Clinical and pathobiological heterogeneity of asthma—Mechanisms of severe and glucocorticoid-resistant asthma

Abstract

It is increasingly recognized that asthma represents a syndrome, and there is clinical and pathobiological heterogeneity. Many genes are reported to be associated with asthma, and may be involved in the disease heterogeneity. Diverse cells, such as T helper 1 (Th1)-cells, Th2-cells, Th17-cells, airway epithelial cells, and innate and adaptive immunity associated cells, contribute to the pathobiology of asthma independently of each other or they can also coexist and interact. Although, generally, Th2 immunity is important in most asthma endotypes, non- Th2-driven inflammation tends to be difficult to manage. Recently, increased attention has been focused on severe asthma and glucocorticoid (GC)-resistant (GC-R) asthma, in which diverse inflammatory processes may be involved. Treatment approaches should take into account pathological differences.

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Matsumura, Y. (2013) Clinical and pathobiological heterogeneity of asthma—Mechanisms of severe and glucocorticoid-resistant asthma. Health, 5, 344-350. doi: 10.4236/health.2013.52A046.

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1] Anderson GP. (2008) Endotyping asthma: New insights into key pathogenic mechanisms in a complex, heteroge neous disease. Lancet, 372, 1107-1119. doi:10.1016/S0140-6736(08)61452-X
[2] Kim, H.Y., DeKruyff, R.H. and Umetsu, D.T. (2010) The many paths to asthma: Phenotype shaped by innate and adaptive immunity. Nature Immunology, 11, 577-584. Epub 18 June 2010. doi:10.1038/ni.1892
[3] Bhakta, N.R. and Woodruff, P.G. (2011) Human asthma phenotypes: From the clinic, to cytokines, and back again. Immunological Reviews, 242, 220-232. doi:10.1111/j.1600-065X.2011.01032.x
[4] Vercelli D. (2008) Discovering susceptibility genes for asthma and allergy. Nature reviews. Immunology, 8, 169 182. doi:10.1038/nri2257
[5] Moffatt, M.F., Gut, I.G., Demenais, F., Strachan, D.P., Bouzigon, E., Heath, S., von Mutius, E., Farrall, M., Lathrop, M. and Cookson, W.O.; GABRIEL Consortium (2010) A large-scale, consortium-based genomewide association study of asthma. The New England Journal of Medicine, 363, 1211-1221. doi:10.1056/NEJMoa0906312
[6] Torgerson, D.G., Ampleford, E.J., Chiu, G.Y., Gauderman, W.J., Gignoux, C.R., Graves, P.E., Himes, B.E., Levin, A.M., Mathias, R.A., Hancock, D.B., Baurley, J.W., Eng, C., Stern, D.A., Celedón, J.C., Rafaels, N., Capurso, D., Conti, D.V., Roth, L.A., Soto-Quiros, M., Togias, A., Li, X., Myers, R.A., Romieu, I., Van Den Berg, D.J., Hu, D., Hansel, N.N., Hernandez, R.D., Israel, E., Salam, M.T., Galanter, J., Avila, P.C., Avila, L., Rodriquez-Santana, J.R., Chapela, R., Rodriguez-Cintron, W., Diette, G.B., Adkinson, N.F., Abel, R.A., Ross ,K.D., Shi, M., Faruque, M.U., Dunston, G.M., Watson, H.R., Mantese, V.J., Ezurum. S.C., Liang, L., Ruczinski, I., Ford, J.G., Huntsman, S., Chung, K.F., Vora, H., Li, X., Calhoun, W.J., Castro, M., Sienra-Monge, J.J., del Rio-Navarro, B., Deichmann, K.A., Heinzmann, A., Wenzel, S.E., Busse, W.W., Gern, J.E., Lemanske