Transiently, paralleled upregulation of arginase and nitric oxide synthase and the effect of both enzymes on the pathology of asthma

Takemoto, Kazuo; Oginö, Kazuhíde; Shibamori, Masafumi; Gondo, Toshikazu; Hitomi, Yoshiaki; Takigawa, Tomoko; Wang, Da Hong; Takaki, Jiro; Ichimura, Hiroshi; Fujikura, Yoshihisa; Ishiyama, H.

doi:10.1152/ajplung.00418.2006

Cited by 50 publications

(61 citation statements)

References 52 publications

(53 reference statements)

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“…Microarray analysis of gene expression in these models revealed that genes related to L-arginine metabolism, including the cytosolic isoform arginase I and the mitochondrial isoform arginase II, belonged to the most prominently overexpressed genes [22]. Increased arginase expression and activity in mouse lung has also been found in other studies, after challenge with either ovalbumin [50][51][52], Nippostrongylus brasiliensis [52], Schistosoma mansoni eggs [53], Dermatophagoides farinae [54] or trimellic anhydride [51]. In addition, ovalbumin increased arginase activity in the lungs of sensitised rats [55].…”

Section: +supporting

confidence: 60%

l-Arginine deficiency causes airway hyperresponsiveness after the late asthmatic reaction

Maarsingh¹,

Bossenga²,

Bos³

et al. 2009

Eur Respir J

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ABSTRACT:Peroxynitrite has been shown to be crucially involved in airway hyperresponsiveness (AHR) after the late asthmatic reaction (LAR). Peroxynitrite production may result from simultaneous synthesis of nitric oxide (NO) and superoxide by inducible NOsynthase (iNOS) at low L-arginine concentrations. L-Arginine availability to iNOS is regulated by its cellular uptake, which can be inhibited by eosinophil-derived polycations and by arginase, which competes with iNOS for the common substrate.Using a guinea pig model of allergic asthma, we investigated whether aberrant L-arginine homeostasis could underlie peroxynitrite-mediated AHR after the LAR.After the LAR, arginase activity in the airways and eosinophil peroxidase release from bronchoalveolar lavage cells were increased. These changes were associated with a 2.0-fold AHR to methacholine as measured in isolated perfused tracheal preparations. AHR was reduced by exogenous L-arginine administration. Moreover, both the arginase inhibitor N v -hydroxy-nor-Larginine (nor-NOHA) and the polycation antagonist heparin normalised airway responsiveness. These effects were reversed by the nitric oxide synthase inhibitor N v -nitro-L-arginine methyl ester (L-NAME), indicating that both agents reduced AHR by restoring bronchodilating NO production.In conclusion, in allergen-challenged guinea pigs, the AHR after the LAR is caused by arginaseand polycation-induced attenuation of L-arginine availability to iNOS, which may switch the enzyme to simultaneous production of superoxide and NO, and, consequently, peroxynitrite.

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Section: +supporting

confidence: 60%

l-Arginine deficiency causes airway hyperresponsiveness after the late asthmatic reaction

Maarsingh¹,

Bossenga²,

Bos³

et al. 2009

Eur Respir J

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“…Hematoxylin and eosin (H&E) staining was used to assess the degree of inflammation (16). Azan and periodic acid-Schiff (PAS) stainings were also done to observe interstitial collagen deposition and goblet cell hyperplasia, respectively (35). The levels of inflammation in peribronchial and perivascular spaces of the lung were determined by an ordinal scale ranging from 0 to 3, as described elsewhere (36).…”

Section: Bronchoalveolar Lavage Fluidmentioning

confidence: 99%

Direct inhibition of arginase attenuated airway allergic reactions and inflammation in a Dermatophagoides farinae-induced NC/Nga mouse model

Takahashi

Oginö

Takemoto

et al. 2010

American Journal of Physiology-Lung Cellular and Molecular Phys

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The expression of arginase I has been a focus of research into the pathogenesis of experimental asthma, because arginase deprives nitric oxide synthase (NOS) of arginine and therefore participates in the attenuation of bronchodilators such as nitric oxide (NO). The present study used an intranasal mite-induced NC/Nga mouse model of asthma to investigate the contribution of arginase to the asthma pathogenesis, using an arginase inhibitor, N -hydroxy-nor-L-arginine (nor-NOHA). The treatment with nor-NOHA inhibited the increase in airway hyperresponsiveness (AHR) and the number of eosinophils in bronchoalveolar lavage fluid. NOx levels in the lung were elevated despite suppressed NOS2 mRNA expression. Accompanied by the attenuated activity of arginase, the expression of arginase I at both the mRNA and protein level was downregulated. The levels of mRNA for T helper 2 cytokines such as IL-4, IL-5, and IL-13, and for chemotactants such as eotaxin-1 and eotaxin-2, were reduced. Moreover, the accumulation of inflammatory cells and the ratio of goblet cells in the bronchiole were decreased. The study concluded that the depletion of NO caused by arginase contributes to AHR and inflammation, and direct administration of an arginase inhibitor to the airway may be beneficial and could be of use in treating asthma due to its antiinflammatory and airway-relaxing effects, although it is not clear whether the anti-inflammatory effect is direct or indirect. experimental asthma; arginase inhibitor; nor-NOHA

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“…In various mouse and rat models, it has been confirmed that allergen challenge causes a considerable increase in the expression and activity of particularly arginase type I, most probably via Th2 cytokines involved in the asthmatic airway inflammation [120][121][122][123][124][125][126][127]. Notably, by microarray analysis of gene expression in Balb/c mice sensitised to ovalbumin or Aspergillus fumigatus, it was shown that, among the 291 common genes that were induced by these allergens, enzymes involved in L-arginine metabolism, particularly arginase I and II, belonged to the most predominantly overexpressed genes [127].…”

Section: Acute Modulation Of Ahrmentioning

confidence: 99%

Airway hyperresponsiveness in asthma: lessons fromin vitromodel systems and animal models: Fig. 1—

Gosens¹,

Zaagsma²

2008

Eur Respir J

107

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Airway hyperresponsiveness (AHR) is a hallmark clinical symptom of asthma. At least two components of AHR have been identified: 1) baseline AHR, which is persistent and presumably caused by airway remodelling due to chronic recurrent airway inflammation; and 2) acute and variable AHR, which is associated with an episodic increase in airway inflammation due to environmental factors such as allergen exposure.Despite intensive research, the mechanisms underlying acute and chronic AHR are poorly understood. Owing to the complex variety of interactive processes that may be involved, in vitro model systems and animal models are indispensable to the unravelling of these mechanisms at the cellular and molecular level.The present paper focuses on a number of translational studies addressing the emerging central role of the airway smooth muscle cell, as a multicompetent cell involved in acute airway constriction as well as structural changes in the airways, in the pathophysiology of airway hyperresponsiveness.

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Transiently, paralleled upregulation of arginase and nitric oxide synthase and the effect of both enzymes on the pathology of asthma

Cited by 50 publications

References 52 publications

l-Arginine deficiency causes airway hyperresponsiveness after the late asthmatic reaction

l-Arginine deficiency causes airway hyperresponsiveness after the late asthmatic reaction

Direct inhibition of arginase attenuated airway allergic reactions and inflammation in a Dermatophagoides farinae-induced NC/Nga mouse model

Airway hyperresponsiveness in asthma: lessons fromin vitromodel systems and animal models: Fig. 1—

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