This project that has the goal of identifying novel mechanisms of asthma pathogenesis, as well as new treatment approaches for patients with severe disease. The project will utilize murine models of allergic asthma to achieve these goals. Distinct sets of corticosteroid-unresponsive genes modulate disease severity in severe asthma that is refractory to corticosteroid therapy. We hypothesized that the identification of corticosteroid-unresponsive genes may provide new insights into disease pathogenesis and identify novel therapeutic approaches for asthmatic patients. Genome-wide profiling of the lung transcriptome from a clinically relevant, house dust mite (HDM) challenge model of asthma identified the up-regulated expression of apolipoprotein E (apoE), which remained persistently elevated despite treatment with corticosteroids. This lead to the identification of an apoE LDL receptor (LDLR) pathway as an endogenous negative regulator of AHR and goblet cell hyperplasia in asthma (Apolipoprotein E Negatively Regulates House Dust Mite-induced Asthma via a LDL Receptor-mediated Pathway. Yao X, Fredriksson K, Yu ZX, Xu X, Raghavachari N, Keeran KJ, Zywicke GJ, Kwak M, Amar MJ, Remaley AT, Levine SJ. Am J Respir Crit Care Med. 2010 Jul 9. Epub ahead of print). In particular, we showed that apoE is expressed by lung macrophages and negatively regulates airway hyperreactivity and goblet cell hyperplasia via a LDL receptor-dependent mechanism. Furthermore, we showed that these effects are mediated via LDL receptors that are expressed by ciliated airway epithelial cells. This genome-wide analysis of the lung transcriptome in asthma has identified additional steroid-unresponsive genes that are not known to have a role in asthma. Ongoing studies are using mice with targeted deletions in these candidate corticosteroid-unresponsive genes to define the role of these candidate genes in the pathogenesis of asthma. This approach resulted in the identification of peptidoglycan recognition protein 1 as mediating the pathogenesis of house dust mite-induced asthma. HDM-challenged Pglyrp1-/- mice showed decreases in BALF eosinophils and lymphocytes, serum IgE, and mucous cell metaplasia, whereas airway hyperresponisveness was not changed when compared to WT mice. Th2 cytokines were reduced in the lungs of HDM-challenged Pglyrp1-/- mice, which reflected a decreased number of CD4+ Th2 cells. There was also a reduction in C-C chemokines in BALF and lung homogenates from HDM-challenged Pglyrp1-/- mice. Furthermore, secretion of CCL17, CCL22 and CCL24 by alveolar macrophages from HDM-challenged Pglyrp1-/- mice was markedly reduced. Since both inflammatory cells and airway epithelial cells express Pglyrp1, bone marrow transplantation was performed to generate chimeric mice and assess which cell type promotes HDM-induced airway inflammation. Mice lacking Pglyrp1 on hematopoietic cells, not structural cells, showed a reduction in HDM-induced eosinophilic and lymphocytic airway inflammation. This showed that Pglyrp1 expression by hematopoietic cells, such as alveolar macrophages, mediates HDM-induced airway inflammation by up-regulating the production of C-C chemokines that recruit eosinophils and Th2 cells to the lung. This identified a new family of innate immune response proteins that promotes HDM-induced airway inflammation in asthma.

Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2013
Total Cost
$642,009
Indirect Cost
Name
National Heart, Lung, and Blood Institute
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Type
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Yao, Xianglan; Gao, Meixia; Dai, Cuilian et al. (2013) Peptidoglycan Recognition Protein 1 Promotes House Dust Mite-Induced Airway Inflammation in Mice. Am J Respir Cell Mol Biol :
Yao, Xianglan; Dai, Cuilian; Fredriksson, Karin et al. (2011) 5A, an apolipoprotein A-I mimetic peptide, attenuates the induction of house dust mite-induced asthma. J Immunol 186:576-83
Levine, Stewart J; Wenzel, Sally E (2010) Narrative review: the role of Th2 immune pathway modulation in the treatment of severe asthma and its phenotypes. Ann Intern Med 152:232-7