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 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 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.
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 murineasthma 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 RESULTS: Genome-wide expression profiling of the lung transcriptome in a house dust mite-induced model of murineasthma 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: Hakon Hakonarson; Unnur S Bjornsdottir; Eva Halapi; Jonathan Bradfield; Florian Zink; Magali Mouy; Hildur Helgadottir; Asta S Gudmundsdottir; Hjalti Andrason; Asdis E Adalsteinsdottir; Kristleifur Kristjansson; Illugi Birkisson; Thor Arnason; Margret Andresdottir; David Gislason; Thorarinn Gislason; Jeffrey R Gulcher; Kari Stefansson Journal: Proc Natl Acad Sci U S A Date: 2005-10-03 Impact factor: 11.205
Authors: Wendy C Moore; Eugene R Bleecker; Douglas Curran-Everett; Serpil C Erzurum; Bill T Ameredes; Leonard Bacharier; William J Calhoun; Mario Castro; Kian Fan Chung; Melissa P Clark; Raed A Dweik; Anne M Fitzpatrick; Benjamin Gaston; Mark Hew; Iftikhar Hussain; Nizar N Jarjour; Elliot Israel; Bruce D Levy; James R Murphy; Stephen P Peters; W Gerald Teague; Deborah A Meyers; William W Busse; Sally E Wenzel Journal: J Allergy Clin Immunol Date: 2007-02 Impact factor: 10.793
Authors: Peter van den Elzen; Salil Garg; Luis León; Manfred Brigl; Elizabeth A Leadbetter; Jenny E Gumperz; Chris C Dascher; Tan-Yun Cheng; Frank M Sacks; Petr A Illarionov; Gurdyal S Besra; Sally C Kent; D Branch Moody; Michael B Brenner Journal: Nature Date: 2005-10-06 Impact factor: 49.962
Authors: Curtis B Dobson; Sean D Sales; Patrick Hoggard; Matthew A Wozniak; Keith A Crutcher Journal: J Infect Dis Date: 2005-12-28 Impact factor: 5.226
Authors: Kazuhiro Ito; Cristan Herbert; Jessica S Siegle; Chaitanya Vuppusetty; Nicole Hansbro; Paul S Thomas; Paul S Foster; Peter J Barnes; Rakesh K Kumar Journal: Am J Respir Cell Mol Biol Date: 2008-05-12 Impact factor: 6.914
Authors: Partha S Bhattacharjee; Donna M Neumann; Timothy P Foster; Christian Clement; Gyanendra Singh; Hilary W Thompson; Herbert E Kaufman; James M Hill Journal: Invest Ophthalmol Vis Sci Date: 2008-05-30 Impact factor: 4.799
Authors: Bohao Chen; Tamson V Moore; Zhenping Li; Anne I Sperling; Chunling Zhang; Jorge Andrade; Alex Rodriguez; Neil Bahroos; Yong Huang; Edward E Morrisey; Peter J Gruber; Julian Solway Journal: Am J Respir Cell Mol Biol Date: 2014-04 Impact factor: 6.914