Arginase and pulmonary diseases - PubMed (original) (raw)

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

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-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

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-arginine to inducible nitric oxide synthase (iNOS), which is induced during the late asthmatic reaction or in chronic asthma. The reduced

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-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

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-proline downstream of

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-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