[en] Many patients suffering from asthma are not fully controlled by currently available treatments, and some of them display an airway remodeling leading to exaggerated lung function decline. The aim of the present study was to unveil new mediators in asthma to better understand pathophysiology and propose or validate new potential therapeutic targets. A mouse model of asthma mimicking acute or chronic asthma disease was used to select genes undergoing a modulation in both acute and chronic conditions. Mice were exposed to ovalbumin or PBS for 1, 5, and 10 wk [short-, intermediate-, and long-term model (ST, IT, and LT)], and gene expression in the lung was studied using an Affymetrix 430 2.0 genome-wide microarray and further confirmed by RT-PCR and immunohistochemistry for selected targets. We report that 598, 1,406, and 117 genes were upregulated and 490, 153, 321 downregulated at ST, IT, and LT, respectively. Genes related to mucous secretion displayed a progressively amplified expression during the allergen exposure protocol, whereas genes corresponding to growth and differentiation factors, matrix metalloproteinases, and collagens were mainly upregulated at IT. By contrast, genes related to cell division were upregulated at ST and IT and were downregulated at LT. In this study, besides confirming that Arg1, Slc26a4, Ear11, and Mmp12 genes are highly modulated throughout the asthma pathology, we show for the first time that Agr2, Scin, and Cd209e genes are overexpressed throughout the allergen exposure and might therefore be considered as suitable new potential targets for the treatment of asthma.
Garbacki, Nancy ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Protéines et glycoprot. de matr.extracell. et membran.basal.
Guéders, Maud ; Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement
Noël, Agnès ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie cellulaire et moléculaire appliquée à l'homme
Foidart, Jean-Michel ; Université de Liège - ULiège > Département des sciences cliniques > Gynécologie - Obstétrique - Labo de biologie des tumeurs et du développement
Grooten, J.
Colige, Alain ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Protéines et glycoprot. de matr.extracell. et membran.basal.
Piette, Jacques ; Université de Liège - ULiège > Département des sciences de la vie > GIGA-R : Virologie - Immunologie - GIGA-Research
Cataldo, Didier ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biochimie et physiologie générales, humaines et path.
Language :
English
Title :
New asthma biomarkers: lessons from murine models of acute and chronic asthma.
Publication date :
February 2009
Journal title :
American Journal of Physiology - Lung Cellular and Molecular Physiology
ISSN :
1040-0605
eISSN :
1522-1504
Publisher :
American Physiological Society, Bethesda, United States - Maryland
Volume :
296
Issue :
2
Pages :
L185-97
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
F.R.S.-FNRS - Fonds de la Recherche Scientifique [BE]
Ammit AJ, Moir LM, Oliver BG, Hughes JM, Alkhouri H, Ge Q, Burgess JK, Black JL, Roth M. Effect of IL-6 trans-signaling on the pro-remodeling phenotype of airway smooth muscle. Am J Physiol Lung Cell Mol Physiol 292: L199-L206, 2007.
Beissbarth T, Speed TP. GOstat: find statistically overrepresented Gene Ontologies within a group of genes. Bioinformatics 20: 1464-1465, 2004.
Bisset LR, Schmid-Grendelmeier P. Chemokines and their receptors in the pathogenesis of allergic asthma: progress and perspective. Curr Opin Pulm Med 11: 35-42, 2005.
Bracke K, Cataldo D, Maes T, Gueders M, Noel A, Foidart JM, Brusselle G, Pauwels RA. Matrix metalloproteinase-12 and cathepsin D expression in pulmonary macrophages and dendritic cells of cigarette smoke-exposed mice. Int Arch Allergy Immunol 138: 169-179, 2005.
Cataldo DD, Gueders M, Munaut C, Rocks N, Bartsch P, Foidart JM, Noel A, Louis R. Matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases mRNA transcripts in the bronchial secretions of asthmatics. Lab Invest 84: 418-424, 2004.
Cataldo DD, Tournoy KG, Vermaelen K, Munaut C, Foidart JM, Louis R, Noel A, Pauwels RA. Matrix metalloproteinase-9 deficiency impairs cellular infiltration and bronchial hyperresponsiveness during allergen-induced airway inflammation. Am J Pathol 161: 491-498, 2002.
Chiba Y, Yu Y, Sakai H, Misawa M. Increase in the expression of matrix metalloproteinase-12 in the airways of rats with allergic bronchial asthma. Biol Pharm Bull 30: 318-323, 2007.
Cormier SA, Yuan S, Crosby JR, Protheroe CA, Dimina DM, Hines EM, Lee NA, Lee JJ. T(H)2-mediated pulmonary inflammation leads to the differential expression of ribonuclease genes by alveolar macrophages. Am J Respir Cell Mol Biol 27: 678-687, 2002.
