New Progress in Targeted Therapy for Bronchial Asthma_Chinese Journal of Respiratory and Critical Care Medicine

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ZHANG Lina ¹ , CHEN Ping ²

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支气管哮喘( 简称哮喘) 是由多种细胞包括气道的炎性细胞和结构细胞( 如嗜酸粒细胞、肥大细胞、T 淋巴细胞、中性粒细胞、平滑肌细胞、气道上皮细胞等) 和细胞组分参与的气道慢性炎症性疾病。近年来其患病率在全球范围内呈逐年增长趋势, 虽然90% ～95% 的哮喘患者应用吸入β2 激动剂和糖皮质激素治疗能够控制症状, 但停药后症状可能再次出现, 部分患者对激素治疗抵抗。随着对哮喘发病机制的深入认识, 探索了多种新的靶向治疗, 但目前还处于研发和临床试验过程中。现简要概述免疫调节剂相关的哮喘靶向治疗的作用机制、效应及与之相关的不良事件。

Citation： ZHANG Lina,CHEN Ping. New Progress in Targeted Therapy for Bronchial Asthma. Chinese Journal of Respiratory and Critical Care Medicine, 2009, 09(4): 411-414. doi: Copy

1.	Borish LC, Nelson HS, Lanz MJ, et al. Interleukin- 4 Receptor in Moderate Atopic Asthma: a phase I/ II randomized, placebocontrolled trial. Am J Respir Crit Care Med, 1999, 160: 1816-1823.
2.	Borish LC, Nelson HS, Corren J, et al. Efficacy of soluble IL-4 receptor for the treatment of adults with asthma. J Allergy Clin Immunol, 2001, 107: 963-970.
3.	KipsJC,O’Connor BJ, Langley SJ, et al. Effect of SCH55700, a humanized anti-human interleukin-5 antibody, in severe persistent asthma: a pilot study. Am J Respir Crit Care Med, 2003, 167: 1655- 1659.
4.	Büttner C, Lun A, Splettstoesser T, et al. Monoclonal antiinterleukin- 5 treatment suppresses eosinophil but not T-cell function. Eur Respir J, 2003, 21: 799-803.
5.	Krieg AM. Therapeutic potential of Toll-like receptor 9 activation. Nat Rev Drug Discov, 2006, 5: 471-484.
6.	Leckie MJ, ten Brinke A, Khan J, et al. Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyperresponsiveness, and the late asthmatic response. Lancet, 2000 , 356 : 2144 -2148 .
7.	Bree A, Schlerman FJ, Wadanoli M, et al. IL-13 blockade reduces lung inflammation after Ascaris suum challenge in cynomolgus monkeys. J Allergy Clin Immunol, 2007, 119: 1251-1257.
8.	Blanchard C, Mishra A, Saito-Akei H, et al. Inhibition of human interleukin-13-induced respiratory and oesophageal inflammation by anti-human-interleukin-13 antibody ( CAT-354 ) . Clin Exp Allergy, 2005, 35: 1096-1103.
9.	Busse WW, Israel E, Nelson HS, et al. Daclizumab improves asthma control in patients with moderate to severe persistent asthma: a randomized, controlled trial. Am JRespir Crit Care Med, 2008, 178 : 1002-1008.
10.	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: 15-20.
11.	Erin EM, Leaker BR, Nicholson GC, et al. The effects of a monoclonal antibody directed against tumor necrosis factor-( alpha) in asthma. Am J Respir Crit Care Med, 2006, 174: 753-762.
12.	Morjaria JB, Chauhan AJ, Babu KS, et al. The role of a soluble TNFalpha receptor fusion protein ( etanercept ) in corticosteroid refractory asthma: a double blind, randomised, placebo controlled trial. Thorax, 2008, 63: 584-591.
13.	Nq LG, Sutherland AP, Newton R, et al. B cell-activating factor belonging to the TNF family ( BAFF) -R is the principal BAFF receptor facilitating BAFF costimulation of circulating T and B cells. J Immumol, 2004, 173: 807-817.
14.	Kang JS, Yoon YD, Ahn JH, et al. B cell-activating factor is a novel diagnosis parameter for asthma. Int Arch Allergy Immunol, 2006 , 141: 181-188.
15.	Moon EY, Ryu SK. TACI: Fc scavenging B cell activating factor ( BAFF) alleviates ovalbumin-induced bronchial asthma in mice. Exp Mol Med, 2007, 39: 343-532.
16.	Bilsborough J, Chadwick E, Mudri S, et al. TACI-Ig prevents the development of airway hyperresponsiveness in a murine model of asthma. Clin Exp Allergy, 2008, 38: 1959-1968.
