Apolipoprotein E Negatively Regulates House Dust Mite-induced Asthma via a Low-Density Lipoprotein Receptor-mediated Pathway

Title
Apolipoprotein E Negatively Regulates House Dust Mite-induced Asthma via a Low-Density Lipoprotein Receptor-mediated Pathway
Author(s)
곽민정Xianglan Yao[Xianglan Yao]Karin Fredriksson[Karin Fredriksson]Zu-Xi Yu[Zu-Xi Yu]Xiuli Xu[Xiuli Xu]Nalini Raghavachari[Nalini Raghavachari]Karen J Keeran[Karen J Keeran]Gayle J Zywicke[Gayle J Zywicke]Marcelo JA Amar[Marcelo JA Amar]Alan T Remaley[Alan T Remaley]
Keywords
MIMETIC PEPTIDE; AIRWAY HYPERRESPONSIVENESS; ALTERNATIVE ACTIVATION; RESEARCH-PROGRAM; IN-VIVO; CELLS; INFLAMMATION; DISEASE; MACROPHAGES; ANTIGEN
Issue Date
201011
Publisher
AMER THORACIC SOC
Citation
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, v.182, no.10, pp.1228 - 1238
Abstract
Rationale Distinct sets of corticosteroid unresponsive genes rnodulate disease severity in asthma Objectives To identify corticosteroid unresponsive genes that provide new insights into disease pathogenesis and asthma therapeutics Methods Experimental murine asthma was induced by nasal ad ministration of house dust mite for 5 days per week Dexamethasone and apolipoprotein E (apo E) mimetic peptides were administered via osmotic minipumps Measurements and Main Results Genome wide expression profiling of the lung transcriptome in a house dust mite-induced model of murine asthma identified increases in apo E mRNA levels that persisted despite corticosteroid treatment House dust mite-challenged apo E(-/-) mice displayed enhanced airway hyperreactivity and goblet cell hyperplasia, which could be rescued by administration of an apo E(130-149) mimetic peptide Administration of the apo E(130-149) mimetic peptide to house dust mite-challenged apo E(-/-) mice also inhibited eosinophilic airway inflammation IgE production, and the expression of Th2 and Th17 cytokines House dust mite-challenged low density lipoprotein receptor (LDLR) knockout mice displayed a similar phenotype as apo E(-/-) mice with enhanced airway hyperreactivity goblet cell hyperplasia and mum gene expression, but could not be rescued by the apo E(130-149) mimetic peptide, consistent with a LDLR dependent mechanism Conclusions These findings for the first time identify an apo E-LDLR pathway as an endogenous negative regulator of airway hyperreactivity and goblet cell hyperplasia in asthma Furthermore, our results demonstrate that strategies that activate the apo E-LDLR pathway, such as apo E mimetic peptides, might be developed into a novel treatment approach for patients with asthma
URI
http://hdl.handle.net/YU.REPOSITORY/23349http://dx.doi.org/10.1164/rccm.201002.0308OC
ISSN
1073-449X
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이과대학 > 통계학과 > Articles
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