and Treatment of Severe Asthma. Eur Respir J, 2014, 43(2): 343-373.
4. Bourdin A, Fabry-Vendrand C, Ostinelli J, et al. The burden of severe asthma in France: a case-control study using a medical claims database. J Allergy Clin Immunol Pract, 2019, 7(5): 1477-1487.
5. Xiao C, Puddicombe SM, Field S, et al. Defective epithelial barrier function in asthma. J Allergy Clin Immunol, 2011, 128(3): 549-556,e1-12.
6. Vieira Braga FA, Kar G, Berg M, et al. A cellular census of human lungs identifies novel cell states in health and in asthma. Nat Med, 2019, 25(7): 1153-1163.
7. Frey A, Lunding LP, Ehlers JC, et al. More than just a barrier: the immune functions of the airway epithelium in asthma pathogenesis. Front Immunol, 2020, 11: 761.
8. Buckley A, Turner JR. Cell biology of tight junction barrier regulation and mucosal disease. Cold Spring Harb Perspect Biol, 2018, 10(1): a029314.
9. Lee PH, Kim BG, Lee SH, et al. Alteration in claudin-4 contributes to airway inflammation and responsiveness in asthma. Allergy Asthma Immunol Res, 2018, 10(1): 25-33.
10. Yang YM, Jia M, Ou YW, et al. Mechanisms and biomarkers of airway epithelial cell damage in asthma: a review. Clin Respir J, 2021, 15(10): 1027-1045.
11. Aghasafari P, George U, Pidaparti R. A review of inflammatory mechanism in airway diseases. Inflamm Res, 2019, 68(1): 59-74.
12. Georas SN, Rezaee F. Epithelial barrier function: at the front line of asthma immunology and allergic airway inflammation. J Allergy Clin Immunol, 2014, 134: 509-520.
13. Potaczek DP, Miethe S, Schindler V, et al. Role of airway epithelial cells in the development of different asthma phenotypes. Cell Signal, 2020, 69: 109523.
14. Lachowicz-Scroggins ME, Yuan SP, Kerr SC, et al. Abnormalities in MUC5AC and MUC5B protein in airway mucus in asthma. Am J Respir Crit Care Med, 2016, 194(10): 1296-1299.
15. Pardo-Saganta A, Law BM, Gonzalez-Celeiro M, et al. Ciliated cells of pseudostratified airway epithelium do not become mucous cells after ovalbumin challenge. Am J Respir Cell Mol Biol, 2013, 48(3): 364-373.
16. Hellings PW, Steelant B. Epithelial barriers in allergy and asthma. J Allergy Clin Immunol, 2020, 145(6): 1499-1509.
17. Kardas G, Kuna P, Panek M. Biological therapies of severe asthma and their possible effects on airway remodeling. Front Immunol, 2020, 11: 1134.
18. Yagi R, Zhu JF, Paul WE. An updated view on transcription factor GATA3-mediated regulation of T_h1 and T_h2 cell differentiation. Int Immunol, 2011, 23(7): 415-420.
19. Kiwamoto T, Ishii Y, Morishima Y, et al. Transcription factors T-bet and GATA-3 regulate development of airway remodeling. Am J Respir Crit Care Med, 2006, 174(2): 142-151.
20. Liang Z, Luo ZC, Chen J, et al. Bavachin inhibits IL-4 expression by downregulating STAT6 phosphorylation and GATA-3 expression and ameliorates asthma inflammation in an animal model. Immunobiology, 2022, 227(2): 152182.
21. 王丹, 杨丹, 王小虎, 等. 支气管哮喘发病中的固有免疫机制. 中华结核和呼吸杂志, 2018, 41(3): 228-231.
22. Kuruvilla ME, Lee FE, Lee GB. Understanding asthma pheno-types, endotypes, and mechanisms of disease. Clin Rev Allergy Immunol, 2019, 56(2): 219-233.
23. Liang YS, Yu BH, Chen JC, et al. Thymic stromal lymphopoietin epigenetically upregulates Fc receptor γ subunit-related receptors on antigen-presenting cells and induces T_H2/T_H17 polarization through dectin-2. J Allergy Clin Immunol, 2019, 144(4): 1025-1035, e7.
24. Ray A, Kolls JK. Neutrophilic inflammation in asthma and association with disease severity. Trends Immunol, 2017, 38(12): 942-954.
25. Gauvreau GM, Sehmi R, Ambrose CS, et al. Thymic stromal lymphopoietin: its role and potential as a therapeutic target in asthma. Expert Opin Ther Targets, 2020, 24(8): 777-792.
26. Li Y, Wang W, Lv Z, et al. Elevated expression of IL-33 and TSLP in the airways of human asthmatics in vivo: a potential biomarker of severe refractory disease. J Immunol, 2018, 200(7): 2253-2262.
27. Kouzaki H, Tojima I, Kita H, et al. Transcription of interleukin-25 and extracellular release of the protein is regulated by allergen proteases in airway epithelial cells. Am J Respir Cell Mol Biol, 2013, 49(5): 741-750.
28. Hurst SD, Muchamuel T, Gorman DM, et al. New IL-17 family members promote Th1 or Th2 responses in the lung: in vivo function of the novel cytokine IL-25. J Immunol, 2002, 169(1): 443-453.
29. Saikumar Jayalatha AK, Hesse L, Ketelaar ME, et al. The central role of IL-33/IL-1RL1 pathway in asthma: from pathogenesis to intervention. Pharmacol Ther, 2021, 225: 107847.
