MOLECULAR AND PHARMACOGENETIC MECHANISMS OF SEVERE ASTHMA

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Abstract


This review summarizes the results of studies to identify the dominant mechanisms of development and persistence of inflammation in severe asthma and results of pharmacogenetic studies of determination response to drugs. These mechanisms could potentially be used for diagnostic purposes and become the new targets of asthma therapy. Pharmacogenetic information will enable the use of a personalized approach to the asthma management which will adjust the therapy technology and increase the possibility of achieving disease control.

 


E. S. Kulikov

Siberian State Medical University, Tomsk, Russian Federation

Author for correspondence.
Email: evgeny.s.kulikov@gmail.com

Russian Federation

кандидат медицинских наук, ассистент кафедры общей врачебной практики с курсом поликлинической терапии ГБОУ ВПО СибГМУ Минздрава России
Адрес: 634050, Томск, Московский тракт, д. 2; тел.: (3822) 51-49-67

L. M. Ogorodnova

Siberian State Medical University, Tomsk, Russian Federation

Email: lm-ogorodova@mail.ru

Russian Federation

доктор медицинских наук, профессор, член-корреспондент РАМН, заведующая кафедрой факультетской педиатрии с курсом детских болезней лечебного факультета ГБОУ ВПО СибГМУ Минздрава России
Адрес: 634050, Томск, Московский тракт, д. 2; тел.: (3822) 51-49-67

M. B. Freidin

Research Institute of Medical Genetics, Tomsk, Russian Federation

Email: mfreidin@medgenetics.ru

Russian Federation

кандидат биологических наук, старший научный сотрудник лаборатории популяционной генетики ФГБУ «НИИ медицинской генетики» СО РАМН
Адрес: 634050, Томск, ул. Набережная р. Ушайки, д. 10; тел.: (3822) 42-09-56

I. A. Deev

Siberian State Medical University, Tomsk, Russian Federation

Email: ivandeyev@yandex.ru

Russian Federation доктор медицинских наук, профессор кафедры факультетской педиатрии с курсом детских болезней лечебного факультета ГБОУ ВПО СибГМУ Минздрава России
Адрес: 634050, Томск, Московский тракт, д. 2; тел.: (3822) 51-49-67

P. A. Selivanova

Siberian State Medical University, Tomsk, Russian Federation

Email: p.selivanova@mail.ru

Russian Federation кандидат медицинских наук, ассистент кафедры госпитальной терапии с курсом физической реабилитации и спортивной медицины ГБОУ ВПО СибГМУ Минздрава России
Адрес: 634050, Томск, Московский тракт, д. 2; тел.: (3822) 51-49-67

S. V. Fedosenko

Siberian State Medical University, Tomsk, Russian Federation

Email: s-fedosenko@mail.ru

Russian Federation кандидат медицинских наук, ассистент кафедры госпитальной терапии с курсом физической реабилитации и спортивной медицины ГБОУ ВПО СибГМУ Минздрава России
Адрес: 634050, Томск, Московский тракт, д. 2; тел.: (3822) 51-49-67

N. A. Kirillova

Siberian State Medical University, Tomsk, Russian Federation

Email: kirillova.natalya@gmail.com

Russian Federation

кандидат медицинских наук, ассистент кафедры общей врачебной практики с курсом поликлинической терапии ГБОУ ВПО СибГМУ Минздрава России
Адрес: 634050, Томск, Московский тракт, д. 2; тел.: (3822) 51-49-67