17.	Gagliardo R, Chanez P, Mathieu M, et al. Persistent activation of nuclear factor-kappaB signaling pathway in severe uncontrolled asthma. Am J Respir Crit Care Med, 2003, 168: 1190-1198.
18.	Sugita A, Ogawa H, Azuma M, et al. Antiallergic and antiinflammatory effects of a novel IkappaB kinase beta inhibitor, IMD- 0354, in a mouse model of allergic inflammation. Int Arch Allergy Immunol, 2009, 148: 186-198.
19.	Barnes PJ. Role of GATA-3 in allergic diseases. Curr Mol Med, 2008, 8: 330-334.
20.	Nakamura Y, Ghaffar O, Olivenstein R, et al. Gene expression of the GATA-3 transcription factor is increased in atopic asthma. J Allergy Clin Immunol, 1999, 103: 215-222.
21.	Caramori G, Lim S, Ito K, et al. Expression of GATA family of transcription factors in T-cells, monocytes and bronchial biopsies. Eur Respir J, 2001, 18: 466-473.
22.	Maneechotesuwan K, Xin Y, Ito K, et al. Regulation of Th2 cytokine genes by p38 MAPK-mediated phosphorylation of GATA-3 . J Immunol, 2007, 178: 2491-2498.
23.	邓群益, 张珍祥, 徐永健. 反义GATA-3 治疗哮喘气道炎症的实验研究. 实用医学杂志, 2005, 21 : 2355 -2357 .
24.	Cousins DJ, McDonald J, Lee TH. Therapeutic approaches for control of transcription factors in allergic disease. J Allergy Clin Immunol, 2008, 121: 803-809.
25.	Belvisi MG, Hele DJ, Birrell MA. Peroxisome proliferator-activated receptor gamma agonists as therapy for chronic airway inflammation. Eur J Pharmacol, 2006, 533: 101-109.
26.	Hashimoto Y, Nakahara K. Improvement of asthma after administration of pioglitazone. Diabetes Care, 2002, 25 : 401.
27.	Usami A, Ueki S, Ito W, et al. Theophylline and dexamethasone induce peroxisome proliferator-activated receptor-gamma expression in human eosinophils. Pharmacology, 2006, 77: 33 -37 .
28.	Quarcoo D, Weixler S, Groneberg D, et al. Inhibition of signal transducer and activator of transcription 1 attenuates allergeninduced airway inflammation and hyperreactivity. J Allergy Clin Immunol, 2004, 114: 288-295.
29.	周晓慧, 白建文, 吴燕灵, 等. Syk 在哮喘发病中的作用及其可能的靶向治疗. 国际呼吸杂志, 2007, 27: 440-442.
30.	Yamamoto N, Takeshita K, Shichijo M, et al. The orally available spleen tyrosine kinase inhibitor 2 -[ 7 -( 3 , 4 -dimethoxyphenyl ) - imidazo[ 1, 2 -c ] pyrimidin-5 -ylamino] nicotinamide dihydrochloride ( BAY 61-3606) blocks antigen-induced airway inflammation in rodents. J Pharmacol Exp Ther, 2003, 306: 1174-1181.
31.	Planaqum　A, Kazani S, Mariqowda G, et al. Airway lipoxin A4 generation and lipoxin A4 receptor expression are decreased in severe asthma. Am J Respir Crit Care Med, 2008, 178: 574-582.
32.	Levy BD, Lukacs NW, Berlin AA, et al. Lipoxin A4 stable analogs reduce allergic airway responses via mechanisms distinct from CysLT1 receptor antagonism. FASEB J, 2007, 21: 3877-3884.
33.	Busse W, Corren J, Lanier BQ, et al. Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma. J Allergy Clin Immunol, 2001, 108: 184-190.
34.	National Asthma Education and Prevention Program. Guidelines for the diagnosis and management of asthma: expert panel report 3 . Bethesda ( MD) : National Institutes of Health /National Heart, Lung, and Blood Institute; 2007. Publication no. 08-4051. Available at: ww. nhlbi. nih. gov/ guildelines /asthma/ asthgdln. htm.
35.	US Food and Drug Administration statement. Available at: http: / / www. fda. gov / cder/drug / InfoSheets /HCP/ omalizumabHCP. htm. Accessed September 27 , 2007.
36.	Prescribing information: summary of product characteristics. Available at: http: / / www. xolair. com. Accessed September 27 , 2007.
37.	Limb SL, Starke PR, Lee CE, et al. Delayed onset and protracted progression of anaphylaxis after omalizumab administration in patients with asthma. J Allergy Clin Immunol, 2007, 120: 1378 - 1381.