Jr., R.F., Beaty, T.H., Bleecker, E.R., Raby, B.A., Meyers, D.A., London, S.J.; Mexico City Child hood Asthma Study (MCAAS),, Gilliland, F.D.; Children’s Health Study (CHS) And HARBORS Study, Bur chard, E.G.; Genetics of Asthma in Latino Americans (GALA) Study, Study of Genes-Environment and Ad mixture in Latino Americans (GALA2) and Study of African Americans, Asthma, Genes & Environments (SAGE), Martinez, F.D.; Childhood Asthma Research and Education (CARE) Network, Weiss, S.T.; Childhood Asthma Management Program (CAMP), Williams, L.K.; Study of Asthma Phenotypes and Phar-macogenomic Interactions by Race-Ethnicity (SAP-PHIRE), Barnes, K.C.; Genetic Research on Asthma in African Diaspora (GRAAD) Study, Ober, C. and Nicolae, D.L. (2011) Meta-analysis of ge nome-wide association studies of asthma in ethnically diverse North American populations. Nature Genetics, 43, 887-892. doi:10.1038/ng.888
[7] Ober, C. and Yao, T.C. (2011) The genetics of asthma and allergic disease: A 21st century perspective. Immunological Reviews, 242, 10-30. doi:10.1111/j.1600-065X.2011.01029.x
[8] Cui, J., Pazdziorko, S., Miyashiro, J.S., Thakker, P., Pelker, J.W., Declercq, C., Jiao, A., Gunn, J., Mason, L., Leonard, J.P., Williams, C.M. and Marusic, S. (2005) TH1-mediated airway hyperresponsiveness independent of neutrophilic inflammation. The Journal of Allergy and Clinical Immunology, 115, 309-315. doi:10.1016/j.jaci.2004.10.046
[9] Hayashi, N., Yoshimoto, T., Izuhara, K., Matsui, K., Tanaka, T. and Nakanishi, K. (2007) T helper 1 cells stimulated with ovalbumin and IL-18 induce airway hyperre sponsiveness and lung fibrosis by IFN-gamma and IL-13 production. Proceedings of the National Academy of Sciences of the United States of America, 104, 14765-14770. Epub August 31 2007. doi:10.1073/pnas.0706378104
[10] Wakashin, H., Hirose, K., Maezawa, Y., Kagami, S., Suto, A., Watanabe, N., Saito, Y., Hatano, M., Tokuhisa, T., Iwakura, Y., Puccetti, P., Iwamoto, I. and Nakajima, H. (2008) IL-23 and Th17 cells enhance Th2-cell-mediated eosinophilic airway inflammation in mice. American Journal of Respiratory and Critical Care Medicine, 178, 1023-1032. Epub 11 September 2008. doi:10.1164/rccm.200801-086OC
[11] Wilson, R.H., Whitehead, G.S., Nakano, H., Free, M.E., Kolls, J.K. and Cook, D.N. (2009) Allergic sensitization through the airway primes Th17-dependent neutrophilia and airway hyperresponsiveness. American Journal of Respiratory and Critical Care Medicine, 180, 720-730. Epub 6 August 2009. doi:10.1164/rccm.200904-0573OC
[12] Yang, X.O., Chang, S.H., Park, H., Nurieva, R., Shah, B., Acero, L., Wang, Y.H., Schluns, K.S., Broaddus, R.R., Zhu, Z. and Dong, C. (2008) Regulation of inflammatory responses by IL-17F. The Journal of Experimental Medicine, 205, 1063-1075. Epub 14 April 2008. doi:10.1084/jem.20071978
[13] Pène, J., Chevalier, S., Preisser, L., Vénéreau, E., Guil leux, M.H., Ghannam, S., Molès, J.P., Danger, Y., Ravon, E., Lesaux, S., Yssel, H. and Gascan, H. (2008) Chronically inflamed human tissues are infiltrated by highly differentiated Th17 lymphocytes. The Journal of Immunology: Official Journal of the American Association of Immunologists, 180, 7423-7430.
