BACKGROUND: The cause of corticosteroid-resistant (CR) asthma is unknown. OBJECTIVE: We sought to perform gene microarray analyses by using bronchoalveolar lavage (BAL) cells from well-characterized subjects with CR asthma and subject with corticosteroid-sensitive (CS) asthma to elucidate the differential expression of genes that contribute to the development of corticosteroid resistance. METHODS: The patients were characterized as having CR or CS asthma based on FEV(1) percent predicted improvement after a 1-week course of oral prednisone. Expression of selected gene targets was verified by means of real-time PCR and ELISA. RESULTS: Microarray analyses demonstrated significantly higher levels (>3-fold increase, P < .05) of transcripts for TNF-alpha, IL-1 alpha, IL-1 beta, IL-6, CXCL1, CXCL2, CXCL3, CXCL8 (IL-8), CCL3, CCL4, and CCL20 in BAL cells of subjects with CR asthma. These findings, confirmed by means of RT-PCR in additional BAL samples, were consistent with classical macrophage activation by bacterial products. In contrast, markers of alternatively activated macrophages, arginase I and CCL24, were decreased. Genes associated with activation of the LPS signaling pathway (early growth response 1, dual-specificity phosphatase 2, molecule possessing ankyrin repeats induced by LPS, and TNF-alpha-induced protein 3) were significantly increased in BAL samples from subjects with CR asthma (P < .05). These patients had significantly higher amounts (1444.0 +/- 457.3 pg/mg total protein) of LPS in BAL fluid than seen in subjects with CS asthma (270.5 +/- 216.0 pg, P < .05), as detected by using the LAL assay and confirmed by means of gas chromatographic/mass spectrometric analysis. Prolonged exposure to LPS induced functional steroid resistance to dexamethasone in normal human monocytes, as demonstrated by persistently increased IL-6 levels in the presence of dexamethasone. CONCLUSIONS: Classical macrophage activation and induction of LPS signaling pathways along with high endotoxin levels detected in BAL fluid from subjects with CR asthma suggest that LPS exposure might contribute to CR asthma.
BACKGROUND: The cause of corticosteroid-resistant (CR) asthma is unknown. OBJECTIVE: We sought to perform gene microarray analyses by using bronchoalveolar lavage (BAL) cells from well-characterized subjects with CR asthma and subject with corticosteroid-sensitive (CS) asthma to elucidate the differential expression of genes that contribute to the development of corticosteroid resistance. METHODS: The patients were characterized as having CR or CS asthma based on FEV(1) percent predicted improvement after a 1-week course of oral prednisone. Expression of selected gene targets was verified by means of real-time PCR and ELISA. RESULTS: Microarray analyses demonstrated significantly higher levels (>3-fold increase, P < .05) of transcripts for TNF-alpha, IL-1 alpha, IL-1 beta, IL-6, CXCL1, CXCL2, CXCL3, CXCL8 (IL-8), CCL3, CCL4, and CCL20 in BAL cells of subjects with CR asthma. These findings, confirmed by means of RT-PCR in additional BAL samples, were consistent with classical macrophage activation by bacterial products. In contrast, markers of alternatively activated macrophages, arginase I and CCL24, were decreased. Genes associated with activation of the LPS signaling pathway (early growth response 1, dual-specificity phosphatase 2, molecule possessing ankyrin repeats induced by LPS, and TNF-alpha-induced protein 3) were significantly increased in BAL samples from subjects with CR asthma (P < .05). These patients had significantly higher amounts (1444.0 +/- 457.3 pg/mg total protein) of LPS in BAL fluid than seen in subjects with CS asthma (270.5 +/- 216.0 pg, P < .05), as detected by using the LAL assay and confirmed by means of gas chromatographic/mass spectrometric analysis. Prolonged exposure to LPS induced functional steroid resistance to dexamethasone in normal human monocytes, as demonstrated by persistently increased IL-6 levels in the presence of dexamethasone. CONCLUSIONS: Classical macrophage activation and induction of LPS signaling pathways along with high endotoxin levels detected in BAL fluid from subjects with CR asthma suggest that LPS exposure might contribute to CR asthma.
