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

Maarsingh, Harm; Bossenga, B. E.; Bos, I. Sophie T.; Volders, Haukeline H.; Zaagsma, Johan; Meurs, Herman

doi:10.1183/09031936.00105408

Cited by 43 publications

(60 citation statements)

References 117 publications

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“…Arginase activity was determined in lung homogenates, by measuring the conversion of [ 14 C]-L-arginine to [ 14 C]-urea, as previously described [15]. Arginase activity was expressed as pmol urea produced per mg protein per min.…”

Section: Arginase Activitymentioning

confidence: 99%

“…Increased expression and/or activity of arginase has been observed in airways and lung tissue obtained from various animal models of allergic asthma [9] and from patients [10][11][12]. Increased consumption of L-arginine by arginase contributes to the development of allergen-induced AHR in acute allergic asthma by limiting the bioavailability of L-arginine to nitric oxide synthase (NOS) isozymes [13][14][15], which hydrolyse the amino acid into nitric oxide and Lcitrulline. This leads to a deficiency of bronchodilating nitric oxide, and increased formation of the highly reactive proinflammatory and procontractile nitric oxide metabolite peroxynitrite, both of which underlie AHR in animal models of allergic asthma [13][14][15][16][17][18].…”

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confidence: 99%

“…Increased consumption of L-arginine by arginase contributes to the development of allergen-induced AHR in acute allergic asthma by limiting the bioavailability of L-arginine to nitric oxide synthase (NOS) isozymes [13][14][15], which hydrolyse the amino acid into nitric oxide and Lcitrulline. This leads to a deficiency of bronchodilating nitric oxide, and increased formation of the highly reactive proinflammatory and procontractile nitric oxide metabolite peroxynitrite, both of which underlie AHR in animal models of allergic asthma [13][14][15][16][17][18]. In a guinea pig model of allergic asthma, inhalation of the specific arginase inhibitor 2(S)-amino-6-boronohexanoic acid (ABH) acutely reversed allergeninduced AHR in vivo both after the early and late asthmatic reaction, to a similar extent as treatment with inhaled L-arginine [19].…”

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Increased arginase activity contributes to airway remodelling in chronic allergic asthma

Maarsingh

Dekkers²,

Zuidhof³

et al. 2011

European Respiratory Journal

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Airway remodelling, characterised by increased airway smooth muscle (ASM) mass, subepithelial fibrosis, goblet cell hyperplasia and mucus gland hypertrophy, is a feature of chronic asthma. Increased arginase activity could contribute to these features via increased formation of polyamines and L-proline downstream of the arginase product L-ornithine, and via reduced nitric oxide synthesis.Using the specific arginase inhitibor 2(S)-amino-6-boronohexanoic acid (ABH), we studied the role of arginase in airway remodelling using a guinea pig model of chronic asthma. Ovalbuminsensitised guinea pigs were treated with ABH or PBS via inhalation before each of 12 weekly allergen or saline challenges, and indices of arginase activity, and airway remodelling, inflammation and responsiveness were studied 24 h after the final challenge.Pulmonary arginase activity of repeatedly allergen-challenged guinea pigs was increased. Allergen challenge also increased ASM mass and maximal contraction of denuded tracheal rings, which were prevented by ABH. ABH also attenuated allergen-induced pulmonary hydroxyproline (fibrosis) and putrescine, mucus gland hypertrophy, goblet cell hyperplasia, airway eosinophilia and interleukin-13, whereas an increased L-ornithine/L-citrulline ratio in the lung was normalised. Moreover, allergen-induced hyperresponsiveness of perfused tracheae was fully abrogated by ABH.These findings demonstrate that arginase is prominently involved in allergen-induced airway remodelling, inflammation and hyperresponsiveness in chronic asthma.

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Section: Arginase Activitymentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Increased arginase activity contributes to airway remodelling in chronic allergic asthma

Maarsingh

Dekkers²,

Zuidhof³

et al. 2011

European Respiratory Journal

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“…The discrepancy may be caused by the amount of rIL13 instilled into the lung (10 g), which exceeds the content of IL-13 in OVA/OVAtreated lungs (ϳ100 pg/mg lung protein) by three orders of magnitude. Pharmacological inhibition of arginase activity decreased R N in OVA/OVA-treated guinea pigs (32,34) and mice (19, 40) but did not change H or G, although one mouse study found no change R N and an increase in H and G (7).…”

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Ablation of Arg1 in hematopoietic cells improves respiratory function of lung parenchyma, but not that of larger airways or inflammation in asthmatic mice