1. Borish LC, Nelson HS, Lanz MJ, et al. Interleukin- 4 Receptor in Moderate Atopic Asthma: a phase I/ II randomized, placebocontrolled trial. Am J Respir Crit Care Med, 1999, 160: 1816-1823.
2. Borish LC, Nelson HS, Corren J, et al. Efficacy of soluble IL-4 receptor for the treatment of adults with asthma. J Allergy Clin Immunol, 2001, 107: 963-970.
3. KipsJC,O’Connor BJ, Langley SJ, et al. Effect of SCH55700, a humanized anti-human interleukin-5 antibody, in severe persistent asthma: a pilot study. Am J Respir Crit Care Med, 2003, 167: 1655- 1659.
4. Büttner C, Lun A, Splettstoesser T, et al. Monoclonal antiinterleukin- 5 treatment suppresses eosinophil but not T-cell function. Eur Respir J, 2003, 21: 799-803.
5. Krieg AM. Therapeutic potential of Toll-like receptor 9 activation. Nat Rev Drug Discov, 2006, 5: 471-484.
6. Leckie MJ, ten Brinke A, Khan J, et al. Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyperresponsiveness, and the late asthmatic response. Lancet, 2000 , 356 : 2144 -2148 .
7. Bree A, Schlerman FJ, Wadanoli M, et al. IL-13 blockade reduces lung inflammation after Ascaris suum challenge in cynomolgus monkeys. J Allergy Clin Immunol, 2007, 119: 1251-1257.
8. Blanchard C, Mishra A, Saito-Akei H, et al. Inhibition of human interleukin-13-induced respiratory and oesophageal inflammation by anti-human-interleukin-13 antibody ( CAT-354 ) . Clin Exp Allergy, 2005, 35: 1096-1103.
9. Busse WW, Israel E, Nelson HS, et al. Daclizumab improves asthma control in patients with moderate to severe persistent asthma: a randomized, controlled trial. Am JRespir Crit Care Med, 2008, 178 : 1002-1008.
10. 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: 15-20.
11. Erin EM, Leaker BR, Nicholson GC, et al. The effects of a monoclonal antibody directed against tumor necrosis factor-( alpha) in asthma. Am J Respir Crit Care Med, 2006, 174: 753-762.
12. Morjaria JB, Chauhan AJ, Babu KS, et al. The role of a soluble TNFalpha receptor fusion protein ( etanercept ) in corticosteroid refractory asthma: a double blind, randomised, placebo controlled trial. Thorax, 2008, 63: 584-591.
13. Nq LG, Sutherland AP, Newton R, et al. B cell-activating factor belonging to the TNF family ( BAFF) -R is the principal BAFF receptor facilitating BAFF costimulation of circulating T and B cells. J Immumol, 2004, 173: 807-817.
14. Kang JS, Yoon YD, Ahn JH, et al. B cell-activating factor is a novel diagnosis parameter for asthma. Int Arch Allergy Immunol, 2006 , 141: 181-188.
15. Moon EY, Ryu SK. TACI: Fc scavenging B cell activating factor ( BAFF) alleviates ovalbumin-induced bronchial asthma in mice. Exp Mol Med, 2007, 39: 343-532.
16. Bilsborough J, Chadwick E, Mudri S, et al. TACI-Ig prevents the development of airway hyperresponsiveness in a murine model of asthma. Clin Exp Allergy, 2008, 38: 1959-1968.
17. Gagliardo R, Chanez P, Mathieu M, et al. Persistent activation of nuclear factor-kappaB signaling pathway in severe uncontrolled asthma. Am J Respir Crit Care Med, 2003, 168: 1190-1198.
18. Sugita A, Ogawa H, Azuma M, et al. Antiallergic and antiinflammatory effects of a novel IkappaB kinase beta inhibitor, IMD- 0354, in a mouse model of allergic inflammation. Int Arch Allergy Immunol, 2009, 148: 186-198.
19. Barnes PJ. Role of GATA-3 in allergic diseases. Curr Mol Med, 2008, 8: 330-334.