Ehre C, Rossi AH, Abdullah LH, De Pestel K, Hill S, Olsen JC, Davis CW. Barrier role of actin filaments in regulated mucin secretion from airway goblet cells. Am J Physiol Cell Physiol 288: C46-C56, 2005.
Ekmekci OB, Donma O, Ekmekci H, Yildirim N, Uysal O, Sardogan E, Demirel H, Demir T. Plasma paraoxonase activities, lipoprotein oxidation, and trace element interaction in asthmatic patients. Biol Trace Elem Res 111: 41-52, 2006.
Fulkerson PC, Zimmermann N, Hassman LM, Finkelman FD, Rothenberg ME. Pulmonary chemokine expression is coordinately regulated by STAT1, STAT6, and IFN-gamma. J Immunol 173: 7565-7574, 2004.
Gerard NP, Gerard C. Complement in allergy and asthma. Curr Opin Immunol 14: 705-708, 2002.
Gueders MM, Foidart JM, Noel A, Cataldo DD. Matrix metallopro-teinases (MMPs) and tissue inhibitors of MMPs in the respiratory tract: potential implications in asthma and other lung diseases. Eur J Pharmacol 533: 133-144, 2006.
Hantos Z, Daroczy B, Suki B, Nagy S, Fredberg JJ. Input impedance and peripheral inhomogeneity of dog lungs. J Appl Physiol 72: 168-178, 1992.
Kanters D, ten Hove W, Luijk B, van Aalst C, Schweizer RC, Lammers JW, Leufkens HG, Raaijmakers JA, Bracke M, Koenderman L. Expression of activated Fc gamma RII discriminates between multiple granulocyte-priming phenotypes in peripheral blood of allergic asthmatic subjects. J Allergy Clin Immunol 120: 1073-1081, 2007.
Komiya T, Tanigawa Y, Hirohashi S. Cloning of the gene gob-4, which is expressed in intestinal goblet cells in mice. Biochim Biophys Acta 1444: 434-438, 1999.
Lange P, Parner J, Vestbo J, Schnohr P, Jensen G. A 15-year follow-up study of ventilatory function in adults with asthma. N Engl J Med 339: 1194 -1200, 1998.
Liu D, Rudland PS, Sibson DR, Platt-Higgins A, Barraclough R. Human homologue of cement gland protein, a novel metastasis inducer associated with breast carcinomas. Cancer Res 65: 3796-3805, 2005.
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-ΔΔC T) method. Methods 25: 402-408, 2001.
Louis R, Lau LC, Bron AO, Roldaan AC, Radermecker M, Djukanovic R. The relationship between airways inflammation and asthma severity. Am J Respir Crit Care Med 161: 9-16, 2000.
Lukacs NW. Role of chemokines in the pathogenesis of asthma. Nat Rev Immunol 1: 108-116, 2001.
Masoli M, Fabian D, Holt S, Beasley R. The global burden of asthma: executive summary of the GINA Dissemination Committee report. Allergy 59: 469-478, 2004.
Nakao I, Kanaji S, Ohta S, Matsushita H, Arima K, Yuyama N, Yamaya M, Nakayama K, Kubo H, Watanabe M, Sagara H, Sug-iyama K, Tanaka H, Toda S, Hayashi H, Inoue H, Hoshino T, Shiraki A, Inoue M, Suzuki K, Aizawa H, Okinami S, Nagai H, Hasegawa M, Fukuda T, Green ED, Izuhara K. Identification of pendrin as a common mediator for mucus production in bronchial asthma and chronic obstructive pulmonary disease. J Immunol 180: 6262-6269, 2008.
Nurminsky D, Magee C, Faverman L, Nurminskaya M. Regulation of chondrocyte differentiation by actin-severing protein adseverin. Dev Biol 302: 427-437, 2007.
Park CG, Takahara K, Umemoto E, Yashima Y, Matsubara K, Matsuda Y, Clausen BE, Inaba K, Steinman RM. Five mouse homo-logues of the human dendritic cell C-type lectin, DC-SIGN. Int Immunol 13: 1283-1290, 2001.
Park SG, Choi JW, Kim H, Roh GS, Bok J, Go MJ, Kwack K, Oh B, Kim Y. Genome-wide profiling of antigen-induced time course expression using murine models for acute and chronic asthma. Int Arch Allergy Immunol 146: 44-56, 2008.
Pascual RM, Peters SP. Airway remodeling contributes to the progressive loss of lung function in asthma: an overview. J Allergy Clin Immunol 116: 477-486; quiz 487, 2005.
Pedemonte N, Caci E, Sondo E, Caputo A, Rhoden K, Pfeffer U, Di Candia M, Bandettini R, Ravazzolo R, Zegarra-Moran O, Galietta LJ. Thiocyanate transport in resting and IL-4-stimulated human bronchial epithelial cells: role of pendrin and anion channels. J Immunol 178: 5144-5153, 2007.
