SNOR and wheeze: the asthma enzyme?

doi:10.1016/j.molmed.2005.09.009

Trends in Molecular Medicine

Volume 11, Issue 11, November 2005, Pages 481-484

https://doi.org/10.1016/j.molmed.2005.09.009 Get rights and content

Conventionally, asthma is defined as involving both airway inflammation and airway smooth muscle hyper-responsiveness. However, Que and coworkers have recently uncoupled these concepts, showing that mice lacking an S-nitrosothiol reductase have allergen-induced airway inflammation but do not have airway hyper-responsiveness. These data are consistent with recent clinical evidence that: (i) S-nitrosothiol signaling is abnormal in human asthma, (ii) nitric oxide in exhaled air might be only a biomarker for the metabolism of more physiologically relevant nitrogen oxides and (iii) the biochemical response to airway inflammation is central to asthma pathophysiology.

Section snippets

Introduction: have we been thinking incorrectly about asthma?

‘My thoughts are not your thoughts’ – Isaiah 55:8

In the past several decades, most asthma research efforts and clinical practice guidelines have been developed based on the premise that identification of the cause of asthmatic airway inflammation will lead to effective asthma control 1, 2. However, despite comprehensive understanding of the causes of asthmatic airway inflammation, the worldwide asthma epidemic continues unabated 2, 3, 4. Recent data from Que et al. [5] demonstrate that mice

Why does the answer always have to be ‘NO’?

Exhaled nitric oxide (NO) levels are generally higher than normal in asthma [6]. Many publications are therefore predicated on the assumption that NO is the biologically important product of NO synthase (NOS) activation in asthma. The data of Que et al. [5] challenge this belief. Indeed, the low part-per-billion range NO levels present in exhaled air appear to be too low, even in asthma, to mediate most NOS bioactivities relevant to the airways, such as airway smooth muscle relaxation and

The SNOR woke us up

Que et al. have awoken the asthma research community to the reality that NO is not the only relevant NOS product; indeed, that it might only be a biomarker for the metabolism of other airway nitrogen oxides. They have found that mice lacking the enzyme GSNOR are protected from experimental asthma [5]. Thus, endogenously produced GSNO – when it is not broken down by GSNOR – protects against ovalbumin-induced airway hyper-responsiveness to methacholine, a cholinergic agonist and

What is asthma?

Classically, asthma is considered to involve both airway inflammation and airway hyper-responsiveness. Que et al. [5], however, have uncoupled inflammation and hyper-responsiveness, showing that GSNOR^−/− mice have the following phenotype: (i) they are less responsive than wild-type mice to methacholine, in the absence of airway inflammation; (ii) they have an inflammatory response to antigen challenge that is similar to wild-type mice, including mucous cell hyperplasia [13] and (iii) they are

Concluding remarks

Que et al. have challenged the assumption that NO is the only physiologically relevant product of NOS activation. The facts are now clear: mice rendered genetically incapable of breaking down GSNO are protected from experimental asthma. Further, these mice are not protected against allergen-induced inflammation or mucous cell hyperplasia, uncoupling airway hyper-reactivity from asthmatic airway inflammation. These data suggest that it might now be misguided to focus most asthma research on the

Acknowledgements

NIH: RO1 HL 69170 (The Severe Asthma Research Program), 1U19-A134607, and RO1 HL 59337; The Ivy Foundation.

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Protection from experimental asthma by an endogenous bronchodilator

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Cited by (26)

