RATIONALE: Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide synthase (NOS) inhibitor that competes with L-arginine for binding to NOS. It has been suggested that ADMA contributes to inflammation, collagen deposition, nitrosative stress, and lung function in murine models. OBJECTIVES: To test the hypothesis that ADMA is increased in asthma and that NOS inhibition by ADMA contributes to airways obstruction. METHODS: We assessed alterations of L-arginine, ADMA, and symmetric dimethylarginine (SDMA) levels in a murine model of allergic airways inflammation using LC-tandem mass spectrometry. Based on the levels of ADMA observed in the murine model, we further tested the direct effects of nebulized inhaled ADMA on airways responsiveness in naive control mice. We also assessed alterations of L-arginine, ADMA, and SDMA in humans in adult lung specimens and sputum samples from pediatric patients with asthma. MEASUREMENTS AND MAIN RESULTS: ADMA was increased in lungs from the murine model of allergic airways inflammation. Exogenous administration of ADMA to naive mice, at doses consistent with the levels observed in the allergically inflamed lungs, resulted in augmentation of the airways responsiveness to methacholine. ADMA levels were also increased in human asthma lungs and sputum samples. CONCLUSIONS: ADMA levels are increased in asthma and contribute to NOS-related pathophysiology.
RATIONALE: Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide synthase (NOS) inhibitor that competes with L-arginine for binding to NOS. It has been suggested that ADMA contributes to inflammation, collagen deposition, nitrosative stress, and lung function in murine models. OBJECTIVES: To test the hypothesis that ADMA is increased in asthma and that NOS inhibition by ADMA contributes to airways obstruction. METHODS: We assessed alterations of L-arginine, ADMA, and symmetric dimethylarginine (SDMA) levels in a murine model of allergic airways inflammation using LC-tandem mass spectrometry. Based on the levels of ADMA observed in the murine model, we further tested the direct effects of nebulized inhaled ADMA on airways responsiveness in naive control mice. We also assessed alterations of L-arginine, ADMA, and SDMA in humans in adult lung specimens and sputum samples from pediatric patients with asthma. MEASUREMENTS AND MAIN RESULTS:ADMA was increased in lungs from the murine model of allergic airways inflammation. Exogenous administration of ADMA to naive mice, at doses consistent with the levels observed in the allergically inflamed lungs, resulted in augmentation of the airways responsiveness to methacholine. ADMA levels were also increased in humanasthma lungs and sputum samples. CONCLUSIONS:ADMA levels are increased in asthma and contribute to NOS-related pathophysiology.
Authors: D Winnica; L G Que; C Baffi; H Grasemann; K Fiedler; Z Yang; E Etling; K Wasil; S E Wenzel; B Freeman; F Holguin Journal: Clin Exp Allergy Date: 2016-10-04 Impact factor: 5.018
Authors: Alaadin Vögeli; Manuel Ottiger; Marc A Meier; Christian Steuer; Luca Bernasconi; Andreas Huber; Mirjam Christ-Crain; Christoph Henzen; Claus Hoess; Robert Thomann; Werner Zimmerli; Beat Mueller; Philipp Schuetz Journal: Lung Date: 2017-08-29 Impact factor: 2.584
Authors: Fernando Holguin; Suzy A A Comhair; Stanley L Hazen; Robert W Powers; Sumita S Khatri; Eugene R Bleecker; William W Busse; William J Calhoun; Mario Castro; Anne M Fitzpatrick; Benjamin Gaston; Elliot Israel; Nizar N Jarjour; Wendy C Moore; Stephen P Peters; W Gerald Teague; Kian Fan Chung; Serpil C Erzurum; Sally E Wenzel Journal: Am J Respir Crit Care Med Date: 2012-11-29 Impact factor: 21.405
Authors: Angela L Linderholm; Jennifer M Bratt; Gertrud U Schuster; Amir A Zeki; Nicholas J Kenyon Journal: Immunol Allergy Clin North Am Date: 2014-08-29 Impact factor: 3.479