Competitive metabolism of L -arginine: arginase as a therapeutic target in asthma

Abstract

Exhaled breath nitric oxide (NO) is an accepted asthma biomarker. Lung concentrations of NO and its amino acid precursor, L-arginine, are regulated by the relative expressions of the NO synthase (NOS) and arginase isoforms. Increased expression of arginase I and NOS2 occurs in murine models of allergic asthma and in biopsies of asthmatic airways. Although clinical trials involving the inhibition of NO-producing enzymes have shown mixed results, small molecule arginase inhibitors have shown potential as a therapeutic intervention in animal and cell culture models. Their transition to clinical trials is hampered by concerns regarding their safety and potential toxicity. In this review, we discuss the paradigm of arginase and NOS competition for their substrate L-arginine in the asthmatic airway. We address the functional role of L-arginine in inflammation and the potential role of arginase inhibitors as therapeutics.

Increased mitochondrial arginine metabolism supports bioenergetics in asthma

“…We (1,2,4,19) and others (6,(14)(15)(16)(17)(18) have shown that arginine metabolic pathways, including iNOS and ARG, are increased in the airway epithelium in asthma. To address whether de novo epithelium to support the greater arginine metabolism via iNOS and ARG2, which is consistent with the tracer-measured increase in whole-body de novo arginine synthesis in asthma.…”

“…Although higher-than-normal levels of arginine/NO have been long described in asthma, and F E NO has been standardized for clinical assessment of inflammation in asthma, we (19) and others (6,(14)(15)(16)(17)(18) have found that ARG activity is increased in asthma, but little was known of the consequences of increased ARG activity for asthma pathobiology. This study reveals that the greater mitochondrial arginine metabolism is linked to changes in mitochondrial endotype and a shift toward oxidative bioenergetic pathways.…”

“…1-3 and Figure 1A). Although iNOS expression and F E NO are increased in asthma and promote inflammatory injury via nitration (2,4), airway hyper -responsiveness is not diminished in mice with genetic deletion of iNOS (5), and arginine-analog inhibitors of iNOS pathways have poor efficacy in asthma (6). This caused us to consider that metabolism of arginine may mechanistically contribute to asthma through pathways other than generation of NO.…”

“…6,[14][15][16][17][18][19]. ARG1 is present exclusively in the cytosol of hepatic cells as part of the urea cycle, but ARG2 is found in mitochondria of many tissues without a functioning complete urea cycle, including the lung (18).…”

Distinct Metabolic Profile of Inhaled Budesonide and Salbutamol in Asthmatic Children during Acute Exacerbation

“…Arginase was of particular importance for competing with nitric oxide synthesis. Increased arginase activity results in the production of nitric oxide in the bronchioles and potentiates airway reactivity [29]. Research findings have also suggested that in a murine asthma model, arginine treatment not only ameliorated the inflammatory airway response and attenuated the increases in arginase Fig.…”