[14] Pillai, S.G., Tang, Y., van den Oord, E., Klotsman, M., Barnes, K., Carlsen. K., Gerritsen, J., Lenney, W., Silver man, M., Sly, P., Sundy, J., Tsanakas, J., von Berg, A., Whyte, M., Ortega, H.G., Anderson, W.H. and Helms, P.J. (2008) Factor analysis in the Genetics of Asthma Interna tional Network family study identifies five major quantitative asthma phenotypes. Clinical and Experimental Allergy: Journal of the British Society for Allergy and Clinical Immunology, 38, 421-429. Epub 2 January 2008. doi:10.1111/j.1365-2222.2007.02918.x
[15] Haldar, P., Pavord, I.D., Shaw, D.E., Berry, M.A., Thomas, M., Brightling, C.E., Wardlaw, A.J. and Green, R.H. (2008) Cluster analysis and clinical asthma phenotypes. American Journal of Respiratory and Critical Care Medicine, 178, 218-224. Epub 14 May 2008. doi:10.1164/rccm.200711-1754OC
[16] Weatherall, M., Travers, J., Shirtcliffe, P.M., Marsh, S.E., Williams, M.V., Nowitz, M.R., Aldington, S. and Beasley, R. (2009) Distinct clinical phenotypes of airways disease defined by cluster analysis. The European Respiratory Journal: Official Journal of the European Society for Clinical Respiratory Physiology, 34, 812-818. Epub 8 April 2009. doi:10.1183/09031936.00174408
[17] Moore, W.C., Meyers, D.A., Wenzel, S.E., Teague, W.G., Li, H., Li, X., D’Agostino Jr., R., Castro, M., Curran Everett, D., Fitzpatrick, A.M., Gaston, B., Jarjour, N.N., Sorkness, R., Calhoun, W.J., Chung, K.F., Comhair, S.A., Dweik, R.A., Israel, E., Peters, S.P., Busse, W.W., Erzu rum, S.C. and Bleecker, E.R.; National Heart, Lung, and Blood Institute’s Severe Asthma Research Program (2010) Identification of asthma phenotypes using cluster analysis in the severe asthma research program. American Journal of Respiratory and Critical Care Medicine, 181, 315-323. Epub 5 November 2009. doi:10.1164/rccm.200906-0896OC
[18] Brasier, A.R., Victor, S., Boetticher, G., Ju, H., Lee, C., Bleecker, E.R., Castro, M., Busse, W.W. and Calhoun, W.J. (2008) Molecular phenotyping of severe asthma using pattern recognition of bronchoalveolar lavage-derived cytokines. The Journal of Allergy and Clinical Immunology, 121, 30-37, e6. doi:10.1016/j.jaci.2007.10.015
[19] Holgate, S.T. (2003) The ENFUMOSA cross-sectional European multicentre study of the clinical phenotype of chronic severe asthma. European network for understanding mechanisms of severe asthma. The European Respiratory Journal: Official Journal of the European Society for Clinical Respiratory Physiology, 22, 470-477.
[20] Moore, W.C., Bleecker, E.R., Curran-Everett, D., Erzu rum, S.C., Ameredes, B.T., Bacharier, L., Calhoun, W.J., Castro, M., Chung, K.F., Clark, M.P., Dweik, R.A., Fitz patrick, A.M., Gaston, B., Hew, M., Hussain, I., Jarjour, N.N., Israel, E., Levy, B.D., Murphy, J.R., Peters, S.P., Teague, W.G., Meyers, D.A., Busse, W.W. and Wenzel, S.E.; National Heart, Lung, Blood Institute’s Severe Asthma Research Program (2007) Characterization of the severe asthma phenotype by the national heart, lung, and blood institute’s severe asthma research program. The Journal of Allergy and Clinical Immunology, 119, 405 413. doi:10.1016/j.jaci.2006.11.639
[21] Pulleyn, L.J., Newton, R., Adcock, I.M. and Barnes, P.J. (2001) TGFbeta1 allele association with asthma severity. Human Genetics, 109, 623-627. Epub27 October 2001.
