Functionally important role for arginase 1 in the airway hyperresponsiveness of asthma

Abstract

l-Arginine metabolism by the arginase and nitric oxide (NO) synthase (NOS) families of enzymes is important in NO production, and imbalances between these pathways contribute to airway hyperresponsiveness (AHR) in asthma. To investigate the role of arginase isozymes (ARG1 and ARG2) in AHR, we determined the protein expression of ARG1, ARG2, the NOS isozymes, and other proteins involved in l-arginine metabolism in lung tissues from asthma patients and in acute (3-wk) and chronic (12-wk) murine models of ovalbumin-induced airway inflammation. Expression of ARG1 was increased in human asthma, whereas ARG2, NOS isoforms, and the other l-arginine-related proteins (i.e., cationic amino acid transporters 1 and 2, agmatinase, and ornithine decarboxylase) were unchanged. In the acute murine model of allergic airway inflammation, augmentation of ARG1 expression was similarly the most dramatic change in protein expression. However, ARG2, NOS1, NOS2, and agmatinase were also increased, whereas NOS3 expression was decreased. Arginase inhibition in vivo with nebulized S-(2-boronoethyl)-l-cysteine attenuated the methacholine responsiveness of the central airways in mice from the acute model. Further investigations in the chronic murine model revealed an expression profile that more closely paralleled the human asthma samples: only ARG1 expression was significantly increased. Interestingly, in the chronic mouse model, which generates a remodeling phenotype, arginase inhibition attenuated methacholine responsiveness of the central and peripheral airways. The similarity in arginase expression between human asthma and the chronic model and the attenuation of AHR after in vivo treatment with an arginase inhibitor suggest the potential for therapeutic modification of arginase activity in asthma.

Deficiency of α7 Nicotinic Acetylcholine Receptor Attenuates Bleomycin-Induced Lung Fibrosis in Mice

“…The composition and function of the cell population in BAL and digested lung cells are different, which may explain why lack of α7 nAChR did not affect the BAL cell population ( Figure 6A). In the lung, arginase 1 can be expressed by distal airway epithelial cells and endothelial cells besides alveolar macrophages (64)(65)(66). This may explain why more than 90% arginase1 +…”

Competition of NO synthases and arginase in the airways hyperreactivity

“…It is probably a reason why NO prevents more the contraction of the large airways than small ones (Dewachter et al 1997). Also, North et al (2009) obtained different response of the central and peripheral airways. They determined expression of arginase 1, arginase 2 and NOS isoenzymes in asthma patients and in murine model of ovalbumin-induced airway inflammation.…”

L-Arginine Metabolism in the Lung: Reciprocal Regulation of the NOS and Arginase Pathways

“…Although the arginase isozymes share 58% sequence homology/identity, they exhibit different organ-specific and intracellular expression patterns [29]. Arginase 1 is a cytoplasmic enzyme that is highly constitutively expressed in the liver and is inducible in other cell types, such as macrophages and epithelial cells [28,30]. Arginase 2 is localized to the mitochondria and is expressed in many extrahepatic cell types [31].…”

“…The primary mechanism by which arginase is currently believed to affect NOS activity is by reducing the bioavailability of L-arginine substrate, at both the tissue and intracellular level (i.e., in tissues and cells in which both isozyme families are expressed, described in the following section) [33]. Evidence for this comes from several studies showing that arginase inhibition or exogenous L-arginine administration decreases airways hyperresponsiveness [30,[34][35][36][37][38]. Furthermore, cationic amino acids, including L-ornithine, the product of arginase, can also compete with L-arginine for uptake via the CAT transporters [39,40], also leading to intracellular substrate depletion.…”

“…Additionally, infiltrating inflammatory cells have been shown to express high levels of both NOS2 and arginase 1 (Fig. 1B) [30,48,49]. The presence of increased inflammatory cells may therefore also be involved in further decreasing the extracellular L-arginine bioavailability for transport into smooth muscle cells and epithelia, and increasing levels of peroxynitrite.…”