FTI 277 HCl br Conflicts of interest br Introduction Arginas

Conflicts of interest
Introduction Arginase catalyzes the reaction in which l-arginine is converted to l-ornithine and urea. In humans, two arginase isoenzymes have been identified, arginase 1 and arginase 2, that differ in cellular location and tissue distribution [1]. Both arginase enzymes are constitutively expressed in the airways. The cytosolic arginase 1 and mitochondrial arginase 2 can particularly be found in airway endothelial cells, epithelial cells, fibroblasts and macrophages [2]. Furthermore, the expression of both enzymes can be induced in airway smooth muscle FTI 277 HCl [3, 4]. Downstream metabolism of l-ornithine leads to the formation of polyamines and l-proline, which are involved in cell proliferation and differentiation, and collagen production, respectively [1, 5•]. Next to the effects of metabolic products of arginases, many biological effects of the enzymes are related to their competition with nitric oxide synthases (NOS) for the common substrate l-arginine. Three distinct NOS enzymes are expressed in mammals; endothelial NOS (eNOS), neuronal NOS (nNOS) and inducible NOS (iNOS). As eNOS and nNOS are constitutively expressed in the airway epithelium, in inhibitory nonadrenergic noncholinergic neurons (nNOS) and airway vascular endothelial cells (eNOS), they are also referred to as constitutive NOS (cNOS). All NOS isoenzymes use l-arginine for the formation of nitric oxide (NO) and l-citrulline. Increases in intracellular calcium concentrations, through the action of agonists or membrane depolarization, trigger cNOS to produce relatively low amounts of NO. iNOS is particularly expressed in epithelial cells and macrophages during inflammation. In contrast to cNOS, iNOS produces large amounts of NO and enzyme activation is dependent on changes gene expression, among others induced by proinflammatory cytokines [6]. Furthermore, when l-arginine levels are low, for example due to elevated arginase activity, NOS is uncoupled and superoxide is formed. Superoxide rapidly reacts with NO to form peroxynitrite, often leading to detrimental effects in the tissue by nitration of tyrosine residues [7]. The arginase and NOS pathways may interact at different levels (Figure 1). This could be through competition for l-arginine, inhibition of arginase by the intermediate NOS metabolite Nω-hydroxy-l-arginine and through l-ornithine that causes feedback inhibition of arginase and inhibition of l-arginine uptake by cells producing NO. Next to arginase, NOS and their metabolic products, also methylated arginines such as the arginine derivatives asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) can greatly influence l-arginine homeostasis [8]. ADMA and its inactive stereoisomer SDMA are primarily formed as byproducts during the degradation of methylated arginine containing residues. Furthermore, small amounts of ADMA may be produced from free arginine directly [9]. Whereas ADMA serves as an endogenous competitive inhibitor of NOS, SDMA influences NO synthesis by competing with arginine and other methylated arginines for cellular transport [8]. We and others previously showed that an increased arginase activity in the airway contributes to airway obstruction and hyperresponsiveness, by reducing the available substrate for cNOS and iNOS [10]. As a result, production of bronchodilatory NO is decreased and superoxides are formed, which react with NO to form peroxynitrite, thereby enhancing airway contraction and inflammation. Furthermore, elevated airway arginase activity leads to increased l-ornithine production. Which potentially contributes to airway remodeling by increased cell proliferation and collagen formation [10, 11]. The disrupted l-arginine homeostasis, through changes in arginase and NOS expression and activity, does not only play a central role in the development of various airways diseases such as asthma or COPD. It possibly also affects l-arginine homeostasis throughout the body contributing to the emergence of co-morbidities. This review focusses on the role of arginase and NOS in co-morbidities of asthma and COPD (Table 1) and speculates on their possible connection.