Biomarkers of Disease and Treatment in Murine and Cynomolgus Models of Chronic Asthma

Abstract

BackgroundBiomarkers facilitate early detection of disease and measurement of therapeutic efficacy, both at clinical and experimental levels. Recent advances in analytics and disease models allow comprehensive screening for biomarkers in complex diseases, such as asthma, that was previously not feasible.ObjectiveUsing murine and nonhuman primate (NHP) models of asthma, identify biomarkers associated with early and chronic stages of asthma and responses to steroid treatment.MethodsThe total protein content from thymic stromal lymphopoietin transgenic (TSLP Tg) mouse BAL fluid was ascertained by shotgun proteomics analysis. A subset of these potential markers was further analyzed in BAL fluid, BAL cell mRNA, and lung tissue mRNA during the stages of asthma and following corticosteroid treatment. Validation was conducted in murine and NHP models of allergic asthma.ResultsOver 40 proteins were increased in the BAL fluid of TSLP Tg mice that were also detected by qRT-PCR in lung tissue and BAL cells, as well as in OVA-sensitive mice and house dust mite-sensitive NHP. Previously undescribed as asthma biomarkers, KLK1, Reg3γ, ITLN2, and LTF were modulated in asthmatic mice, and Clca3, Chi3l4 (YM2), and Ear11 were the first lung biomarkers to increase during disease and the last biomarkers to decline in response to therapy. In contrast, GP-39, LCN2, sICAM-1, YM1, Epx, Mmp12, and Klk1 were good indicators of early therapeutic intervention. In NHP, AMCase, sICAM-1, CLCA1, and GP-39 were reduced upon treatment with corticosteroids.Conclusions and clinical relevanceThese results significantly advance our understanding of the biomarkers present in various tissue compartments in animal models of asthma, including those induced early during asthma and modulated with therapeutic intervention, and show that BAL cells (or their surrogate, induced sputum cells) are a viable choice for biomarker examination.

Biosignature for airway inflammation in a house dust mite-challenged murine model of allergic asthma

“…Of the DE genes, 31 were increased by >2-fold, whereas only three transcripts were downregulated after HDM-challenge ( Table 1 ). Among the transcripts that were increased after HDM-challenge, most markedly induced were those for the chloride channel calcium activated member 3 ( clca3 ), Eosinophil associated ribonuclease A family 11 ( ear11 ) and Mucin-5AC ( Muc5ac ), each of these has been previously identified as potential biomarkers in asthma ( Laprise et al, 2004 ; Woodruff et al, 2007 ; Park et al, 2008 ; Louten et al, 2012 ). As expected, Th2-driven cytokines and related receptors ( il-13 , il-13ra2 , il-4 ), chemokines ( ccl11 , ccl12 and ccl24 ), and genes associated with allergic diseases arginase 1 ( arg1 ) and chitinase ( chia1 ) ( Woodruff et al, 2007 ; Lloyd and Hessel, 2010 ; Zhu, 2010 ) were also significantly upregulated in the HDM-challenged compared to allergen-naïve lungs ( Table 1 ).…”

“…Therefore in this study, we employed a quantitative PCR array to profile the expression of a panel of 84 genes known to contribute to the pathogenesis of allergy and asthma, primarily curated from human data. The most abundant and significantly upregulated mRNA in the DE genes from HDM lungs ( Table 1 ) were molecules that have been previous shown to be induced in human asthma ( Thai et al, 2005 ; Kulkarni et al, 2010 ; Louten et al, 2012 ; Bhakta et al, 2013 ) such as chloride channel calcium activated member-3 ( clca3 ), eosinophil associated ribonuclease A family 11 ( ear11 ) and mucin-5AC, those associated with allergic diseases ( il-13 , il-13ra2 , il-10 and il-21 ), and chemokines involved in cellular recruitment to the lungs ( ccl11 , ccl12 and ccl24 ). The biological processes that were predicted to be significantly activated as a consequence of the DE genes were predominantly those associated with leukocyte recruitment especially eosinophils, AHR, secretion of mucus and cytokine signaling, all relevant to the pathophysiology of human allergic asthma.…”

IL-1β expression in the distal lung epithelium disrupts lung morphogenesis and epithelial cell differentiation in fetal mice

“…Pendrin regulates airway surface liquid, increases airway reactivity (38), and is associated with increased mucus production in asthma and chronic obstructive pulmonary disease (39). Ym1 and Ym2 are associated with alternatively activated macrophages (15), allergic lung inflammation (51), and murine models of asthma (35,59).…”

Serum pharmacodynamic biomarkers for chronic corticosteroid treatment of children

“…Among these potential corticosteroid efficacy biomarkers, some have been previously reported showing steroid-responsive decreases in animal model systems or other adult inflammatory disorders. MMP12 was reported to be decreased by dexamethasone in an asthmatic mouse model 28 , CCL22 by dexamethasone in patients with atopic dermatitis 22 , FCER2 by prednisone in patients with giant cell arteritis 29 , LTa1/b2 by prednisone in patients with acquired hemophilia 30 , and IGFBP2 by deflazacort after renal transplantation 31 . The corticosteroid-responsive decreases in serum concentrations of the remaining markers IL22RA2, LY9, ITGa1/b1, ANGPT2 and FGG by corticosteroids are novel to our report.…”