title: Gata5 deficiency causes airway constrictor hyperresponsiveness in mice.
abstract: Gata5 is a transcription factor expressed in the lung, but its physiological role is unknown. To test whether and how Gata5 regulates airway constrictor responsiveness, we studied Gata5(-/-), Gata5(+/-), and wild-type mice on the C57BL/6J background. Cholinergic airway constrictor responsiveness was assessed invasively in mice without and with induction of allergic airway inflammation through ovalbumin sensitization and aerosol exposure. Gata5-deficient mice displayed native airway constrictor hyperresponsiveness (AHR) in the absence of allergen-induced inflammation. Gata5-deficient mice retained their relatively greater constrictor responsiveness even in ovalbumin-induced experimental asthma. Gata5 deficiency did not alter the distribution of cell types in bronchoalveolar lavage fluid, but bronchial epithelial mucus metaplasia was more prominent in Gata5(-/-) mice after allergen challenge. Gene expression profiles revealed that apolipoprotein E (apoE) was the fifth most down-regulated transcript in Gata5-deficient lungs, and quantitative RT-PCR and immunostaining confirmed reduced apoE expression in Gata5(-/-) mice. Quantitative RT-PCR also revealed increased IL-13 mRNA in the lungs of Gata5-deficient mice. These findings for the first time show that Gata5 regulates apoE and IL-13 expression in vivo and that its deletion causes AHR. Gata5-deficient mice exhibit an airway phenotype that closely resembles that previously reported for apoE(-/-) mice: both exhibit cholinergic AHR in native and experimental asthma states, and there is excessive goblet cell metaplasia after allergen sensitization and challenge. The Gata5-deficient phenotype also shares features that were previously reported for IL-13-treated mice. Together, these results indicate that Gata5 deficiency induces AHR, at least in part, by blunting apoE and increasing IL-13 expression.
authors.affiliation: 1 Department of Medicine and.
authors.forename: Bohao
authors.initials: B
authors.lastname: Chen
authors.forename: Tamson V
authors.initials: TV
authors.lastname: Moore
authors.forename: Zhenping
authors.initials: Z
authors.lastname: Li
authors.forename: Anne I
authors.initials: AI
authors.lastname: Sperling
authors.forename: Chunling
authors.initials: C
authors.lastname: Zhang
authors.forename: Jorge
authors.initials: J
authors.lastname: Andrade
authors.forename: Alex
authors.initials: A
authors.lastname: Rodriguez
authors.forename: Neil
authors.initials: N
authors.lastname: Bahroos
authors.forename: Yong
authors.initials: Y
authors.lastname: Huang
authors.forename: Edward E
authors.initials: EE
authors.lastname: Morrisey
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Gruber
authors.forename: Julian
authors.initials: J
authors.lastname: Solway
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D001249:Asthma / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D016084:Bronchoconstriction; D004195:Disease Models, Animal; D050992:GATA5 Transcription Factor / Q000172:deficiency* / Q000235:genetics; D005786:Gene Expression Regulation; D005838:Genotype; D020397:Goblet Cells / Q000378:metabolism / Q000473:pathology; D018793:Interleukin-13 / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000378:metabolism* / Q000503:physiopathology; D008679:Metaplasia; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D010047:Ovalbumin; D010641:Phenotype; D011014:Pneumonia / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D001057:Apolipoproteins E; D050992:GATA5 Transcription Factor; C494756:Gata5 protein, mouse; D018793:Interleukin-13; D010047:Ovalbumin