Arginine homeostasis in allergic asthma

Harm Maarsingh*, Johan Zaagsma, Herman Meurs

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

53 Citations (Scopus)

Abstract

Allergic asthma is a chronic disease characterized by early and late asthmatic reactions, airway hyperresponsiveness, airway inflammation and airway remodelling. Changes in L-arginine homeostasis may contribute to all these features of asthma by decreased nitric oxide (NO) production and increased formation of peroxynitrite, polyamines and L-proline. Intracellular L-arginine levels are regulated by at least three distinct mechanisms: (i) cellular uptake by cationic amino acid (CAT) transporters, (ii) metabolism by NO-synthase (NOS) and arginase, and (iii) recycling from L-citrulline. Ex vivo studies using animal models of allergic asthma have indicated that attenuated L-arginine bioavailability to NOS causes deficiency of bronchodilating NO and increased production of procontractile peroxynitrite, which importantly contribute to allergen-induced airway hyperresponsiveness after the early and late asthmatic reaction, respectively. Decreased cellular uptake of L-arginine, due to (eosinophil-derived) polycations inhibiting CATs, as well as increased consumption by increased arginase activity are major causes of substrate limitation to NOS. Increasing substrate availability to NOS by administration Of L-arginine, L-citrulline, the polycation scavenger heparin, or an arginase inhibitor alleviates allergen-induced airway hyperresponsiveness by restoring the production of bronchodilating NO. In addition, reduced L-arginine levels may contribute to the airway inflammation associated with the development of airway hyperresponsiveness, which similarly may involve decreased NO synthesis and increased peroxynitrite formation. Increased arginase activity could also contribute to airway remodelling and persistent airway hyperresponsiveness in chronic asthma via increased synthesis of L-ornithine, the precursor of polyamines and L-proline. Drugs that increase the bioavailability of L-arginine in the airways - particularly arginase inhibitors - may have therapeutic potential in allergic asthma. (C) 2008 Elsevier B.V. All rights reserved.

Original languageEnglish
Pages (from-to)375-384
Number of pages10
JournalEuropean Journal of Pharmacology
Volume585
Issue number2-3
DOIs
Publication statusPublished - 13-May-2008

Keywords

  • airway hyperresponsiveness
  • airway inflammation
  • airway remodelling
  • arginase
  • L-arginine
  • cationic amino acid transporter
  • L-citrulline
  • nitric oxide synthase
  • peroxynitrite1
  • NITRIC-OXIDE SYNTHASE
  • AIRWAY SMOOTH-MUSCLE
  • INDUCED BRONCHIAL HYPERREACTIVITY
  • ORNITHINE DECARBOXYLASE ACTIVITY
  • UNRESTRAINED GUINEA-PIGS
  • NF-KAPPA-B
  • RABBIT ALVEOLAR MACROPHAGES
  • MARROW-DERIVED MACROPHAGES
  • MOLECULAR-WEIGHT HEPARIN
  • AMINO-ACID TRANSPORTER

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