Apolipoprotein E negatively regulates house dust mite-induced asthma via a low-density lipoprotein receptor-mediated pathway.
Am J Respir Crit Care Med
; 182(10): 1228-38, 2010 Nov 15.
Article
in En
| MEDLINE
| ID: mdl-20622028
ABSTRACT
RATIONALE Distinct sets of corticosteroid-unresponsive genes modulate 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 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 MAINRESULTS:
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 Eâ»(/)â» 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 Eâ»(/)â» 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 Eâ»(/)â» 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.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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Apolipoproteins E
/
Asthma
/
Receptors, LDL
/
Pyroglyphidae
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Am J Respir Crit Care Med
Journal subject:
TERAPIA INTENSIVA
Year:
2010
Document type:
Article
Affiliation country: