title: Apolipoprotein E negatively regulates house dust mite-induced asthma via a low-density lipoprotein receptor-mediated pathway.
abstract: BACKGROUND
  Distinct sets of corticosteroid-unresponsive genes modulate disease severity in asthma.
  
  
  OBJECTIVE
  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.
  
  
  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 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.
authors.affiliation: Pulmonary and Vascular Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892-1590, USA.
authors.forename: Xianglan
authors.initials: X
authors.lastname: Yao
authors.forename: Karin
authors.initials: K
authors.lastname: Fredriksson
authors.forename: Zu-Xi
authors.initials: ZX
authors.lastname: Yu
authors.forename: Xiuli
authors.initials: X
authors.lastname: Xu
authors.forename: Nalini
authors.initials: N
authors.lastname: Raghavachari
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Keeran
authors.forename: Gayle J
authors.initials: GJ
authors.lastname: Zywicke
authors.forename: Minjung
authors.initials: M
authors.lastname: Kwak
authors.forename: Marcelo J A
authors.initials: MJ
authors.lastname: Amar
authors.forename: Alan T
authors.initials: AT
authors.lastname: Remaley
authors.forename: Stewart J
authors.initials: SJ
authors.lastname: Levine
mesh_terms: D000305:Adrenal Cortex Hormones / Q000494:pharmacology; D000818:Animals; D001057:Apolipoproteins E / Q000502:physiology*; D001249:Asthma / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000503:physiopathology; D005260:Female; D020869:Gene Expression Profiling; D020397:Goblet Cells / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D006965:Hyperplasia; D008168:Lung / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D010446:Peptide Fragments / Q000502:physiology; D039981:Pyroglyphidae / Q000276:immunology*; D011973:Receptors, LDL / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D000305:Adrenal Cortex Hormones; D001057:Apolipoproteins E; D010446:Peptide Fragments; D011973:Receptors, LDL