Ramos-Barbon D, Ludwig MS, Martin JG. Airway remodeling: lessons from animal models. Clin Rev Allergy Immunol 27: 3-21, 2004.
Rodriguez Del Castillo A, Lemaire S, Tchakarov L, Jeyapragasan M, Doucet JP, Vitale ML, Trifaró JM. Chromaffin cell scinderin, a novel calcium-dependent actin filament-severing protein. EMBO J 9: 43-52, 1990.
Sarma VJ, Huber-Lang M, Ward PA. Complement in lung disease. Autoimmunity 39: 387-394, 2006.
Syed F, Huang CC, Li K, Liu V, Shang T, Amegadzie BY, Griswold DE, Song XY, Li L. Identification of interleukin-13 related biomarkers using peripheral blood mononuclear cells. Biomarkers 12: 414 -423, 2007.
Tailleux L, Pham-Thi N, Bergeron-Lafaurie A, Herrmann JL, Charles P, Schwartz O, Scheinmann P, Lagrange PH, de Blic J, Tazi A, Gicquel B, Neyrolles O. DC-SIGN induction in alveolar macrophages defines privileged target host cells for mycobacteria in patients with tuberculosis. PLoS Med 2: e381, 2005.
Thompson DA, Weigel RJ. hAG-2, the human homologue of the Xeno-pus laevis cement gland gene XAG-2, is coexpressed with estrogen receptor in breast cancer cell lines. Biochem Biophys Res Commun 251:111-116, 1998.
van der Sluis M, Vincent A, Bouma J, Male AK, van Goudoever JB, Renes IB, Van Seuningen I. Forkhead box transcription factors Foxa1 and Foxa2 are important regulators of Muc2 mucin expression in intestinal epithelial cells. Biochem Biophys Res Commun 369: 1108-1113, 2008.
Van Scoyk M, Randall J, Sergew A, Williams LM, Tennis M, Winn RA. Wnt signaling pathway and lung disease. Transl Res 151: 175-180, 2008.
Wang Z, Hao Y, Lowe AW. The adenocarcinoma-associated antigen, AGR2, promotes tumor growth, cell migration, and cellular transformation. Cancer Res 68: 492-497, 2008.
Ward JM, Yoon M, Anver MR, Haines DC, Kudo G, Gonzalez FJ, Kimura S. Hyalinosis and Ym1/Ym2 gene expression in the stomach and respiratory tract of 129S4/SvJae and wild-type and CYP1A2-null B6, 129 mice. Am J Pathol 158: 323-332, 2001.
Wills-Karp M, Chiaramonte M. Interleukin-13 in asthma. Curr Opin Pulm Med 9: 21-27, 2003.
Wong WS, Zhao J. Proteome analysis of chronically inflamed lungs in a mouse chronic asthma model. Int Arch Allergy Immunol 147: 179-189, 2008.
Yamashita N, Tashimo H, Ishida H, Matsuo Y, Arai H, Nagase H, Adachi T, Ohta K. Role of insulin-like growth factor-I in allergen-induced airway inflammation and remodeling. Cell Immunol 235: 85-91, 2005.
Zhang JS, Gong A, Cheville JC, Smith DI, Young CY. AGR2, an androgen-inducible secretory protein overexpressed in prostate cancer. Genes Chromosomes Cancer 43: 249 -259, 2005.
Zhao J, Zhu H, Wong CH, Leung KY, Wong WS. Increased lungkine and chitinase levels in allergic airway inflammation: a proteomics approach. Proteomics 5: 2799-2807, 2005.
Zheng W, Rosenstiel P, Huse K, Sina C, Valentonyte R, Mah N, Zeitlmann L, Grosse J, Ruf N, Nurnberg P, Costello CM, Onnie C, Mathew C, Platzer M, Schreiber S, Hampe J. Evaluation of AGR2 and AGR3 as candidate genes for inflammatory bowel disease. Genes Immun 7: 11-18, 2006.
Zhou T, Chen Y, Hao L, Zhang Y. DC-SIGN and immunoregulation. Cell Mol Immunol 3: 279-283, 2006.
Zimmermann N, Hershey GK, Foster PS, Rothenberg ME. Chemo-kines in asthma: cooperative interaction between chemokines and IL-13. J Allergy Clin Immunol 111: 227-242; quiz 243, 2003.
Zimmermann N, King NE, Laporte J, Yang M, Mishra A, Pope SM, Muntel EE, Witte DP, Pegg AA, Foster PS, Hamid Q, Rothenberg ME. Dissection of experimental asthma with DNA microarray analysis identifies arginase in asthma pathogenesis. J Clin Invest 111: 1863-1874, 2003.
Zimmermann N, Rothenberg ME. The arginine-arginase balance in asthma and lung inflammation. Eur J Pharmacol 533: 253-262, 2006.