Authors: James A Platts-Mills; Natalie J Custis; Judith A Woodfolk; Thomas A E Platts-Mills Journal: J Allergy Clin Immunol Date: 2005-08 Impact factor: 10.793
Authors: Peter S Thorne; Katarina Kulhánková; Ming Yin; Richard Cohn; Samuel J Arbes; Darryl C Zeldin Journal: Am J Respir Crit Care Med Date: 2005-09-01 Impact factor: 21.405
Authors: Ichiro Nomura; Bifeng Gao; Mark Boguniewicz; Marc A Darst; Jeffrey B Travers; Donald Y m Leung Journal: J Allergy Clin Immunol Date: 2003-12 Impact factor: 10.793
Authors: Prescott G Woodruff; Homer A Boushey; Gregory M Dolganov; Chris S Barker; Yee Hwa Yang; Samantha Donnelly; Almut Ellwanger; Sukhvinder S Sidhu; Trang P Dao-Pick; Carlos Pantoja; David J Erle; Keith R Yamamoto; John V Fahy Journal: Proc Natl Acad Sci U S A Date: 2007-09-26 Impact factor: 11.205
Authors: Nives Zimmermann; Nina E King; Johanne Laporte; Ming Yang; Anil Mishra; Sam M Pope; Emily E Muntel; David P Witte; Anthony A Pegg; Paul S Foster; Qutayba Hamid; Marc E Rothenberg Journal: J Clin Invest Date: 2003-06 Impact factor: 14.808
Authors: Elena Goleva; Leisa P Jackson; J Kirk Harris; Charles E Robertson; E Rand Sutherland; Clifton F Hall; James T Good; Erwin W Gelfand; Richard J Martin; Donald Y M Leung Journal: Am J Respir Crit Care Med Date: 2013-11-15 Impact factor: 21.405
Authors: F M C Silva; E E Oliveira; A C C Gouveia; A S S Brugiolo; C C Alves; J O A Correa; J Gameiro; J Mattes; H C Teixeira; A P Ferreira Journal: Clin Exp Immunol Date: 2017-03-31 Impact factor: 4.330
Authors: Y A Bochkov; K M Hanson; S Keles; R A Brockman-Schneider; N N Jarjour; J E Gern Journal: Mucosal Immunol Date: 2009-08-26 Impact factor: 7.313
Authors: Ilse M E Beck; Wim Vanden Berghe; Linda Vermeulen; Keith R Yamamoto; Guy Haegeman; Karolien De Bosscher Journal: Endocr Rev Date: 2009-11-04 Impact factor: 19.871
Authors: J Diaz; L Warren; L Helfner; X Xue; P K Chatterjee; M Gupta; M H Solanki; M Esposito; V Bonagura; C N Metz Journal: Immunol Res Date: 2015-12 Impact factor: 2.829
Authors: G S Whitehead; S Hussain; R Fannin; C S Trempus; C L Innes; S H Schurman; D N Cook; S Garantziotis Journal: Lung Date: 2020-02-14 Impact factor: 2.584
Authors: Boyko Kabakchiev; Dan Turner; Jeffrey Hyams; David Mack; Neal Leleiko; Wallace Crandall; James Markowitz; Anthony R Otley; Wei Xu; Pingzhao Hu; Anne M Griffiths; Mark S Silverberg Journal: PLoS One Date: 2010-09-30 Impact factor: 3.240
Authors: Ruby Fernandez-Boyanapalli; Elena Goleva; Christena Kolakowski; Elysia Min; Brian Day; Donald Y M Leung; David W H Riches; Donna L Bratton; E Rand Sutherland Journal: J Allergy Clin Immunol Date: 2012-11-13 Impact factor: 10.793