  1. Chung K.F., Godard P., Adelroth E. Difficult/therapy-resistant asthma. Eur. Respir. J. 1999; 13: 1198–1208.
  2. Difficult asthma. S. Holgate (ed.). Dunitz: Martin Ltd. 1999. 567 p.
  3. American Thoracic Society. Proceedings of the ATS workshop on refractory asthma: current understanding, recommendations, and unanswered questions. Am. J. Respir. Crit. Care Med. 2000; 162: 2341–2351.
  4. Miller M.K., Johnson C., Miller D.P., Deniz Y., Bleecker E.R., Wenzel S.E.; TENOR Study Group. Severity assessment in asthma: an evolving concept. J. Allergy Clin. Immunol. 2005; 116: 990–995.
  5. Chuchalin A.G., Ogorodova L.M., Petrovskii F.I., Zhestkov A.V., Il'kovich M.M., Martynenko T.I., Rebrova A.P., Reutova L.Yu., Tereshchenko Yu.A., Fassakhov R.S., Chernyak B.A. Monitoring and treatment of severe asthma in adults: results of a national multicenter study ALARM. Ter. arkhiv = Therapeutic archive. 2005; 77 (3): 36–42.
  6. Chuchalin A.G., Ogorodova L.M., Petrovskii F.I., Zhestkov A.V., Il'kovich M.M., Martynenko T.I., Rebrov A.P., Reutova L.Yu., Tereshchenko Yu.A., Fassakhov R.S., Chernyak B.A., Kulikov E.SBasic therapy of severe asthma. Data from a national study of ALARM. Pul'monologiya = Pulmonology. 2004; 6: 32.
  7. Bel E.H. Clinical phenotypes of asthma. Curr. Opin. Pulm. Med. 2004; 10: 44–50.
  8. Wenzel S.E. Asthma: defining of the persistent adult phenotypes. Lancet. 2006; 26; 368 (9537): 804–813.
  9. Moore W.C., Meyers D.A., Wenzel S.E. Identification of asthma phenotypes using cluster analysis in the severe asthma research program. Am. J. Respir. Crit. Care Med. 2010; 18: 315–323.
  10. Evans W.E., McLeod H.L. Pharmacogenomics — drug disposition, drug targets, and side effects. N. Engl. J. Med. 2003; 348 (6): 538–549.
  11. Turato G., Baraldo S., Zuin R. The laws of attraction: chemokines, neutrophils and eosinophils in severe exacerbations of asthma. Thorax. 2007; 62 (6): 465–466.
  12. Dente F.L., Carnevali S., Bartoli M.L. Profiles of proinflammatory cytokines in sputum from different groups of severe asthmatic patients. Ann. All. Asthma Immunol. 2006; 97 (3): 312–320.
  13. Ogorodova L.M., Selivanova P.A., Gereng E.A. Bogamyakov V.S., Volkova L.I., Pleshko R.I. Pathological characteristics of unstable asthma (phenotype brittle). Ter. arkhiv = Therapeutic archive. 2008; 80 (3): 39–43.
  14. Mukhopadhyay S., Hoidal J., Mukherjee T. Role of TNF α in pulmonary pathophysiology. Respir. Res. 2006; 7 (1): 125.
  15. Kuperman D.A., Huang X., Koth L.L. Direct effects of interleukin 13 on epithelial cells cause airway hyperreactivity and mucus overproduction in asthma. Nat. Med. 2002; 8 (8): 885–889.
  16. Vignola A.M., Chiappara G., Siena L. Proliferation and activation of bronchial epithelial cells in corticosteroid-dependent asthma. J. Allergy Clin. Immunol. 2001; 108 (5): 738–746.
  17. Bonnans C., Chanez P., Meziane H. Glucocorticoid receptor-binding characteristics in severe asthma. Eur. Respir. J. 2003; 21: 985–988.
  18. Lane S.J., Lee T.H. Corticosteroid resistance in other disease states and tissues. Am. J. Respir. Crit. Care Med. 1996; 154: 62–65.
  19. Sher E.R., Leung D.Y., Surs W., Kam J.C., Zieg G., Kamada A.K., Szefler S.J. Steroid-resistant asthma. Cellular mechanisms contributing to inadequate response to glucocorticoid therapy. J. Clin. Investig. 1994; 93: 33–39.