Cloots

Sankaranarayanan

Theije

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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Cloots RH, Sankaranarayanan S, de Theije CC, Poynter ME, Terwindt E, van Dijk P, Hakvoort TB, Lamers WH, Köhler SE. Ablation of Arg1 in hematopoietic cells improves respiratory function of lung parenchyma, but not that of larger airways or inflammation in asthmatic mice. Am J Physiol Lung Cell Mol Physiol 305: L364-L376, 2013. First published July 5, 2013; doi:10.1152/ajplung.00341.2012.-Asthma is a chronic inflammatory disease of the small airways, with airway hyperresponsiveness (AHR) and inflammation as hallmarks. Recent studies suggest a role for arginase in asthma pathogenesis, possibly because arginine is the substrate for both arginase and NO synthase and because NO modulates bronchial tone and inflammation. Our objective was to investigate the importance of increased pulmonary arginase 1 expression on methacholine-induced AHR and lung inflammation in a mouse model of allergic asthma. Arginase 1 expression in the lung was ablated by crossing Arg1 fl/fl with Tie2Cre tg/Ϫ mice. Mice were sensitized and then challenged with ovalbumin. Lung function was measured with the Flexivent. Adaptive changes in gene expression, chemokine and cytokine secretion, and lung histology were quantified with quantitative PCR, ELISA, and immunohistochemistry. Arg1 deficiency did not affect the allergic response in lungs and large-airway resistance, but it improved peripheral lung function (tissue elastance and resistance) and attenuated adaptive increases in mRNA expression of arginine-catabolizing enzymes Arg2 and Nos2, arginine transporters Slc7a1 and Slc7a7, chemokines Ccl2 and Ccl11, cytokines Tnfa and Ifng, mucus-associated epithelial markers Clca3 and Muc5ac, and lung content of IL-13 and CCL11. However, expression of Il4, Il5, Il10, and Il13 mRNA; lung content of IL-4, IL-5, IL-10, TNF-␣, and IFN-␥ protein; and lung pathology were not affected. Correlation analysis showed that Arg1 ablation disturbed the coordinated pulmonary response to ovalbumin challenges, suggesting arginine (metabolite) dependence of this response. Arg1 ablation in the lung improved peripheral lung function and affected arginine metabolism but had little effect on airway inflammation. airway hyperresponsiveness; arginine; inflammation ALLERGIC ASTHMA IS A CHRONIC inflammatory disorder of the lung that is characterized by a reversible limitation of the airflow due to an allergic reaction in the airways with the characteristics of a T H 2-predominant airway inflammation. The airway inflammation is initiated by the binding of inhaled allergens to complementary IgEs on IgE receptor-bearing cells. Upon activation, these cells release histamine, cytokines, and proteases, resulting in the activation of the inflammatory cascade with lung infiltration of eosinophils and mononuclear cells. Increased mucus production, mucosal edema, and a disproportionate smooth-muscle contraction lead to airway hyperresponsiveness (AHR). As a result of the recurring inflammation, airway remodeling develops as a consequence of fibrosis and airway wall thickening (2,3,6,36).Rec...

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“…We propose that a potency of lower dose was probably weak for full inhibition of arginase activity and for inhibition of its detrimental effects. In addition, reduced L-arginine availability for NOS by arginase may lead to an increased production of peroxynitrite, contributing to cell damage and increased airway smooth muscle contractility (Maarsingh et al 2009). Similar results were obtained by Ckless et al (2008) who reported that the inhibition of arginase led to an augmentation of the inflammatory response and bronchial hyperreactivity in mouse model.…”

Section: Discussionmentioning

confidence: 99%

Competition of NO synthases and arginase in the airways hyperreactivity

Strapková

Antošová²

2011

gpb

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Abstract. The competition between arginases and NO synthases (NOS) for their common substrate L-arginine can be important in the airways hyperreactivity. We investigated the effect of the simultaneous modulation of arginase and NOS activities in allergen-induced airways hyperreactivity. We analysed the response of tracheal and lung tissue smooth muscle to histamine or acetylcholine after administration N ω -nitro-L-arginine methyl ester (L-NAME), aminoguanidine (AG) and N ω -hydroxy-L-arginine (NOHA) in the combinations in in vitro conditions. The results show the decrease of ovalbumin-induced hyperreactivity after inhibition of arginase activity with NOHA. A supplementation of L-arginine caused favourable effect on the airway smooth muscle response. We found the airway reactivity decrease on the whole if we used the combination of NOS and arginase inhibitors. The inhibition of both types of enzymes caused more expressive effect in tracheal smooth muscles. We recorded the difference in the response to histamine or acetylcholine. The simultaneous inhibition of iNOS (with AG) and arginase (with NOHA) evoked the most expressive effect. Results show the importance of competition of both types enzymes -NOS and arginase for the balance of theirs activities in the control of airways bronchomotoric tone in the conditions of the airways hyperreactivity.

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

Cited by 43 publications

References 117 publications

Increased arginase activity contributes to airway remodelling in chronic allergic asthma

Increased arginase activity contributes to airway remodelling in chronic allergic asthma

Ablation of Arg1 in hematopoietic cells improves respiratory function of lung parenchyma, but not that of larger airways or inflammation in asthmatic mice

Competition of NO synthases and arginase in the airways hyperreactivity

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