Asthma has been an inflammatory disorder accompanied by tissue remodeling and protease-antiprotease imbalance in lungs. The SNPs of alpha-1 antitrypsin (α1AT) and tissue inhibitor of metalloproteinase-1 (TIMP-1) genes were studied for their association with asthma. Genotyping of α1AT and TIMP-1 genes was performed in 202 asthmatics and 204 controls. Serum levels of α1AT, TIMP-1 and cytokines were estimated to find if the interplay between genotypes and cellular biomarkers determines the pathogenesis of asthma. The analysis of results showed significantly low level of α1AT in the serum of asthmatics as compared to controls ( ), whereas cytokines were elevated in patients. No significant difference was observed in the concentration of TIMP-1 in patients and controls. Genotyping led to the identification of 3 SNPs (Val213Ala, Glu363Lys, and Glu376Asp) in α1AT gene. The novel SNP Glu363Lys of α1AT was found to be associated with asthma ( ). The analysis of TIMP-1 gene showed the occurrence of seven SNPs, including a novel intronic SNP at base G3774A. The allele frequency of G3774A and Phe124Phe was significantly higher in asthmatics as compared to controls. Thus, the SNP Glu363Lys of α1AT and G3774A and Phe124Phe of TIMP-1 could be important genetic markers for use in better management of the disease. 1. Introduction Asthma pathophysiology involves extensive remodeling of lung tissue structure, and the protease-antiprotease imbalance has been considered to play a significant role in the pathogenesis of the disease [1]. The neutrophils and alveolar macrophages (AM) synthesize neutrophil elastase (NE) and matrix metallo proteinase (MMP), respectively, which have been the prominent proteolytic enzymes released during the inflammatory events [2]. The NE is a protease which destroys major structural proteins of the alveolar wall. Since the expression and the activity of NE are required to be kept under check for the maintenance of the lung structure and integrity, an antiprotease alpha-1 antitrypsin (α1AT) is produced in the body. The α1AT, primarily synthesized by hepatocytes, attenuates NE in the lungs [3]. The MMPs have been reported to play an important role in regulating a variety of cellular processes including proliferation, differentiation, migration (adhesion/dispersion), angiogenesis, host defense, and apoptosis [4, 5]. The activity of MMP-9, a major MMP present in lung tissues, is kept under tight control by the tissue inhibitor of metalloproteinase-1 (TIMP-1) [6]. It has been reported that the balance between MMP-9 and TIMP-1 gets disturbed in the
References
[1]
J. Bousquet, P. K. Jeffery, W. W. Busse, M. Johnson, and A. M. Vignola, “Asthma: from bronchoconstriction to airways inflammation and remodeling,” American Journal of Respiratory and Critical Care Medicine, vol. 161, no. 5, pp. 1720–1745, 2000.
[2]
T. Betsuyaku, M. Nishimura, K. Takeyabu et al., “Neutrophil granule proteins in bronchoalveolar lavage fluid from subjects with subclinical emphysema,” American Journal of Respiratory and Critical Care Medicine, vol. 159, no. 6, pp. 1985–1991, 1999.
[3]
D. W. Cox, “α1-Antitrypsin deficiency,” in The Metabolic Basis of Inherited Disease, C. R. Scriber, A. L. Beaudet, W. S. Sly, and D. Valle, Eds., pp. 2409–2437, McGraw Hill, New York, NY, USA, 6th edition, 1989.
[4]
W. C. Parks, C. L. Wilson, and Y. S. López-Boado, “Matrix metalloproteinases as modulators of inflammation and innate immunity,” Nature Reviews Immunology, vol. 4, no. 8, pp. 617–629, 2004.
[5]
M. D. Sternlicht and Z. Werb, “How matrix metalloproteinases regulate cell behavior,” Annual Review of Cell and Developmental Biology, vol. 17, pp. 463–516, 2001.
[6]
Y. Okada, Y. Gonoji, K. Naka et al., “Matrix metalloproteinase 9 (92-kDa gelatinase/type IV collagenase) from HT 1080 human fibrosarcoma cells. Purification and activation of the precursor and enzymic properties,” The Journal of Biological Chemistry, vol. 267, no. 30, pp. 21712–21719, 1992.
[7]
D. D. Cataldo, J. Bettiol, A. No？l, P. Bartsch, J. M. Foidart, and R. Louis, “Matrix metalloproteinase-9, but not tissue inhibitor of matrix metalloproteinase-1, increases in the sputum from allergic asthmatic patients after allergen challenge,” Chest, vol. 122, no. 5, pp. 1553–1559, 2002.