[22] Wang, X., Saito, J., Ishida, T. and Munakata, M. (2006) Polymorphism of egfr Intron1 is associated with susceptibility and severity of asthma. The Journal of Asthma: Official Journal of the Association for the Care of Asthma, 43, 711-715. doi:10.1007/s00439-001-0617-y
[23] Sandford, A.J., Chagani, T., Zhu, S., Weir, T.D., Bai, T.R., Spinelli, J.J., Fitzgerald, J.M., Behbehani, N.A., Tan, W.C. and Paré, P.D. (2000) Polymorphisms in the IL4, IL4RA, and FCERIB genes and asthma severity. The Journal of Allergy and Clinical Immunology, 106, 135-140. doi:10.1067/mai.2000.107926
[24] Wenzel, S.E., Schwartz, L.B., Langmack, E.L., Halliday, J.L., Trudeau, J.B., Gibbs, R.L. and Chu, H.W. (1999) Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics. American Journal of Respiratory and Critical Care Medicine, 160, 1001-1008.
[25] Gibson, P.G., Simpson, J.L. and Saltos, N. (2001) Het erogeneity of airway inflammation in persistent asthma: Evidence of neutrophilic inflammation and increased sputum interleukin-8. Chest, 119, 1329-1336. doi:10.1378/chest.119.5.1329
[26] Takaoka, A., Tanaka, Y., Tsuji, T., Jinushi, T., Hoshino, A., Asakura, Y., Mita, Y., Watanabe, K., Nakaike, S., Togashi, Y., Koda, T., Matsushima, K. and Nishimura, T. (2001) A critical role for mouse CXC chemokine(s) in pulmonary neutrophilia during Thtype 1-dependent airway inflammation. The Journal of Immunology: Official Journal of the American Association of Immunologists, 167, 2349 2353.
[27] Watanabe, T., Asai, K., Fujimoto, H., Tanaka, H., Kana zawa, H. and Hirata, K. (2011) Increased levels of HMGB 1 and endogenous secretory RAGE in induced sputum from asthmatic patients. Respiratory Medicine, 105, 519 525. Epub 30 October 2010. doi:10.1016/j.rmed.2010.10.016
[28] Fahy, J.V., Kim, K.W., Liu, J. and Boushey, H.A. (1995) Prominent neutrophilic inflammation in sputum from subjects with asthma exacerbation. The Journal of Allergy and Clinical Immunology, 95, 843-852. doi:10.1016/S0091-6749(95)70128-1
[29] Haldar, P. and Pavord, I.D. (2007) Noneosinophilic asthma: A distinct clinical and pathologic phenotype. The Journal of Allergy and Clinical Immunology, 119, 1043 1052; Quiz 1053-1054. doi:10.1016/j.jaci.2007.02.042
[30] Balzar, S., Fajt, M.L., Comhair, S.A., Erzurum, S.C., Bleecker, E., Busse, W.W., Castro, M., Gaston, B., Israel, E., Schwartz, L.B., Curran-Everett, D., Moore, C.G. and Wenzel, S.E. (2011) Mast cell phenotype, location, and activation in severe asthma. Data from the Severe Asthma Research Program. American Journal of Respiratory and Critical Care Medicine, 183, 299-309. Epub 2 September 2010. doi:10.1164/rccm.201002-0295OC
[31] Pohunek, P., Warner, J.O., Turzíková, J., Kudrmann, J. and Roche, W.R. (2005) Markers of eosinophilic inflammation and tissue re-modelling in children before clinically diagnosed bronchial asthma. Pediatric Allergy and Immunology: Official Publication of the European Society of Pediatric Allergy and Immunology, 16, 43-51.
