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摘要
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
- 出版日期2010-11-15
- 单位NIH