  20. Barnes P.J. Corticosteroid effects on cell signaling. Eur. Respir. J. 2006; 27: 413–426.
  21. Gagliardo R., Chanez P., Vignola A.M. Glucocorticoid receptor alpha and beta in glucocorticoid dependent asthma. Am. J. Respir. Crit. Care Med. 2000; 162 (1): 7–13.
  22. Tillie-Leblond I., de Blic J., Jaubert F. Airway remodeling is correlated with obstruction in children with severe asthma. Allergy. 2008; 63 (5): 533–541.
  23. Bourdin A., Neveu D., Vachier I. Specificity of basement membrane thickening in severe asthma. J. Allergy Clin. Immunol. 2007; 119 (6): 1367–1374.
  24. Cohen L., Tarsi J., Ramkumar T. Epithelial cell proliferation contributes to airway remodeling in severe asthma. Am. J. Respir. Crit. Care Med. 2007; 176 (2): 138–145.
  25. Gereng E.A., Selivanova P.AMorpho-functional characteristics of bronchial mucosa in patients with various forms of severe asthma. Sibirskii konsilium = Siberian consultation. 2007; 7 (62): 30–31.
  26. Chen G., Khalil N. TGF-beta1 increases proliferation of airway smooth muscle cells by phosphorylation of map kinases. Respir. Res. 2006; 3: 7: 2.
  27. Voelkel N., Spiegel S. Why is effective treatment of asthma so difficult? An integrated systems biology hypothesis of asthma. Immunol. Cell Biol. 2009; 87 (8): 601–605.
  28. Mattos W., Lim S., Russell R. Matrix metalloproteinase-9 expression in asthma: effect of asthma severity, allergen challenge, and inhaled corticosteroids. Chest. 2002; 122 (5): 1543–1552.
  29. Levine S.J., Wenzel S.E. Narrative review: the role of Th2 immune pathway modulation in the treatment of severe asthma and its phenotypes. Ann. Intern. Med. 2010; 152 (4): 232–237.
  30. Maneechotesuwan K., Xin Y., Ito K. Regulation of Th2 cytokine genes by p38 MAPK-mediated phosphorylation of GATA-3. J. Immunol. 2007; 178 (4): 2491–2498.
  31. Siegel M.D., Zhang D.H., Ray P., Ray A. Activation of the interleukin-5 promoter by cAMP in murine EL-4 cells requires the GATA-3 and CLE0 elements. J. Biol. Chem. 1995; 270: 24548–24555.
  32. Zhu J., Yamane H., Cote-Sierra J. GATA-3 promotes Th2 responses through three different mechanisms: induction of Th2 cytokine production, selective growth of Th2 cells and inhibition of Th1 cell-specific factors. Cell Res. 2006; 16 (1): 3–10.
  33. Nakamura Y. Gene expression of the GATA-3 transcription factor is increased in atopic asthma. J. Allergy Clin. Immunol. 1999; 103: 215–222.
  34. Kim P.J., Pai S.Y., Brigl M. GATA-3 regulates the development and function of invariant NKT cells. J. Immunol. 2006; 177 (10): 6650–6659.
  35. Marusina A., Kim D., Lieto L. GATA-3 is an important transcription factor for regulating human NKG2A gene expression. J. Immunol. 2005; 174: 2152–2159.
  36. Yamashita N., Tashimo H., Ishida H. Involvement of GATA-3-dependent Th2 lymphocyte activation in airway hyperresponsiveness. Am. J. Physiol. Lung Cell Mol. Physiol. 2006; 290: 1045–1051.
  37. Bian T., Yin K.S., Jin S.X. Treatment of allergic airway inflammation and hyperresponsiveness by imiquimod modulating transcription factors T-bet and GATA-3. Chin. Med. J. (Engl.). 2006; 119 (8): 640–648.
  38. Szabo S.J., Kim S.T., Costa G.L., Zhang X., Fathman C.G., Glimcher L.H. A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell. 2000; 100: 655–669.
  39. Lugo-Villarino G., Maldonado-Lopez R., Possemato R., Penaranda C., Glimcher L.H. T-bet is required for optimal production of IFN-gamma and antigen-specific T cell activation by dendritic cells. Proc. Natl. Acad. Sci. USA. 2003; 100: 7749–7754.
