New asthma biomarkers: lessons from murine models of acute and chronic asthma

Abstract

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.

Matrix metalloproteinase 12 silencing: A therapeutic approach to treat pathological lung tissue remodeling?

“…Results were normalized using 28s mRNA as previously described and p-values were calculated using the Graphpad Quickcalcs software (t test, www.graphpad.com) [27]. Each value is the mean ± SD of two independent experiments analysed in duplicate each.…”

“…Over the past 15 years, many authors reported the sensitization of mice and rats with various allergens to mimick asthma development allowing to address mechanisms leading to airway remodeling and inflammation [8,[24][25][26][27]. The airway wall thickening is correlated to smooth muscle proliferation that leads to bronchial hyper-responsiveness resulting in bronchoconstriction.…”

“…Our laboratory is currently studying pulmonary subepithelial fibrosis resulting from chronic asthma by using a model of ovalbumin sensitization [27]. As a complement to our gene expression study based on high density microarray [27], we are currently evaluating the implication of the RNA interference machinery during the evolution of the disease.…”

“…As a complement to our gene expression study based on high density microarray [27], we are currently evaluating the implication of the RNA interference machinery during the evolution of the disease. Among several regulated miRNA, mmumiR-672 and mmu-miR-143 were found to be deeply down-regulated (preliminary data).…”

“…Among them are complement receptors (CR3, CR4), lymphocyte function-associated antigen-1 (LFA-1) and Fc fragment of IgG, low affinity II, receptor (FCGR2) [128]. FCGR2B can be of particular interest as it has been demonstrated to be upregulated in immune cells in acute and chronic mouse asthma models [27,[129][130][131].…”