• Am. J. Respir. Crit. Care Med. · Nov 2010

    Apolipoprotein E negatively regulates house dust mite-induced asthma via a low-density lipoprotein receptor-mediated pathway.

    • Xianglan Yao, Karin Fredriksson, Zu-Xi Yu, Xiuli Xu, Nalini Raghavachari, Karen J Keeran, Gayle J Zywicke, Minjung Kwak, Marcelo J A Amar, Alan T Remaley, and Stewart J Levine.
    • Pulmonary and Vascular Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892-1590, USA.
    • Am. J. Respir. Crit. Care Med. 2010 Nov 15; 182 (10): 1228-38.

    RationaleDistinct sets of corticosteroid-unresponsive genes modulate disease severity in asthma.ObjectivesTo identify corticosteroid-unresponsive genes that provide new insights into disease pathogenesis and asthma therapeutics.MethodsExperimental murine asthma was induced by nasal administration 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 ResultsGenome-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 mucin gene expression, but could not be rescued by the apo E(130-149) mimetic peptide, consistent with a LDLR-dependent mechanism.ConclusionsThese 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.

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