[8]
R. M. Katz, J. Lieberman, and S. C. Siegel, “Alpha-1 antitrypsin levels and prevalence of Pi variant phenotypes in asthmatic children,” Journal of Allergy and Clinical Immunology, vol. 57, no. 1, pp. 41–45, 1976.
[9]
E. Eden, C. Strange, B. Holladay, and L. Xie, “Asthma and allergy in alpha-1 antitrypsin deficiency,” Respiratory Medicine, vol. 100, no. 8, pp. 1384–1391, 2006.
[10]
J. Gupta, D. P. Bhadoria, M. K. Lal et al., “Association of the PIM3 allele of the alpha-1-antitrypsin gene with chronic obstructive pulmonary disease,” Clinical Biochemistry, vol. 38, no. 5, pp. 489–491, 2005.
[11]
M. Kumar, D. P. Bhadoria, K. Dutta et al., “Combinatorial effect of TIMP-1 and α 1 AT gene polymorphisms on development of chronic obstructive pulmonary disease,” Clinical Biochemistry, vol. 44, no. 13, pp. 1067–1073, 2011.
[12]
S. A. Miller, D. D. Dykes, and H. F. Polesky, “A simple salting out procedure for extracting DNA from human nucleated cells,” Nucleic Acids Research, vol. 16, no. 3, p. 1215, 1988.
[13]
J. Gupta, D. Chattopadhaya, D. P. Bhadoria et al., “T lymphocyte subset profile and serum alpha-1-antitrypsin in pathogenesis of chronic obstructive pulmonary disease,” Clinical and Experimental Immunology, vol. 149, no. 3, pp. 463–469, 2007.
[14]
S. Eriksson, “Studies in alpha 1-antitrypsin deficiency,” Acta Medica Scandinavica, Supplement, vol. 432, pp. 1–85, 1965.
[15]
M. H. Welch, M. E. Reinecke, J. F. Hammarsten, and C. A. Guenter, “Antitrypsin deficiency in pulmonary disease: the significance of intermediate levels,” Annals of Internal Medicine, vol. 71, no. 3, pp. 533–542, 1969.
[16]
J. Ihrig, H. J. Schwartz, D. J. Rynbrandt, and J. Kleinerman, “Serum trypsin inhibitory capacity and Pi phenotypes. II. Prevalence of α1 antitrypsin deficiency in an allergy population,” American Journal of Clinical Pathology, vol. 64, no. 3, pp. 297–303, 1975.
[17]
M. Miravitlles, S. Vilà, M. Torrella et al., “Influence of deficient α1-anti-trypsin phenotypes on clinical characteristics and severity of asthma in adults,” Respiratory Medicine, vol. 96, no. 3, pp. 186–192, 2002.
[18]
W. I. Aderele, C. Ojo, V. O. Osanyintuyi, and O. Oduwole, “Serum alpha-1-antitrypsin level in asthmatic children,” African Journal of Medicine and Medical Sciences, vol. 14, no. 3-4, pp. 161–167, 1985.
[19]
I. Scroyen, L. Cosemans, and H. R. Lijnen, “Effect of tissue inhibitor of matrix metalloproteinases-1 on in vitro and in vivo adipocyte differentiation,” Thrombosis Research, vol. 124, no. 5, pp. 578–583, 2009.
[20]
B. Meissburger, L. Stachorski, E. R？der, G. Rudofsky, and C. Wolfrum, “Tissue inhibitor of matrix metalloproteinase 1 (TIMP1) controls adipogenesis in obesity in mice and in humans,” Diabetologia, vol. 54, no. 6, pp. 1468–1479, 2011.
[21]
E. A. B. Kelly, W. W. Busse, and N. N. Jarjour, “Increased matrix metalloproteinase-9 in the airway after allergen challenge,” American Journal of Respiratory and Critical Care Medicine, vol. 162, no. 3 I, pp. 1157–1161, 2000.
[22]
Y. Higashimoto, Y. Yamagata, T. Iwata et al., “Increased serum concentrations of tissue inhibitor of metalloproteinase-1 in COPD patients,” European Respiratory Journal, vol. 25, no. 5, pp. 885–890, 2005.
[23]
M. Hoshino, M. Takahashi, Y. Takai, and J. Sim, “Inhaled corticosteroids decrease subepithelial collagen deposition by modulation of the balance between matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 expression in asthma,” Journal of Allergy and Clinical Immunology, vol. 104, no. 2, pp. 356–363, 1999.
[24]
G. B. Karakoc, A. Inal, M. Yilmaz, D. U. Altintas, and S. G. Kendirli, “Exhaled breath condensate MMP-9 levels in children with bronchiectasis,” Pediatric Pulmonology, vol. 44, no. 10, pp. 1010–1016, 2009.
