Sputum transcriptomics implicates increased p38 signalling activity in severe asthma.
Adult
Aged
Asthma
/ genetics
Case-Control Studies
Computational Biology
Cross-Sectional Studies
Female
Forced Expiratory Volume
Gene Expression Profiling
Humans
Inflammation
/ metabolism
Male
Middle Aged
Neutrophils
/ pathology
Phosphorylation
RNA, Messenger
/ metabolism
Severity of Illness Index
Signal Transduction
Sputum
/ metabolism
Transcriptome
Vital Capacity
p38 Mitogen-Activated Protein Kinases
/ genetics
asthma
gene expression
immune system
inflammation
sputum
Journal
Respirology (Carlton, Vic.)
ISSN: 1440-1843
Titre abrégé: Respirology
Pays: Australia
ID NLM: 9616368
Informations de publication
Date de publication:
07 2020
07 2020
Historique:
received:
18
06
2019
revised:
12
09
2019
accepted:
28
10
2019
pubmed:
7
12
2019
medline:
23
6
2021
entrez:
7
12
2019
Statut:
ppublish
Résumé
Severe asthma is responsible for a disproportionate burden of illness and healthcare costs spent on asthma. This study analyses sputum transcriptomics to investigate the mechanisms and novel treatment targets of severe asthma. Induced sputum samples were collected in a cross-sectional study from participants with severe asthma (n = 12, defined as per GINA criteria), non-severe uncontrolled (n = 21) and controlled asthma (n = 21) and healthy controls (n = 15). Sputum RNA was extracted and transcriptomic profiles were generated (Illumina HumanRef-8 V2) and analysed (GeneSpring). Sputum protein lysates were analysed for p38 activation in a validation study (n = 24 asthma, n = 8 healthy) by western blotting. There were 2166 genes differentially expressed between the four groups. In severe asthma, the expression of 1875, 1308 and 563 genes was altered compared to healthy controls, controlled and uncontrolled asthma, respectively. Of the 1875 genes significantly different to healthy controls, 123 were >2-fold change from which four networks were identified. Thirty genes (>2-fold change) were significantly different in severe asthma compared to both controlled asthma and healthy controls. There was enrichment of genes in the p38 signalling pathway that were associated with severe asthma. Phosphorylation of p38 was increased in a subset of severe asthma samples, correlating with neutrophilic airway inflammation. Severe asthma is associated with substantial differences in sputum gene expression that underlie unique cellular mechanisms. The p38 signalling pathway may be important in the pathogenesis of severe asthma, and future investigations into p38 inhibition are warranted as a 'non-Th2' therapeutic option.
Sections du résumé
BACKGROUND AND OBJECTIVE
Severe asthma is responsible for a disproportionate burden of illness and healthcare costs spent on asthma. This study analyses sputum transcriptomics to investigate the mechanisms and novel treatment targets of severe asthma.
METHODS
Induced sputum samples were collected in a cross-sectional study from participants with severe asthma (n = 12, defined as per GINA criteria), non-severe uncontrolled (n = 21) and controlled asthma (n = 21) and healthy controls (n = 15). Sputum RNA was extracted and transcriptomic profiles were generated (Illumina HumanRef-8 V2) and analysed (GeneSpring). Sputum protein lysates were analysed for p38 activation in a validation study (n = 24 asthma, n = 8 healthy) by western blotting.
RESULTS
There were 2166 genes differentially expressed between the four groups. In severe asthma, the expression of 1875, 1308 and 563 genes was altered compared to healthy controls, controlled and uncontrolled asthma, respectively. Of the 1875 genes significantly different to healthy controls, 123 were >2-fold change from which four networks were identified. Thirty genes (>2-fold change) were significantly different in severe asthma compared to both controlled asthma and healthy controls. There was enrichment of genes in the p38 signalling pathway that were associated with severe asthma. Phosphorylation of p38 was increased in a subset of severe asthma samples, correlating with neutrophilic airway inflammation.
CONCLUSION
Severe asthma is associated with substantial differences in sputum gene expression that underlie unique cellular mechanisms. The p38 signalling pathway may be important in the pathogenesis of severe asthma, and future investigations into p38 inhibition are warranted as a 'non-Th2' therapeutic option.
Substances chimiques
RNA, Messenger
0
p38 Mitogen-Activated Protein Kinases
EC 2.7.11.24
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
709-718Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2019 Asian Pacific Society of Respirology.
Références
McDonald VM, Maltby S, Gibson PG. Severe asthma: we can fix it? We can try! Respirology 2018; 23: 260-1.
