支氣管哮喘靶向治療的新進展_《中國呼吸與危重監護雜志》

作者：

張麗娜 ¹ , 陳萍 ²

1 第四軍醫大學西京醫院呼吸內科（陜西西安 710032）;;
2 沈陽軍區總醫院呼吸內科（遼寧沈陽 110016）;

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支氣管哮喘( 簡稱哮喘) 是由多種細胞包括氣道的炎性細胞和結構細胞( 如嗜酸粒細胞、肥大細胞、T 淋巴細胞、中性粒細胞、平滑肌細胞、氣道上皮細胞等) 和細胞組分參與的氣道慢性炎癥性疾病。近年來其患病率在全球范圍內呈逐年增長趨勢, 雖然90% ～95% 的哮喘患者應用吸入β2 激動劑和糖皮質激素治療能夠控制癥狀, 但停藥后癥狀可能再次出現, 部分患者對激素治療抵抗。隨著對哮喘發病機制的深入認識, 探索了多種新的靶向治療, 但目前還處于研發和臨床試驗過程中。現簡要概述免疫調節劑相關的哮喘靶向治療的作用機制、效應及與之相關的不良事件。

引用本文： 張麗娜,陳萍. 支氣管哮喘靶向治療的新進展. 中國呼吸與危重監護雜志, 2009, 09(4): 411-414. doi: 復制

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.	鄧群益, 張珍祥, 徐永健. 反義GATA-3 治療哮喘氣道炎癥的實驗研究. 實用醫學雜志, 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.	周曉慧, 白建文, 吳燕靈, 等. Syk 在哮喘發病中的作用及其可能的靶向治療. 國際呼吸雜志, 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. 鄧群益, 張珍祥, 徐永健. 反義GATA-3 治療哮喘氣道炎癥的實驗研究. 實用醫學雜志, 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. 周曉慧, 白建文, 吳燕靈, 等. Syk 在哮喘發病中的作用及其可能的靶向治療. 國際呼吸雜志, 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.

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支氣管哮喘靶向治療的新進展

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《中國呼吸與危重監護雜志》

支氣管哮喘靶向治療的新進展

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