Overexpression of dimethylarginine dimethylaminohydrolase 1 attenuates airway inflammation in a mouse model of asthma.
Levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, are increased in lung, sputum, exhaled breath condensate and plasma samples from asthma patients. ADMA is metabolized primarily by dimethylarginine dimethylaminohydrolase 1 (DDAH1) and DDAH2. We determined the effect of DDAH1 overexpression on development of allergic inflammation in a mouse model of asthma. The expression of DDAH1 and DDAH2 in mouse lungs was determined by RT-quantitative PCR (qPCR). ADMA levels in bronchoalveolar lavage fluid (BALF) and serum samples were determined by mass spectrometry. Wild type and DDAH1-transgenic mice were intratracheally challenged with PBS or house dust mite (HDM). Airway inflammation was assessed by bronchoalveolar lavage (BAL) total and differential cell counts. The levels of IgE and IgG1 in BALF and serum samples were determined by ELISA. Gene expression in lungs was determined by RNA-Seq and RT-qPCR. Our data showed that the expression of DDAH1 and DDAH2 was decreased in the lungs of mice following HDM exposure, which correlated with increased ADMA levels in BALF and serum. Transgenic overexpression of DDAH1 resulted in decreased BAL total cell and eosinophil numbers following HDM exposure. Total IgE levels in BALF and serum were decreased in HDM-exposed DDAH1-transgenic mice compared to HDM-exposed wild type mice. RNA-Seq results showed downregulation of genes in the inducible nitric oxide synthase (iNOS) signaling pathway in PBS-treated DDAH1-transgenic mice versus PBS-treated wild type mice and downregulation of genes in IL-13/FOXA2 signaling pathway in HDM-treated DDAH1-transgenic mice versus HDM-treated wild type mice. Our findings suggest that decreased expression of DDAH1 and DDAH2 in the lungs may contribute to allergic asthma and overexpression of DDAH1 attenuates allergen-induced airway inflammation through modulation of Th2 responses.
Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
Kayla G
KG
Kinker
Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
Aaron M
AM
Gibson
Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
Stacey A
SA
Bass
Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
Brandy P
BP
Day
Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.
Jingyuan
J
Deng
Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.
Mario
M
Medvedovic
Department of Chemistry, University of Cincinnati, Cincinnati, Ohio, United States of America.
Julio A Landero
JA
Figueroa
Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America ; Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
Gurjit K Khurana
GK
Hershey
Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
Weiguo
W
Chen
D000485:Allergens / Q000276:immunology; D000581:Amidohydrolases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001249:Asthma / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000276:immunology; D004195:Disease Models, Animal; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D039981:Pyroglyphidae / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology
D000485:Allergens; D052247:Nitric Oxide Synthase Type II; D000581:Amidohydrolases; C059999:dimethylargininase