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Review
. 2011 Nov;1810(11):1008-16.
doi: 10.1016/j.bbagen.2011.06.009. Epub 2011 Jun 21.

Nitric oxide metabolism in asthma pathophysiology

Sudakshina Ghosh  1 , Serpil C Erzurum
Affiliations
Review

Nitric oxide metabolism in asthma pathophysiology

Sudakshina Ghosh et al. Biochim Biophys Acta. 2011 Nov.

Abstract

Background: Asthma, a chronic inflammatory disease is typically characterized by bronchoconstriction and airway hyper-reactivity.

Scope of review: A wealth of studies applying chemistry, molecular and cell biology to animal model systems and human asthma over the last decade has revealed that asthma is associated with increased synthesis of the gaseous molecule nitric oxide (NO).

Major conclusion: The high NO levels in the oxidative environment of the asthmatic airway lead to greater formation of reactive nitrogen species (RNS) and subsequent oxidation and nitration of proteins, which adversely affect protein functions that are biologically relevant to chronic inflammation. In contrast to the high levels of NO and nitrated products, there are lower levels of beneficial S-nitrosothiols (RSNO), which mediate bronchodilation, due to greater enzymatic catabolism of RSNO in the asthmatic airways.

General significance: This review discusses the rapidly accruing data linking metabolic products of NO as critical determinants in the chronic inflammation and airway reactivity of asthma. This article is part of a Special Issue entitled Biochemistry of Asthma.

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Figures

Fig. 1
Fig. 1. Production of reactive oxygen species (ROS)
Superoxide (O2•−) reacts rapidly with itself, or is catalytically converted to form hydrogen peroxide (H2O2) by superoxide dismutase. Under pathologic conditon, extremely toxic reactions of superoxide and hydrogen peroxide which form hydroxyl radical occur via the Haber–Weiss and Fenton chemistry reactions in the presence of metal ions. Hydrogen peroxide is converted by myeloperoxide (MPO) or eosinophil peroxidase (EPO) to highly reactive halogenating acids, such as hypobromous acid (HOX, X=Br/Cl) or hypochlorous acid, which can further react with superoxide to produce halides and hydroxyl radical.
Fig. 2
Fig. 2. Molecular consequences of nitrative stress
Nitric oxide synthase used L-Arg as substrate to produce nitric oxide (N=O•); L-Citrulline is propduced as the by-product of this reaction. Arginases I and II use L-Arg as substrate to generate urea and L-ornithine. Nitric oxide can rapidly oxidize to nitrite (NO2−), which can be further oxidized to nitrate (NO3−). Superoxide (O2•−) reacts rapidly with nitric oxide to produce peroxynitrite (ONOO−), which can readily nitrate proteins. In presence of hydrogen peroxide (H2O2), nitrite (NO2−) and/or halide (X−), myeloperoxidase/eosinophil peroxidase system can also promote protein nitration and/or halogenation. In presence of thiols (RSH), nitrite is also involved in nitrosylation reaction to produce S-nitrosothiols (RSNO).
Fig. 3
Fig. 3. Tyrosine containing amino acid oxidation and cross-linked products
Protein oxidative damage mediated by peroxidase mediated reactive brominating species (HOBr), MPO-generated reactive chlorinating species (HOCl), reactive nitrating species (RNS), tyrosyl radical (Tyr·), may be identified by stable products formed by each pathway.
Fig. 4
Fig. 4. Increased nitrotyrosine in ova sensitized and challenged mouse lung
[A] Western blot analysis of nitrotyrosine in tissue lysate of asthmatic mouse lung at days 0, 2, 4 and 6 (lanes 2, 4, 6 and 8) and corresponding controls at respective days (lanes 1, 3, 5 and 7) revealed more nitration in asthmatic lungs compared to controls. Lower panel is β-actin Western analyses for loading control. [B] Densitometric analysis of the Western blots shows that total nitrotyrosine band intensity compared to β-actin is significantly increased in asthmatic lung compared to control. (*) indicates p<0.05. [C] 2D patterns of anti-nitrotyrosine immunopositive protein in asthmatic mouse lung compared to control at day 6. Lung tissue samples from control and ova/ova mice were subjected to proteomic analysis. Coomassie blue stained polyacrylamide gels of control [I] and ova/ova mouse lung tissue [II] are shown with the corresponding Western blots (lower panel; C and D respectively). Although the control blot [III] shows some degree of nitration, the blot [IV] representing the profile of ova/ova mouse lung shows more intense nitration. The protein spots, corresponding to the immunoreactive proteins observed in western blot [IV] on coomassie stained gel [II] were identified by tandem mass spectrometry. Reproduced with permission from The Journal of Immunology (Copyright 2006. The American Association of Immunologists, Inc.).
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