30. Bahrami Mahneh S, Movahedi M, Aryan Z, et al. Serum IL-33 is elevated in children with asthma and is associated with disease severity. Int Arch Allergy Immunol, 2015, 168(3): 193-196.
31. Xie Y, Abel PW, Casale TB, et al. T_H17 cells and corticosteroid insensitivity in severe asthma. J Allergy Clin Immunol, 2022, 149(2): 467-479.
32. Ivanov II, McKenzie BS, Zhou L, et al. The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17⁺ T helper cells. Cell, 2006, 126(6): 1121-1133.
33. Ramakrishnan RK, Al Heialy S, Hamid Q. Role of IL-17 in asthma pathogenesis and its implications for the clinic. Expert Rev Respir Med, 2019, 13(11): 1057-1068.
34. Chang Y, Al-Alwan L, Risse PA, et al. Th17-associated cytokines promote human airway smooth muscle cell proliferation. FASEB J, 2012, 26(12): 5152-5160.
35. Chien JW, Lin CY, Yang KD, et al. Increased IL-17A secreting CD4+ T cells, serum IL-17 levels and exhaled nitric oxide are correlated with childhood asthma severity. Clin Exp Allergy, 2013, 43(9): 1018-1026.
36. Chen RC, Zhang QL, Chen SY, et al. IL-17F, rather than IL-17A, underlies airway inflammation in a steroid-insensitive toluene diisocyanate-induced asthma model. Eur Respir J, 2019, 53(4): 1801510.
37. Chang Y, Al-Alwan L, Risse PA, et al. T_H17 cytokines induce human airway smooth muscle cell migration. J Allergy Clin Immunol, 2011, 127(4): 1046-1053,e1-e2.
38. Lamb D, De Sousa D, Quast K, et al. RORγt inhibitors block both IL-17 and IL-22 conferring a potential advantage over anti-IL-17 alone to treat severe asthma. Respir Res, 2021, 22(1): 158.
39. Takahashi K, Hirose K, Kawashima S, et al. IL-22 attenuates IL-25 production by lung epithelial cells and inhibits antigen-induced eosinophilic airway inflammation. J Allergy Clin Immunol, 2011, 128(5): 1067-1076. e6.
40. Hirose K, Ito T, Nakajima H. Roles of IL-22 in allergic airway inflammation in mice and humans. Int Immunol, 2018, 30(9): 413-418.
41. Pelaia C, Crimi C, Vatrella A, et al. Molecular targets for biological therapies of severe asthma. Front Immunol, 2020, 11: 603312.
42. Pelaia C, Pelaia G, Crimi C, et al. Tezepelumab: a potential new biological therapy for severe refractory asthma. Int J Mol Sci, 2021, 22(9): 4369.
43. Verstraete K, Peelman F, Braun H, et al. Structure and antagonism of the receptor complex mediated by human TSLP in allergy and asthma. Nat Commun, 2017, 8: 14937.
44. Corren J, Parnes JR, Wang LW, et al. Tezepelumab in adults with uncontrolled asthma. N Engl J Med, 2017, 377(10): 936-946.
45. Menzies-Gow A, Corren J, Bourdin A, et al. Tezepelumab in adults and adolescents with severe, uncontrolled asthma. N Engl J Med, 2021, 384(19): 1800-1809.
46. Nian SJ, Zhu JG, Yu H, et al. Development and identification of a fully human single-chain variable fragment 29 against TSLP. Biotechnol Appl Biochem, 2019, 66(4): 510-516.
47. Mitchell PD, O’Byrne PM. Epithelial-derived cytokines in asthma. Chest, 2017, 151(6): 1338-1344.
48. Chen YL, Gutowska-Owsiak D, Hardman CS, et al. Proof-of-concept clinical trial of etokimab shows a key role for IL-33 in atopic dermatitis pathogenesis. Sci Transl Med, 2019, 11(515): eaax2945.
49. Chinthrajah S, Cao S, Liu C, et al. Phase 2a randomized, placebo-controlled study of anti-IL-33 in peanut allergy. JCI Insight, 2019, 4(22): e131347.
50. Wechsler ME, Ruddy MK, Pavord ID, et al. Efficacy and safety of itepekimab in patients with moderate-to-severe asthma. N Engl J Med, 2021, 385(18): 1656-1668.
51. Wang YB, Zhang ST, Li HY, et al. Small-molecule modulators of toll-like receptors. Acc Chem Res, 2020, 53(5): 1046-1055.
52. Aryan Z, Rezaei N. Toll-like receptors as targets for allergen immunotherapy. Curr Opin Allergy Clin Immunol, 2015, 15(6): 568-574.
53. Pfaar O, Barth C, Jaschke C, et al. Sublingual allergen-specific immunotherapy adjuvanted with monophosphoryl lipid A: a phase I/IIa study. Int Arch Allergy Immunol, 2011, 154(4): 336-344.
54. Musarra A, Bignardi D, Troise C, et al. Long-lasting effect of a monophosphoryl lipid-adjuvanted immunotherapy to parietaria. A controlled field study. Eur Ann Allergy Clin Immunol, 2010, 42: 115-119.
55. Beeh KM, Kanniess F, Wagner F, et al. The novel TLR-9 agonist QbG10 shows clinical efficacy in persistent allergic asthma. J Allergy Clin Immunol, 2013, 131(3): 866-874.
56. Gauvreau GM, Hessel EM, Boulet LP, et al. Immunostimulatory sequences regulate interferon-inducible genes but not allergic airway responses. Am J Respir Crit Care Med, 2006, 174(1): 15-20.

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重症哮喘气道上皮细胞损伤机制及潜在生物治疗靶点

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