Asthma and lower airway disease
Beneficial effects of high dose of L-arginine on airway hyperresponsiveness and airway inflammation in a murine model of asthma

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Background

Disturbance in the delicate balance between L-arginine–metabolizing enzymes such as nitric oxide synthase (NOS) and arginase may lead to decreased L-arginine availability to constitutive forms of NOS (endothelial NOS), thereby increasing the nitro-oxidative stress and airway hyperresponsiveness (AHR).

Objective

In this study, we investigated the effects of high doses of L-arginine on L-arginine–metabolizing enzymes and subsequent biological effects such as cyclic guanosine monophosphate production, lipid peroxidation, peroxynitrite, AHR, and airway inflammation in a murine model of asthma.

Methods

Different doses of L-arginine were administered to ovalbumin–sensitized and challenged mice. Exhaled nitric oxide, AHR, airway inflammation, TH2 cytokines, goblet cell metaplasia, nitro-oxidative stress, and expressions of arginase 1, endothelial NOS, and inducible NOS in lung were determined.

Results

L-arginine significantly reduced AHR and airway inflammation including bronchoalveolar lavage fluid eosinophilia, TH2 cytokines, TGF-β1, goblet cell metaplasia, and subepithelial fibrosis. Further, L-arginine increased ENO levels and cyclic guanosine monophosphate in lung and reduced the markers of nitro-oxidative stress such as nitrotyrosine, 8-isoprostane, and 8-hydroxy-2′-deoxyguanosine. This was associated with reduced activity and expression of arginase 1, increased expression of endothelial NOS, and reduction of inducible NOS in bronchial epithelia.

Conclusion

We conclude that L-arginine administration may improve disordered nitric oxide metabolism associated with allergic airway inflammation, and alleviates some features of asthma.

Section snippets

Animals

Male BALB/c mice (8-10 weeks old; National Institute of Nutrition, Hyderabad, India) were acclimatized for a week before starting the experiments. All animals were maintained according to Committee for the Purpose of Control and Supervision of Experiments on Animals guidelines, and protocols were approved by the Institutional Animal Ethics Committee.

Grouping of mice

In pilot experiments, mice were divided into 5 groups, and each (n = 6) was named according to sensitization/challenge/treatment: SHAM/PBS/vehicle

High-dose exogenous L-ARG reduces AHR and airway inflammation

To determine the possible beneficial effects of exogenous L-ARG supplementation in asthma, the effects of 25, 250, and 500 mg/kg L-ARG on Penh and AI were investigated. In dose titration experiments, allergic control mice (OVA/OVA/VEH) developed not only increased Penh (Fig 2, A) but also a dense infiltration of inflammatory cells, predominantly eosinophils and mononuclear cells, in perivascular and peribronchial regions compared with sham control mice (SHAM/PBS/VEH; Fig 2, B and C). Although

Discussion

L-arginine is a conditionally essential basic amino acid, and human beings normally consume 3.5 to 5 g daily.21 It has multiple pharmacologic properties (antioxidant, anti-inflammatory, antihypercholesterolemic, muscle relaxant, immunomodulatory, and so forth).12 These widespread activities could be a result of its effect on various metabolizing enzymes and their final metabolites.22 The use of L-ARG has been reported for various disease conditions (angina pectoris, congestive heart failure,

References (33)

  • S.T. Holgate et al.

    Mechanisms of airway epithelial damage: epithelial-mesenchymal interactions in the pathogenesis of asthma

    Eur Respir J

    (2003)
  • F.L. Ricciardolo et al.

    Nitric oxide in health and disease of the respiratory system

    Physiol Rev

    (2004)
  • A.C. Keller et al.

    Nitric oxide paradox in asthma

    Mem Inst Oswaldo Cruz

    (2005)
  • J. Boer et al.

    Role of L-arginine in the deficiency of nitric oxide and airway hyperreactivity after the allergen-induced early asthmatic reaction in guinea-pigs

    Br J Pharmacol

    (1999)
  • H.W. de Gouw et al.

    Effect of oral L-arginine on airway hyperresponsiveness to histamine in asthma

    Thorax

    (1999)
  • H. Takano et al.

    Oral administration of L-arginine potentiates allergen-induced airway inflammation and expression of interleukin-5 in mice

    J Pharmacol Exp Ther

    (1998)
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    Supported by projects NWP0033 and MLP 5501 at the Institute of Genomics and Integrative Biology, Council of Scientific and Industrial Research, Government of India. U.M. and G.D.L. are the recipients of fellowships from the Indian Council of Medical Research.

    Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest.

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