[25]
Y. Zhang, L. O. Cardell, and M. Adner, “IL-1β induces murine airway 5-HT2A receptor hyperresponsiveness via a non-transcriptional MAPK-dependent mechanism,” Respiratory Research, vol. 8, article 29, 2007.
[26]
J. I. Herseth, V. Volden, P. E. Schwarze, M. L？g, and M. Refsnes, “IL-1beta differently involved in IL-8 and FGF-2 release in crystalline silica-treated lung cell co-cultures,” Particle and Fibre Toxicology, vol. 5, article 16, 2008.
[27]
A. Ekberg-Jansson, B. Andersson, B. Bake et al., “Neutrophil-associated activation markers in healthy smokers relates to a fall in DLCO and to emphysematous changes on high resolution CT,” Respiratory Medicine, vol. 95, no. 5, pp. 363–373, 2001.
[28]
T. R. Mosmann and R. L. Coffman, “TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties,” Annual Review of Immunology, vol. 7, pp. 145–173, 1989.
[29]
Y. Ohashi, Y. Nakai, H. Okamoto, et al., “Serum level of Interleukin-4 in patients with perernial allergic rhinitis during allergen specifivc immuno-therapy,” Scandinavian Journal of Immunology, vol. 43, no. 6, pp. 680–686, 1996.
[30]
G. M. Cauvreau, R. M. Watson, and P. M. O'Byrne, “Kinetics of allergen-induced airway eosinophilic cytokine production and airway inflammation,” American Journal of Respiratory and Critical Care Medicine, vol. 160, no. 2, pp. 640–647, 1999.
[31]
J. Joseph, S. Benedict, W. Safa, and M. Joseph, “Serum interleukin-5 levels are elevated in mild and moderate persistent asthma irrespective of regular inhaled glucocorticoid therapy,” BMC Pulmonary Medicine, vol. 4, article 2, 2004.
[32]
A. Krisiukeniene, A. Babusyte, K. Stravinskaite, J. Lotvall, R. Sakalauskas, and B. Sitkauskiene, “Smoking affects eotaxin levels in asthma patients,” Journal of Asthma, vol. 46, no. 5, pp. 470–476, 2009.
[33]
D. Adamko, P. Lacy, and R. Moqbel, “Mechanisms of eosinophil recruitment and activation,” Current Allergy and Asthma Reports, vol. 2, no. 2, pp. 107–116, 2002.
[34]
D. F. Fiorentino, A. Zlotnik, P. Vieira et al., “IL-10 acts on the antigen-presenting cell to inhibit cytokine production by Th1 cells,” Journal of Immunology, vol. 146, no. 10, pp. 3444–3451, 1991.
[35]
G. Trinchieri and P. Scott, “Interleukin-12: a proinflammatory cytokine with immunoregulatory functions,” Research in Immunology, vol. 146, no. 7-8, pp. 423–431, 1995.
[36]
H. Takahashi, T. Nukiwa, K. Satoh et al., “Characterization of the gene and protein of the α1-antitrypsin “deficiency” allele M(procida),” The Journal of Biological Chemistry, vol. 263, no. 30, pp. 15528–15534, 1988.
[37]
B. B. Ceyhan, F. Y. Enc, and S. Sahin, “IL-2 and IL-10 levels in induced sputum and serum samples of asthmatics,” Journal of Investigational Allergology and Clinical Immunology, vol. 14, no. 1, pp. 80–85, 2004.
[38]
I. Hinterseher, D. Krex, E. Kuhlisch et al., “Tissue inhibitor of metalloproteinase-1 (TIMP-1) polymorphisms in a Caucasian population with abdominal aortic aneurysm,” World Journal of Surgery, vol. 31, no. 11, pp. 2248–2254, 2007.
[39]
L. Cartegni, J. Wang, Z. Zhu, M. Q. Zhang, and A. R. Krainer, “ESEfinder: a web resource to identify exonic splicing enhancers,” Nucleic Acids Research, vol. 31, no. 13, pp. 3568–3571, 2003.
[40]
F. Lose, P. J. Thompson, D. Duffy, G. A. Stewart, and M. A. Kedda, “A novel tissue inhibitor of metalloproteinase-1 (TIMP-1) polymorphism associated with asthma in Australian women,” Thorax, vol. 60, no. 8, pp. 623–628, 2005.
[41]
C. C. van Diemen, D. S. Postma, M. Siedlinski, A. Blokstra, H. A. Smit, and H. M. Boezen, “Genetic variation in TIMP1 but not MMPs predict excess FEV1 decline in two general population-based cohorts,” Respiratory Research, vol. 12, article 57, 2011.