Exercise-Induced Bronchoconstriction and the Air We Breathe
2018, Immunology and Allergy Clinics of North America
Citation Excerpt :
That finding provides a plausible explanation for the reduction in carbon monoxide diffusing capacity and decreased mid expiratory flow rates after ultrafine particle inhalation noted by Pietropaoli and colleagues.41 Likewise, NO reacts with GSH to form a potent airway bronchodilator, S-nitrosoglutathione (GSNO).42,43 It has been proposed that GSNO is critical in the AHR characteristic of asthma.43
S-Nitrosoglutathione
2013, Biochimica et Biophysica Acta - General Subjects
S-Nitrosoglutathione (GSNO) is the S-nitrosated derivative of glutathione and is thought to be a critical mediator of the down stream signaling effects of nitric oxide (NO). GSNO has also been implicated as a contributor to various disease states.
This review focuses on the chemical nature of GSNO, its biological activities, the evidence that it is an endogenous mediator of NO action, and implications for therapeutic use.
GSNO clearly exerts its cellular actions through both NO- and S-nitrosation-dependent mechanisms; however, the chemical and biological aspects of this compound should be placed in the context of S-nitrosation as a whole.
GSNO is a central intermediate in formation and degradation of cellular S-nitrosothiols with potential therapeutic applications; thus, it remains an important molecule of study. This article is part of a Special Issue entitled Cellular functions of glutathione.
Structure-activity relationship of pyrrole based S-nitrosoglutathione reductase inhibitors: Carboxamide modification
2012, Bioorganic and Medicinal Chemistry Letters
The enzyme S-nitrosoglutathione reductase (GSNOR) is a member of the alcohol dehydrogenase family (ADH) that regulates the levels of S-nitrosothiols (SNOs) through catabolism of S-nitrosoglutathione (GSNO). GSNO and SNOs are implicated in the pathogenesis of many diseases including those in respiratory, gastrointestinal, and cardiovascular systems. The pyrrole based N6022 was recently identified as a potent, selective, reversible, and efficacious GSNOR inhibitor which is currently in clinical development for acute asthma. We describe here the synthesis and structure–activity relationships (SAR) of novel pyrrole based analogs of N6022 focusing on carboxamide modifications on the pendant N-phenyl moiety. We have identified potent and novel GSNOR inhibitors that demonstrate efficacy in an ovalbumin (OVA) induced asthma model in mice.
The biochemistry of asthma
2011, Biochimica et Biophysica Acta - General Subjects
Citation Excerpt :
Using NAD+, it can oxidize S-formyl glutathione to form formic acid. Thus, those patients that have decreased GSNO in their airways may also be those with increased formic acid and associated low pH [14,77]. Therefore, it may be possible non-invasively to identify those patients with decreased GSNO reductase activity as those with decreased EBC pH and increased EBC formic acid [77].
Asthma is not one disease. Different patients have biochemically distinct phenotypes.
Biomarker analysis was developed to identify inflammation in the asthmatic airway. It has led to a renewed interest in biochemical abnormalities in the asthmatic airway. The biochemical determinants of asthma heterogeneity are many. Examples include decreased activity of superoxide dismutases; increased activity of eosinophil peroxidase, S-nitrosoglutathione reductase, and arginases; decreased airway pH; and increased levels of asymmetric dimethyl arginine.
New discoveries suggest that biomarkers such as exhaled nitric oxide reflect complex airway biochemistry. This biochemistry can be informative and therapeutically relevant.
Improved understanding of airway biochemistry will lead to new tests to identify biochemically unique subpopulations of patients with asthma. It will also likely lead to new, targeted treatments for these specific asthma subpopulations. This article is part of a Special Issue entitled Biochemistry of Asthma.
Discovery of potent and novel S-nitrosoglutathione reductase inhibitors devoid of cytochrome P450 activities
2011, Bioorganic and Medicinal Chemistry Letters
The pyrrole based N6022 was recently identified as a potent, selective, reversible, and efficacious S-nitrosoglutathione reductase (GSNOR) inhibitor and is currently undergoing clinical development for the treatment of acute asthma. GSNOR is a member of the alcohol dehydrogenase family (ADH) and regulates the levels of S-nitrosothiols (SNOs) through catabolism of S-nitrosoglutathione (GSNO). Reduced levels of GSNO, as well as other nitrosothiols (SNOs), have been implicated in the pathogenesis of many diseases including those of the respiratory, cardiovascular, and gastrointestinal systems. Preservation of endogenous SNOs through GSNOR inhibition presents a novel therapeutic approach with broad applicability. We describe here the synthesis and structure–activity relationships (SAR) of novel pyrrole based analogues of N6022 focusing on removal of cytochrome P450 inhibition activities. We identified potent and novel GSNOR inhibitors having reduced CYP inhibition activities and demonstrated efficacy in a mouse ovalbumin (OVA) model of asthma.
Determinants of exhaled breath condensate pH in a large population with asthma
2011, Chest
Citation Excerpt :
Both increased allergic symptoms in general (note that samples were obtained in and out of season) and low methacholine PC20 were characteristics of this low-pH, low-FeNO phenotype. Increased GSNO reductase activity in asthma can be associated not only with decreased airway nitric oxide levels but also with increased production of formic acid, an important determinant of asthmatic airway acidification.18,42,43 Therefore, the subset of patients with increased GSNO reductase activity might be predicted to have low FeNO and low EBC pH. One way or another, this subset appears to be biochemically unique and may be a subset in which the metabolomically targeted therapy (for example, with inhaled base7,35) may be particularly beneficial.
Exhaled breath condensate (EBC) pH is 2 log orders below normal during acute asthma exacerbations and returns to normal with antiinflammatory therapy. However, the determinants of EBC pH, particularly in stable asthma, are poorly understood. We hypothesized that patients with severe asthma would have low EBC pH and that there would be an asthma subpopulation of patients with characteristically low values.
We studied the association of EBC pH with clinical characteristics in 572 stable subjects enrolled in the Severe Asthma Research Program. These included 250 subjects with severe asthma, 291 with nonsevere asthma, and 31 healthy control subjects.
Overall, EBC in this population of stable, treated study subjects was not lower in severe asthma (8.02; interquartile range [IQR], 7.61-8.41) or nonsevere asthma (7.90; IQR, 7.52-8.20) than in control subjects (7.9; IQR, 7.40-8.20). However, in subjects with asthma the data clustered below and above pH 6.5. Subjects in the subpopulation with pH < 6.5 had lower fraction of exhaled NO (FeNO) values (FeNO = 22.6 ± 18.1 parts per billion) than those with pH ≥ 6.5 (39.9 ± 40.2 parts per billion; P < .0001). By multiple linear regression, low EBC pH was associated with high BMI, high BAL neutrophil counts, low prebronchodilator FEV₁ ratio, high allergy symptoms, race other than white, and gastroesophageal reflux symptoms.
Asthma is a complex syndrome. Subjects who are not experiencing an exacerbation but have low EBC pH appear to be a unique subpopulation.

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Trends in Molecular Medicine

Research FocusSNOR and wheeze: the asthma enzyme?

Section snippets

Introduction: have we been thinking incorrectly about asthma?

Why does the answer always have to be ‘NO’?

The SNOR woke us up

What is asthma?

Concluding remarks

Acknowledgements

Lancet

J. Biol. Chem.

J. Biol. Chem.

Lancet

J. Pediatr.

Cell

A longitudinal, population-based, cohort study of childhood asthma followed to adulthood

N. Engl. J. Med.

Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema: ISAAC

Lancet

Asthma: more than an inflammatory disease

Curr. Opin. Allergy Clin. Immunol.

Protection from experimental asthma by an endogenous bronchodilator

Science

Research Focus
SNOR and wheeze: the asthma enzyme?