20. Nakamura Y, Ghaffar O, Olivenstein R, et al. Gene expression of the GATA-3 transcription factor is increased in atopic asthma. J Allergy Clin Immunol, 1999, 103: 215-222.
21. Caramori G, Lim S, Ito K, et al. Expression of GATA family of transcription factors in T-cells, monocytes and bronchial biopsies. Eur Respir J, 2001, 18: 466-473.
22. Maneechotesuwan K, Xin Y, Ito K, et al. Regulation of Th2 cytokine genes by p38 MAPK-mediated phosphorylation of GATA-3 . J Immunol, 2007, 178: 2491-2498.
23. 邓群益, 张珍祥, 徐永健. 反义GATA-3 治疗哮喘气道炎症的实验研究. 实用医学杂志, 2005, 21 : 2355 -2357 .
24. Cousins DJ, McDonald J, Lee TH. Therapeutic approaches for control of transcription factors in allergic disease. J Allergy Clin Immunol, 2008, 121: 803-809.
25. Belvisi MG, Hele DJ, Birrell MA. Peroxisome proliferator-activated receptor gamma agonists as therapy for chronic airway inflammation. Eur J Pharmacol, 2006, 533: 101-109.
26. Hashimoto Y, Nakahara K. Improvement of asthma after administration of pioglitazone. Diabetes Care, 2002, 25 : 401.
27. Usami A, Ueki S, Ito W, et al. Theophylline and dexamethasone induce peroxisome proliferator-activated receptor-gamma expression in human eosinophils. Pharmacology, 2006, 77: 33 -37 .
28. Quarcoo D, Weixler S, Groneberg D, et al. Inhibition of signal transducer and activator of transcription 1 attenuates allergeninduced airway inflammation and hyperreactivity. J Allergy Clin Immunol, 2004, 114: 288-295.
29. 周晓慧, 白建文, 吴燕灵, 等. Syk 在哮喘发病中的作用及其可能的靶向治疗. 国际呼吸杂志, 2007, 27: 440-442.
30. Yamamoto N, Takeshita K, Shichijo M, et al. The orally available spleen tyrosine kinase inhibitor 2 -[ 7 -( 3 , 4 -dimethoxyphenyl ) - imidazo[ 1, 2 -c ] pyrimidin-5 -ylamino] nicotinamide dihydrochloride ( BAY 61-3606) blocks antigen-induced airway inflammation in rodents. J Pharmacol Exp Ther, 2003, 306: 1174-1181.
31. Planaqum　A, Kazani S, Mariqowda G, et al. Airway lipoxin A4 generation and lipoxin A4 receptor expression are decreased in severe asthma. Am J Respir Crit Care Med, 2008, 178: 574-582.
32. Levy BD, Lukacs NW, Berlin AA, et al. Lipoxin A4 stable analogs reduce allergic airway responses via mechanisms distinct from CysLT1 receptor antagonism. FASEB J, 2007, 21: 3877-3884.
33. Busse W, Corren J, Lanier BQ, et al. Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma. J Allergy Clin Immunol, 2001, 108: 184-190.
34. National Asthma Education and Prevention Program. Guidelines for the diagnosis and management of asthma: expert panel report 3 . Bethesda ( MD) : National Institutes of Health /National Heart, Lung, and Blood Institute; 2007. Publication no. 08-4051. Available at: ww. nhlbi. nih. gov/ guildelines /asthma/ asthgdln. htm.
35. US Food and Drug Administration statement. Available at: http: / / www. fda. gov / cder/drug / InfoSheets /HCP/ omalizumabHCP. htm. Accessed September 27 , 2007.
36. Prescribing information: summary of product characteristics. Available at: http: / / www. xolair. com. Accessed September 27 , 2007.
37. Limb SL, Starke PR, Lee CE, et al. Delayed onset and protracted progression of anaphylaxis after omalizumab administration in patients with asthma. J Allergy Clin Immunol, 2007, 120: 1378 - 1381.

Chinese Journal of Respiratory and Critical Care Medicine

New Progress in Targeted Therapy for Bronchial Asthma

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