Hekking P-PW, Wener RR, Amelink M, Zwinderman AH, Bouvy ML, Bel EH. The prevalence of severe refractory asthma. J. Allergy Clin. Immunol. 2015; 135: 896-902.
Foster J, McDonald V, Guo M, Reddel H. "I have lost in every facet of my life": the hidden burden of severe asthma. Eur. Respir. J. 2017; 50: 1700765.
Pavord ID, Beasley R, Agusti A, Anderson GP, Bel E, Brusselle G, Cullinan P, Custovic A, Ducharme FM, Fahy JV et al. After asthma: redefining airways diseases. Lancet 2018; 391: 350-400.
Chung KF, Wenzel SE, Brozek JL, Bush A, Castro M, Sterk PJ, Adcock IM, Bateman ED, Bel EH, Bleecker ER et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur. Respir. J. 2014; 43: 343-73.
Ray A, Raundhal M, Oriss TB, Ray P, Wenzel SE. Current concepts of severe asthma. J. Clin. Invest. 2016; 126: 2394-403.
Bush A. Pathophysiological mechanisms of asthma. Front. Pediatr. 2019; 7: 68.
Woodruff PG, Modrek B, Choy DF, Jia G, Abbas AR, Ellwanger A, Arron JR, Koth LL, Fahy JV. T-helper type 2-driven inflammation defines major subphenotypes of asthma. Am. J. Respir. Crit. Care Med. 2009; 180: 388-95.
Panettieri RA. The role of neutrophils in asthma. Immunol. Allergy Clin. North Am. 2018; 38: 629-38.
Baines KJ, Simpson JL, Wood LG, Scott RJ, Gibson PG. Transcriptional phenotypes of asthma defined by gene expression profiling of induced sputum samples. J. Allergy Clin. Immunol. 2011; 127: 153-60.
Baines KJ, Simpson JL, Wood LG, Scott RJ, Fibbens NL, Powell H, Cowan DC, Taylor DR, Cowan JO, Gibson PG. Sputum gene expression signature of 6 biomarkers discriminates asthma inflammatory phenotypes. J. Allergy Clin. Immunol. 2014; 133: 997-1007.
Wang G, Baines KJ, Fu JJ, Wood LG, Simpson JL, VM MD, Cowan DC, Taylor DR, Cowan JO, Gibson PG. Sputum mast cell subtypes relate to eosinophilia and corticosteroid response in asthma. Eur. Respir. J. 2016; 47: 1123-33.
Hekking P, Loza M, Pavlidis S, De Meulder B, Lefaudeux D, Baribaud F, Auffray C, Wagener A, Brinkman P, Lutter R et al.; U-BIOPRED Study Group. Transcriptomic gene signatures associated with persistent airflow limitation in patients with severe asthma. Eur. Respir. J. 2017; 50: 1602298.
Hekking P-P, Loza MJ, Pavlidis S, de Meulder B, Lefaudeux D, Baribaud F, Auffray C, Wagener AH, Brinkman PI, Lutter RI et al. Pathway discovery using transcriptomic profiles in adult-onset severe asthma. J. Allergy Clin. Immunol. 2018; 141: 1280-90.
Kuo C-HS, Pavlidis S, Loza M, Baribaud F, Rowe A, Pandis I, Sousa A, Corfield J, Djukanovic R, Lutter R et al. T-helper cell type 2 (Th2) and non-Th2 molecular phenotypes of asthma using sputum transcriptomics in U-BIOPRED. Eur. Respir. J. 2017; 49: 1602135.
Rossios C, Pavlidis S, Hoda U, Kuo C-H, Wiegman C, Russell K, Sun K, Loza MJ, Baribaud F, Durham AL et al. Sputum transcriptomics reveal upregulation of IL-1 receptor family members in patients with severe asthma. J. Allergy Clin. Immunol. 2018; 141: 560-70.
Global Initiative for Asthma. Difficult-to-Treat & Severe Asthma in Adolescent and Adult Patients. Diagnosis and Management. A GINA Pocket Guide for Health Professionals. Fontana, WI, USA: GINA, 2019. Available from URL: www.ginasthma.org
Gibson PG, Wlodarczyk JW, Hensley MJ, Gleeson M, Henry RL, Cripps AW, Clancy RL. Epidemiological association of airway inflammation with asthma symptoms and airway hyperresponsiveness in childhood. Am. J. Respir. Crit. Care Med. 1998; 158: 36-41.
Simpson JL, Scott R, Boyle MJ, Gibson PG. Inflammatory subtypes in asthma: assessment and identification using induced sputum. Respirology 2006; 11: 54-61.
