Overexpression of endothelial nitric oxide synthase suppresses features of allergic asthma in mice.
BACKGROUND
Asthma is associated with airway hyperresponsiveness and enhanced T-cell number/activity on one hand and increased levels of exhaled nitric oxide (NO) with expression of inducible NO synthase (iNOS) on the other hand. These findings are in paradox, as NO also relaxes airway smooth muscle and has immunosuppressive properties. The exact role of the endothelial NOS (eNOS) isoform in asthma is still unknown. We hypothezised that a delicate regulation in the production of NO and its bioactive forms by eNOS might be the key to the pathogenesis of asthma.


METHODS
The contribution of eNOS on the development of asthmatic features was examined. We used transgenic mice that overexpress eNOS and measured characteristic features of allergic asthma after sensitisation and challenge of these mice with the allergen ovalbumin.


RESULTS
eNOS overexpression resulted in both increased eNOS activity and NO production in the lungs. Isolated thoracic lymph nodes cells from eNOS overexpressing mice that have been sensitized and challenged with ovalbumin produced significantly less of the cytokines IFN-gamma, IL-5 and IL-10. No difference in serum IgE levels could be found. Further, there was a 50% reduction in the number of lymphocytes and eosinophils in the lung lavage fluid of these animals. Finally, airway hyperresponsiveness to methacholine was abolished in eNOS overexpressing mice.


CONCLUSIONS
These findings demonstrate that eNOS overexpression attenuates both airway inflammation and airway hyperresponsiveness in a model of allergic asthma. We suggest that a delicate balance in the production of bioactive forms of NO derived from eNOS might be essential in the pathophysiology of asthma.
Ten Broeke
Robert
R
Department of Pharmacology and Pathophysiology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, PO Box 80.082, 3508 TB Utrecht, The Netherlands. rtenbroeke@yahoo.com
De Crom
Rini
R
Van Haperen
Rien
R
Verweij
Vivienne
V
Leusink-Muis
Thea
T
Van Ark
Ingrid
I
De Clerck
Fred
F
Nijkamp
Frans P
FP
Folkerts
Gert
G
D000818:Animals; D001249:Asthma / Q000201:enzymology / Q000517:prevention & control; D016535:Bronchial Hyperreactivity / Q000201:enzymology / Q000517:prevention & control; D004195:Disease Models, Animal; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis* / Q000235:genetics*; D012130:Respiratory Hypersensitivity / Q000201:enzymology* / Q000517:prevention & control*
D052250:Nitric Oxide Synthase Type III