  40. Kiwamoto T., Ishii Y., Morishima Y. Transcription factors T-bet and GATA-3 regulate development of airway remodeling. Am. J. Respir. Crit. Care Med. 2006; 174: 142–151.
  41. Finotto S., Hausding M., Doganci A. Asthmatic changes in mice lacking T-bet are mediated by IL-13. Int. Immunol. 2005; 17 (8): 993–1007.
  42. Raby B., Hwang E., Steen K. T-bet polymorphisms are associated with asthma and airway hyperresponsiveness. Am. J. Respir. Crit. Care Med. 2006; 173: 64–70.
  43. Bakshi C., Malik M., Carrico P. T-bet deficiency facilitates airway colonization by Mycoplasma pulmonis in a murine model of asthma. J. Immunol. 2006; 177: 1786–1795.
  44. Sullivan B., Jobe O., Lazarevic V. Increased susceptibility of mice lacking T-bet to infection with Mycobacterium tuberculosis correlates with increased IL-10 and decreased IFN-gamma production. J. Immunol. 2005; 175: 4593–4602.
  45. Israel E., Drazen J.M., Liggett S.B., Boushey H.A., Cherniack R.M., Chinchilli V.M., Cooper D.M., Fahy J.V., Fish J.E., Ford J.G., Kraft M., Kunselman S., Lazarus S.C., Lemanske R.F., Martin R.J., McLean D.E., Peters S.P., Silverman E.K., Sorkness C.A., Szefler S.J., Weiss S.T., Yandava C.N. The effect of polymorphisms on the β2adrenergic receptor on the response to regular use of albuterol in asthma. Am. J. Respir. Crit. Care Med. 2000; 162: 75–80.
  46. Metzger N.L., Kockler D.R., Gravatt L.A. Confirmed beta16Arg/Arg polymorphism in a patient with uncontrolled asthma. Ann. Pharmacother. 2008; 42 (6): 874–881.
  47. Basu K., Palmer C.N., Tavendale R., Lipworth B.J., Mukhopadhyay S. Adrenergic b(2)-receptor genotype predisposes to exacerbations in steroid-treated asthmatic patients taking frequent albuterol or salmeterol. J. Allergy Clin. Immunol. 2009; 124 (6): 1188–1194.
  48. Litonjua A.A., Lasky-Su J., Schneiter K., Tantisira K.G., Lazarus R., Klanderman B., Lima J.J., Irvin C.G., Peters S.P., Hanrahan J.P., Liggett S.B., Hawkins G.A., Meyers D.A., Bleecker E.R., Lange C., Weiss S.T. ARG1 is a novel bronchodilator response gene: screening and replication in four asthma cohorts. Am. J. Respir. Crit. Care Med. 2008; 178 (7): 688–694.
  49. Vonk J.M., Postma D.S., Maarsingh H., Bruinenberg M., Koppelman G.H., Meurs H. Arginase 1 and arginase 2 variations associate with asthma, asthma severity and b2 agonist and steroid response. Pharmacogenet. Genomics. 2010; 20 (3): 179–186.
  50. Maarsingh H., Zuidhof A.B., Bos I.S., van Duin M., Boucher J.L., Zaagsma J., Meurs H. Arginase inhibition protects against allergen-induced airway obstruction, hyperresponsiveness, and inflammation. Am. J. Respir. Crit. Care Med. 2008; 178 (6): 565–573.
  51. Moore P.E., Ryckman K.K., Williams S.M., Patel N., Summar M.L., Sheller J.R. Genetic variants of GSNOR and ADRB2 influence response to albuterol in African–American children with severe asthma. Pediatr. Pulmonol. 2009; 44 (7): 649–654.
  52. Choudhry S., Que L.G., Yang Z., Liu L., Eng C., Kim S.O., Kumar G., Thyne S., Chapela R., Rodriguez-Santana J.R., Rodriguez-Cintron W., Avila P.C., Stamler J.S., Burchard E.G. GSNO reductase and b2-adrenergic receptor gene–gene interaction: bronchodilator responsiveness to albuterol. Pharmacogenet. Genomics. 2010; 20 (6): 351–358.