[32] Macedo, P., Hew, M., Torrego, A., Jouneau, S., Oates, T., Durham, A. and Chung, K.F. (2009) Inflammatory bio markers in airways of patients with severe asthma compared with non-severe asthma. Clinical and Experimental Allergy: Journal of the British Society for Allergy and Clinical Immunology, 39, 1668-1676. Epub 20 July 2009. doi:10.1111/j.1365-2222.2009.03319.x
[33] Szefler, S.J., Martin, R.J., King, T.S., Boushey, H.A., Cherniack, R.M., Chinchilli, V.M., Craig, T.J., Dolovich, M., Drazen, J.M., Fagan, J.K., Fahy, J.V., Fish, J.E., Ford, J.G., Israel, E., Kiley, J., Kraft, M., Lazarus, S.C., Lemanske Jr., R.F., Mauger, E., Peters, S.P. and Sorkness, C.A.; Asthma Clinical Research Network of the National Heart Lung, and Blood Institute (2002) Significant variability in response to inhaled corticosteroids for persistent asthma. The Journal of Allergy and Clinical Immunology, 109, 410-418. doi:10.1067/mai.2002.122635
[34] Hawkins, G.A., Lazarus, R., Smith, R.S., Tantisira, K.G., Meyers, D.A., Peters, S.P., Weiss, S.T. and Bleecker, E.R. (2009) The glucocorticoid receptor heterocomplex gene STIP1 is associated with improved lung function in asthmatic subjects treated with inhaled corticosteroids. The Journal of Allergy and Clinical Immunology, 123, 1376-1383, e7. Epub 28 February 2009. doi:10.1016/j.jaci.2009.01.049
[35] Tantisira, K.G., Lasky-Su, J., Harada, M., Murphy, A., Litonjua, A.A., Himes, B.E., Lange, C., Lazarus, R., Syl via, J., Klanderman, B., Duan, Q.L., Qiu, W., Hirota, T., Martinez, F.D., Mauger, D., Sorkness, C., Szefler, S., Lazarus, S.C., Lemanske Jr., R.F., Peters, S.P., Lima, J.J., Nakamura, Y., Tamari, M. and Weiss, S.T. (2001) Ge nomewide association between GLCCI1 and response to glucocorticoid therapy in asthma. The New England Journal of Medicine, 365, 1173-1183. Epub 26 September 2011. doi:10.1056/NEJMoa0911353
[36] Pavord, I.D., Brightling, C.E., Woltmann, G. and Wardlaw, A.J. (1999) Non-eosinophilic corticosteroid unresponsive asthma. Lancet, 26353, 2213-2214. doi:10.1016/S0140-6736(99)01813-9
[37] Yang, M., Kumar, R.K. and Foster, P.S. (2009) Pathogenesis of steroid-resistant airway hyperresponsiveness: Interaction between IFN-gamma and TLR4/MyD88 path ways. The Journal of Immunology: Official Journal of the American Association of Immunologists, 182, 5107-5115. doi:10.4049/jimmunol.0803468
[38] Heaton, T., Rowe, J., Turner, S., Aalberse, R.C., de Klerk, N., Suriyaarachchi, D., Serralha, M., Holt, B.J., Hollams, E., Yerkovich, S., Holt, K., Sly, P.D., Goldblatt, J., Le Souef, P. and Holt, P.G. (2005) An immunoepidemiologi cal approach to asthma: Identification of in-vitro T-cell response patterns associated with different wheezing phenotypes in children. Lancet, 365, 142-149. doi:10.1016/S0140-6736(05)17704-6
[39] Ito, K., Herbert, C., Siegle, J.S., Vuppusetty, C., Hansbro, N., Thomas, P.S., Foster, P.S., Barnes, P.J. and Kumar, R.K. (2008) Steroid-resistant neutrophilic inflammation in a mouse model of an acute exacerbation of asthma. American Journal of Respiratory Cell and Molecular Biology, 39, 543-550. Epub 12 May 2008. doi:10.1165/rcmb.2008-0028OC
[40] McKinley, L., Alcorn, J.F., Peterson, A., Dupont, R.B., Kapadia, S., Logar, A., Henry, A., Irvin, C.G., Piganelli, J.D., Ray, A. and Kolls, J.K. (2008) TH17 cells mediate steroid-resistant airway inflammation and airway hyper responsiveness in mice. The Journal of immunology: Of ficial Journal of the American Association of Immunologists, 181, 4089-4097.
