S-nitrosoglutathione reductase: an important regulator in human asthma.
BACKGROUND
Nitric oxide bioactivity, mediated through the formation of S-nitrosothiols (SNOs), has a significant effect on bronchomotor tone. S-Nitrosoglutathione is an endogenous bronchodilator that is decreased in children with asthmatic respiratory failure and in adults with asthma undergoing segmental airway challenge. Recently we showed that S-nitrosoglutathione reductase (GSNOR) regulates endogenous SNOs. Mice with genetic deletion of GSNOR are protected from airway hyperresponsivity in an allergic asthma model.


OBJECTIVE
We hypothesized that GSNOR is increased in human asthma and correlates with lung SNO content and airway reactivity.


METHODS
We recruited 36 subjects with mild asthma with FEV(1) 88.5 +/- 2.3% predicted and 34 healthy control subjects with FEV(1) 100.7 +/- 2.5% predicted. Bronchoalveolar lavage (BAL) was performed in all subjects. Cell counts, differentials, GSNOR activity, and SNO levels were determined in BAL.


RESULTS
SNO content was decreased in asthmatic BAL compared with control BAL and correlated inversely with GSNOR expression in BAL cell lysates. Furthermore, GSNOR activity measured from BAL samples was significantly increased in subjects with asthma compared with control subjects and correlated inversely with the provocative concentration of methacholine causing a 20% decrease in FEV(1).


CONCLUSIONS
These findings suggest that GSNOR is an important regulator of airway SNO content and airways hyperresponsiveness in human asthma.
Que
Loretta G
LG
Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA. Que00001@mc.duke.edu
Yang
Zhonghui
Z
Stamler
Jonathan S
JS
Lugogo
Njira L
NL
Kraft
Monica
M
D000293:Adolescent; D000328:Adult; D000445:Aldehyde Oxidoreductases / Q000378:metabolism*; D001249:Asthma / Q000175:diagnosis / Q000201:enzymology* / Q000503:physiopathology; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D001999:Bronchoscopy; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005541:Forced Expiratory Volume / Q000502:physiology; D006801:Humans; D008297:Male; D008667:Metalloproteins; D008875:Middle Aged; D009566:Nitrates / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D012720:Severity of Illness Index; D055815:Young Adult
D016207:Cytokines; D008667:Metalloproteins; D009566:Nitrates; D009573:Nitrites; D000445:Aldehyde Oxidoreductases; C087006:formaldehyde dehydrogenase, glutathione-independent