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PROTECTION FROM EXPERIMENTAL ASTHMA BY AN ENDOGENOUS BRONCHODILATOR
Citation:
QUE, L. G., L. LIU, Y. YAM, G. WHITEHEAD, S. H. GAVETT, D. SCHWARTZ, AND J. S. STAMLER. PROTECTION FROM EXPERIMENTAL ASTHMA BY AN ENDOGENOUS BRONCHODILATOR. SCIENCE. American Association for the Advancement of Science (AAAS), Washington, DC, 308(5728):1618-1621, (2005).
Description:
Mechanisms that serve to protect against asthma remain poorly understood. S-nitrosoglutathione (GSNO), an endogenous bronchodilator, is depleted from the airways of asthmatic patients. We show here that mice with targeted deletion of the enzyme GSNO reductase (GSNOR-/-) sustain increases in lung S-nitrosothiols (SNOs) in response to allergen challenge and are thereby protected from airway hyperresponsiveness. By contrast, asthmatic wild-type mice show increases in airway GSNOR and depletion of SNOs, and GSNOR-/- mice that are pharmacologically depleted of SNOs exhibit an asthmatic phenotype indistinguishable from wild-type. Notably, the inflammatory response to allergen is intact in GSNOR-/- mice. In addition, these animals exhibit decreased sensitivity to bronchoconstrictors at basal conditions. Thus GSNOR activity is a critical determinant of airway responsiveness. Our studies indicate that airway tone is regulated by endogenous SNOs, and suggest new therapeutic approaches to asthma. One sentence summary: Endogenous S-nitrosoglutathione regulates basal airway tone and protects against asthma.