[41] Al-Ramli, W., Préfontaine, D., Chouiali, F., Martin, J.G., Olivenstein, R., Lemière, C. and Hamid, Q. (2009) T(H)17 associated cytokines (IL-17A and IL-17F) in severe asthma. The Journal of Allergy and Clinical Immunology, 123, 1185-1187. Epub 10 April 2009. doi:10.1016/j.jaci.2009.02.024
[42] Vazquez-Tello, A., Semlali, A., Chakir, J., Martin, J.G., Leung, D.Y., Eidelman, D.H. and Hamid, Q. (2010) In duction of glucocorticoid receptor-beta expression in epithelial cells of asthmatic airways by T-helper type 17 cytokines. Clinical and Experimental Allergy: Journal of the British Society for Allergy and Clinical Immunology, 40, 1312-1322. Epub 9 June 2010. doi:10.1111/j.1365-2222.2010.03544.x
[43] Beck, I.M., Vanden Berghe, W., Vermeulen, L., Yama moto, K.R., Haegeman, G. and De Bosscher, K. (2009) Crosstalk in inflammation: The interplay of glucocorti coid receptor-based mechanisms and kinases and phosphatases. Endocrine Reviews, 30, 830-882. Epub 4 November 2009. doi:10.1210/er.2009-0013
[44] Kobayashi, Y., Mercado, N., Barnes, P.J. and Ito, K. (2011) Defects of protein phosphatase 2A causes corticosteroid insensitivity in severe asthma. PloS One [Electronic Resource], 6, e27627. Epub19 December 2011. doi:10.1371/journal.pone.0027627
[45] Bouazza, B., Krytska, K., Debba-Pavard, M., Amrani, Y., Honkanen, R.E., Tran, J. and Tliba, O. (2012) Cytokines alter glucocorticoid receptor phosphorylation in airway cells: Role of phosphatases. American Journal of Respi ratory Cell and Molecular Biology, 47, 464-473. Epub 16 May 2012. doi:10.1165/rcmb.2011-0364OC
[46] Hamid, Q.A., Wenzel, S.E., Hauk, P.J., Tsicopoulos, A., Wallaert, B., Lafitte, J.J., Chrousos, G.P., Szefler, S.J. and Leung, D.Y. (1999) Increased glucocorticoid receptor beta in airway cells of glucocorticoid-insensitive asthma. American Journal of Respiratory and Critical Care Medicine, 159, 1600-1604.
[47] Li, L.B., Leung, D.Y., Martin, R.J. and Goleva, E. (2010) Inhibition of histone deacetylase 2 expression by elevated glucocorticoid receptor beta in steroid-resistant asthma. American Journal of Respiratory and Critical Care Medi cine, 182, 877-883. Epub 10 June 2010. doi:10.1164/rccm.201001-0015OC
[48] Butler, C.A., McQuaid, S., Taggart, C.C., Weldon, S., Carter, R., Skibinski, G., Warke, T.J., Choy, D.F., McGarvey, L.P., Bradding, P., Arron, J.R. and Heaney, L.G. (2012) Glucocorticoid receptor β and histone deace tylase 1 and 2 expression in the airways of severe asthma. Thorax, 67, 392-398. Epub 8 December 2011. doi:10.1136/thoraxjnl-2011-200760
[49] Tliba, O., Damera, G., Banerjee, A., Gu, S., Baidouri, H., Keslacy, S. and Amrani, Y. (2008) Cytokines induce an early steroid resistance in airway smooth muscle cells: Novel role of interferon regulatory factor-1. American Journal of Respiratory Cell and Molecular Biology, 38, 463-472. Epub 18 October 2007. doi:10.1165/rcmb.2007-0226OC
[50] Roos, A.B. and Nord, M. (2012) The emerging role of C/EBPs in glucocorticoid signaling: Lessons from the lung. The Journal of Endocrinology, 212, 291-305. Epub 1 November 2011. doi:10.1530/JOE-11-0369