  53. Whalen E.J., Foster M.W., Matsumoto A., Ozawa K., Violin J.D., Que L.G., Nelson C.D., Benhar M., Keys J.R., Rockman H.A., Koch W.J., Daaka Y., Lefkowitz R.J., Stamler J.S. Regulation of b-adrenergic receptor signaling by S-nitrosylation of G-proteincoupled receptor kinase 2. Cell. 2007; 129 (3): 511–522.
  54. Global'naya strategiya lecheniya i profilaktiki bronkhial'noi astmy. Pod red. A.G. Chuchalina [Global strategy for the treatment and prevention of asthma. Edited by A.G. Chuchalin]. Moscow, Atmosfera. 2007. 104 p.
  55. Sayers I., Hall I.P. Pharmacogenetic approaches in the treatment of asthma. Curr. Allergy Asthma Rep. 2005; 5 (2): 101–108.
  56. Tantisira K.G., Lake S., Silverman E.S., Palmer L.J., Lazarus R., Silverman E.K., Liggett S.B., Gelfand E.W., Rosenwasser L.J., Richter B., Israel E., Wechsler M., Gabriel S., Altshuler D., Lander E., Drazen J., Weiss S.T. Corticosteroid pharmacogenetics: association of sequence variants in CRHR1 with improved lung function in asthmatics treated with inhaled corticosteroids. Hum. Mol. Genet. 2004; 13: 1353–1359.
  57. Ye Y.M., Lee H.Y., Kim S.H., Jee Y.K., Lee S.K., Lee S.H., Park H.S. Pharmacogenetic study of the effects of NK2R G231E G>A and TBX21 H33Q C>G polymorphisms on asthma control with inhaled corticosteroid treatment. J. Clin. Pharm. Ther. 2009; 34 (6): 693–701.
  58. Hawkins G.A., Lazarus R., Smith R.S., Tantisira K.G., Meyers D.A., Peters S.P., Weiss S.T., Bleecker E.R. The glucocorticoid receptor heterocomplex gene STIP1 is associated with improved lung function in asthmatic subjects treated with inhaled corticosteroids. J. Allergy Clin. Immunol. 2009; 123 (6): 1376–1383.
  59. Tantisira K.G., Silverman E.S., Mariani T.J., Xu J., Richter B.G., Klanderman B.J., Litonjua A.A., Lazarus R., Rosenwasser L.J., Fuhlbrigge A.L., Weiss S.T. FCER2: a pharmacogenetic basis for severe exacerbations in children with asthma. J. Allergy Clin. Immunol. 2007; 120 (6): 1285–1291.
  60. Koster E.S., Maitland-van der Zee A.H., Tavendale R., Mukhopadhyay S., Vijverberg S.J., Raaijmakers J.A., Palmer C.N. FCER2 T2206C variant associated with chronic symptoms and exacerbations in steroid-treated asthmatic children. Allergy. 2011; 66 (12): 1546–1552.
  61. Hakonarson H., Bjornsdottir U.S., Halapi E., Bradfield J., Zink F., Mouy M., Helgadottir H., Gudmundsdottir A.S., Andrason H., Adalsteinsdottir A.E., Kristjansson K., Birkisson I., Arnason T., Andresdottir M., Gislason D., Gislason T., Gulcher J.R., Stefansson K. Profiling of genes expressed in peripheral blood mononuclear cells predicts glucocorticoid sensitivity in asthma patients. Proc. Natl. Acad. Sci. USA. 2005; 102 (41): 14789–14794.
  62. Kowalski M.L., Cieślak M., Pérez-Novo C.A. Clinical and immunological determinants of severe/refractory asthma (SRA): association with Staphylococcal superantigen-specific IgE-antibodies. Allergy. 2011; 66 (1): 32–38.
  63. Portelli M., Sayers I. Genetic basis for personalized medicine in asthma. Exp. Rev. Respir. Med. 2012; 6 (2): 223–236.
  64. Tse S.M., Tantisira K., Weiss S.T. The pharmacogenetics and pharmacogenomics of asthma therapy. Pharmacogenomics J. 2011; 11 (6): 383–392.
  65. Kazani S., Wechsler M.E., Israel E. The role of pharmacogenomics in improving the management of asthma. J. Allergy Clin. Immunol. 2010; 125 (2): 295–302.

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