Arginase and pulmonary diseases

Abstract

Recent studies have indicated that arginase, which converts L-arginine into L-ornithine and urea, may play an important role in the pathogenesis of various pulmonary disorders. In asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis, increased arginase activity in the airways may contribute to obstruction and hyperresponsiveness of the airways by inducing a reduction in the production of bronchodilatory nitric oxide (NO) that results from its competition with constitutive (cNOS) and inducible (iNOS) NO synthases for their common substrate. In addition, reduced L-arginine availability to iNOS induced by arginase may result in the synthesis of both NO and the superoxide anion by this enzyme, thereby enhancing the production of peroxynitrite, which has procontractile and pro-inflammatory actions. Increased synthesis of L-ornithine by arginase may also contribute to airway remodelling in these diseases. L-Ornithine is a precursor of polyamines and L-proline, and these metabolic products may promote cell proliferation and collagen production, respectively. Increased arginase activity may also be involved in other fibrotic disorders of the lung, including idiopathic pulmonary fibrosis. Finally, through its action of inducing reduced levels of vasodilating NO, increased arginase activity has been associated with primary and secondary forms of pulmonary hypertension. Drugs targeting the arginase pathway could have therapeutic potential in these diseases.

Fig. 1

l-Arginine metabolism catalysed by arginase and nitric oxide synthase (NOS). l-Arginine is a substrate of both NOS, yielding nitric oxide (NO) and l-citrulline, and arginase, which in turn produces l-ornithine and urea. Arginase regulates the production of NO by competing with NOS for their common substrate. On the other hand, -hydroxy-l-arginine (NOHA), an intermediate in the NO synthesis catalysed by NOS, inhibits arginase activity. In addition, the arginase product l-ornithine is the precursor of the polyamines putrescine, spermidine and spermine and of l-proline. OAT Ornithine aminotransferase, ODC ornithine decarboxylase, P5C l-pyrroline-5-carboxylate, 1 pyrroline-5-carboxylate reductase, 2 spermidine synthase, 3 spermine synthase

Fig. 2

Role of increased arginase activity in the pathophysiology of allergic asthma. In allergic asthma, both arginase expression and activity are increased by Th2-cytokines. Increased arginase activity limits the bioavailability of l-arginine to constitutive nitric oxide synthase (cNOS), leading to a reduced production of agonist-induced nitric oxide (NO) by the airway epithelium and neuronal NO by inhibitory nonadrenergic noncholinergic (iNANC) nerves. Under basal conditions, NO induces airway smooth muscle relaxation by increasing the production of cyclic 3′,5′ guanosine monophosphate (cGMP) and/or by opening of calcium-activated potassium channels, thereby attenuating the responsiveness of the airways to contractile stimuli. As a result, arginase-induced deficiency of cNOS-derived NO in allergic asthma contributes to airway hyperresponsiveness (AHR) in this disease. Increased arginase activity also attenuates the availability of l-arginine to inducible nitric oxide synthase (iNOS), which is induced during the late asthmatic reaction or in chronic asthma. The reduced l-arginine availability to iNOS results in the simultaneous production of NO and the O₂ ⁻ superoxide anion by the oxygenase and reductase moieties of the enzyme, respectively, This leads to the rapid formation of the highly reactive nitrogen species peroxynitrite (ONOO ⁻), which has procontractile, proinflammatory and cytotoxic actions in the airways. In addition, increased production of polyamines and l-proline downstream of l-ornithine may contribute to the process of airway remodelling. ASM Airway smooth muscle, CaM calmodulin; e ⁻ electron, K _Ca calcium-activated potassium channel, nNOS neuronal nitric oxide synthase