[51] Roussel, L., Robins, S., Schachter, A., Bérubé, J., Hamid, Q. and Rousseau, S. (2011) Steroids and extracellular signal-regulated kinase 1/2 activity suppress activating transcription factor 3 expression in patients with severe asthma. The Journal of Allergy and Clinical Immunology, 127, 1632-1634. Epub 22 April 2011. doi:10.1016/j.jaci.2011.03.034
[52] Adenuga, D., Caito, S., Yao, H., Sundar, I.K., Hwang, J.W., Chung, S. and Rahman, I. (2010) Nrf2 deficiency influences susceptibility to steroid resistance via HDAC2 reduction. Biochemical and Biophysical Research Communications, 403, 452-456. Epub 19 November 2010. doi:10.1016/j.bbrc.2010.11.054
[53] Irusen, E., Matthews, J.G., Takahashi, A., Barnes, P.J., Chung, K.F. and Adcock, I.M. (2002) p38 Mitogen-activated protein kinase-induced glucocorticoid receptor pho sphorylation reduces its activity: Role in steroid-insensitive asthma. The Journal of Allergy and Clinical Immunology, 109, 649-657. doi:10.1067/mai.2002.122465
[54] Goleva, E., Li, L.B. and Leung, D.Y. (2009) IFN-gamma reverses IL-2 and IL-4-mediated T-cell steroid resistance. American Journal of Respiratory Cell and Molecular Biology, 40, 223-230. Epub 5 September 2008. doi:10.1165/rcmb.2007-0327OC
[55] Bhavsar, P., Khorasani, N., Hew, M., Johnson, M. and Chung, K.F. (2010) Effect of p38 MAPK inhibition on corticosteroid suppression of cytokine release in severe asthma. The European Respiratory Journal: Official Journal of the European Society for Clinical Respiratory Physiology, 35, 750-756. Epub 19 October 2009. doi:10.1183/09031936.00071309
[56] Ito, K., Caramori, G. and Adcock, I.M. (2007) Therapeu tic potential of phosphatidylinositol 3-kinase inhibitors in inflammatory respiratory disease. The Journal of Phar macology and Experimental Therapeutics, 321, 1-8. Epub 4 October 2006. doi:10.1124/jpet.106.111674
[57] Xystrakis, E., Kusumakar, S., Boswell, S., Peek, E., Urry, Z., Richards, D.F., Adikibi, T., Pridgeon, C., Dallman, M., Loke, T.K., Robinson, D.S., Barrat, F.J., O’Garra, A., Lavender, P. Lee, T.H., Corrigan, C. and Hawrylowicz, C.M. (2006) Reversing the defective induction of IL-10 secreting regulatory T cells in glucocorticoid-resistant asthma patients. The Journal of Clinical Investigation, 116, 146-155. Epub 8 December 2005.
[58] Ito, K., Lim, S., Caramori, G., Chung, K.F., Barnes, P.J. and Adcock, I.M. (2001) Cigarette smoking reduces his tone deacetylase 2 expression, enhances cytokine expression, and inhibits glucocorticoid actions in alveolar macro phages. FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology, 15, 1110-1112.
[59] Didon, L., Barton, J.L., Roos, A.B., Gaschler, G.J., Bauer, C.M., Berg, T., St?mpfli, M.R. and Nord, M. (2011) Lung epithelial CCAAT/enhancer-binding protein-β is necessary for the integrity of inflammatory responses to cigarette smoke. American Journal of Respiratory and Critical Care Medicine, 184, 233-242. Epub 11 May 2011. doi:10.1164/rccm.201007-1113OC
[60] Sutherland, E.R., Lehman, E.B., Teodorescu, M. and Wechsler, M.E.; National Heart, Lung, and Blood Institute’s Asthma Clinical Research Network (2009) Body mass index and phenotype in subjects with mild-to-moderate persistent asthma. The Journal of Allergy and Clinical Immunology, 123, 1328-1334, e1. doi:10.1016/j.jaci.2009.04.005

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