Silkoff P, Moore W, Sterk P. Three major efforts to phenotype asthma: severe asthma research program, asthma disease endotyping for personalized therapeutics, and unbiased biomarkers for the prediction of respiratory disease outcome. Clin. Chest Med. 2019; 40: 13-28.
Berthon BS, Gibson PG, Wood LG, MacDonald-Wicks LK, Baines KJ. A sputum gene expression signature predicts oral corticosteroid response in asthma. Eur. Respir. J. 2017; 49: 1700180.
Fricker M, Gibson PG, Powell H, Simpson JL, Yang IA, Upham JW, Reynolds PN, Hodge S, James AL, Jenkins C et al. A sputum 6-gene signature predicts future exacerbations of poorly controlled asthma. J. Allergy Clin. Immunol. 2019; 144: 51-60.e11.
Lefaudeux D, De Meulder B, Loza MJ, Peffer N, Rowe A, Baribaud F, Bansal AT, Lutter R, Sousa AR, Corfield J et al. U-BIOPRED clinical adult asthma clusters linked to a subset of sputum omics. J. Allergy Clin. Immunol. 2017; 139: 1797-807.
Bhavsar P, Hew M, Khorasani N, Torrego A, Barnes PJ, Adcock I, Chung KF. Relative corticosteroid insensitivity of alveolar macrophages in severe asthma compared with non-severe asthma. Thorax 2008; 63: 784-90.
Goleva E, Jackson LP, Harris JK, Robertson CE, Sutherland ER, Hall CF, James T, Good J, Gelfand EW, Martin RJ et al. The effects of airway microbiome on corticosteroid responsiveness in asthma. Am. J. Respir. Crit. Care Med. 2013; 188: 1193-201.
Lea S, Harbron C, Khan N, Booth G, Armstrong J, Singh D. Corticosteroid insensitive alveolar macrophages from asthma patients; synergistic interaction with a p38 mitogen-activated protein kinase (MAPK) inhibitor. Br. J. Clin. Pharmacol. 2015; 79: 756-66.
Goleva E, Li L-b, Eves PT, Strand MJ, Martin RJ, Leung DYM. Increased glucocorticoid receptor β alters steroid response in glucocorticoid-insensitive asthma. Am. J. Respir. Crit. Care Med. 2006; 173: 607-16.
Bhavsar P, Khorasani N, Hew M, Johnson M, Chung KF. Effect of p38 MAPK inhibition on corticosteroid suppression of cytokine release in severe asthma. Eur. Respir. J. 2010; 35: 750-6.
Irusen E, Matthews JG, Takahashi A, Barnes PJ, Chung KF, Adcock IM. p38 Mitogen-activated protein kinase-induced glucocorticoid receptor phosphorylation reduces its activity: role in steroid-insensitive asthma. J. Allergy Clin. Immunol. 2002; 109: 649-57.
Mercado N, Hakim A, Kobayashi Y, Meah S, Usmani OS, Chung KF, Barnes PJ, Ito K. Restoration of corticosteroid sensitivity by p38 mitogen activated protein kinase inhibition in peripheral blood mononuclear cells from severe asthma. PLoS One 2012; 7: e41582.
Coxon P, Rane M, Uriarte S, Powell D, Singh S, Butt W, Chen Q, McLeish K. MAPK-activated protein kinase-2 participates in p38 MAPK-dependent and ERK-dependent functions in human neutrophils. Cell. Signal. 2003; 15: 993-1001.
Liu X, Ma B, Malik AB, Tang H, Yang T, Sun B, Wang G, Minshall RD, Li Y, Zhao Y et al. Bidirectional regulation of neutrophil migration by mitogen-activated protein kinases. Nat. Immunol. 2012; 13: 457.
Chung KF. p38 Mitogen-activated protein kinase pathways in asthma and COPD. Chest 2011; 139: 1470-9.
Liu W, Liang Q, Balzar S, Wenzel S, Gorska M, Alam R. Cell-specific activation profile of extracellular signal-regulated kinase 1/2, Jun N-terminal kinase, and p38 mitogen-activated protein kinases in asthmatic airways. J. Allergy Clin. Immunol. 2008; 121: 893-902.e2.
Vallese D, Ricciardolo FLM, Gnemmi I, Casolari P, Brun P, Sorbello V, Capelli A, Cappello F, Cavallesco GN, Papi A et al. Phospho-p38 MAPK expression in COPD patients and asthmatics and in challenged bronchial epithelium. Respiration 2015; 89: 329-42.
Oudin S, Pugin J. Role of MAP kinase activation in interleukin-8 production by human BEAS-2B bronchial epithelial cells submitted to cyclic stretch. Am. J. Respir. Cell Mol. Biol. 2002; 27: 107-14.