S-Nitrosoglutathione Reductase Inhibition Regulates Allergen-Induced Lung Inflammation and Airway Hyperreactivity

Abstract

Allergic asthma is characterized by Th2 type inflammation, leading to airway hyperresponsivenes, mucus hypersecretion and tissue remodeling. S-Nitrosoglutathione reductase (GSNOR) is an alcohol dehydrogenase involved in the regulation of intracellular levels of S-nitrosothiols. GSNOR activity has been shown to be elevated in human asthmatic lungs, resulting in diminished S-nitrosothiols and thus contributing to increased airway hyperreactivity. Using a mouse model of allergic airway inflammation, we report that intranasal administration of a new selective inhibitor of GSNOR, SPL-334, caused a marked reduction in airway hyperreactivity, allergen-specific T cells and eosinophil accumulation, and mucus production in the lungs in response to allergen inhalation. Moreover, SPL-334 treatment resulted in a significant decrease in the production of the Th2 cytokines IL-5 and IL-13 and the level of the chemokine CCL11 (eotaxin-1) in the airways. Collectively, these observations reveal that GSNOR inhibitors are effective not only in reducing airway hyperresponsiveness but also in limiting lung inflammatory responses mediated by CD4+ Th2 cells. These findings suggest that the inhibition of GSNOR may provide a novel therapeutic approach for the treatment of allergic airway inflammation.

Pharmacological In Vivo Inhibition of S-Nitrosoglutathione Reductase Attenuates Bleomycin-Induced Inflammation and Fibrosis

“…in 50 ml PBS at doses of 0.3, 1.0, and 3.0 mg/kg daily. These doses were chosen based on the results of the previous studies in a mouse ovalbumin model (Ferrini et al, 2013) as well as our unpublished observations in a house dust mite model of asthma. In those studies, these doses were found to be effective yet safe.…”

“…GSNO is present in high levels in lung lining fluid and has been shown to exert bronchodilatory activity with a 100-fold higher potency than theophylline (Gaston et al, 1993(Gaston et al, , 1994. By inhibiting GSNOR, SPL-334 inhibits the catabolism of GSNO, which increases the cellular pool of GSNO and the level of nitroso groups on critical proteins, leading to smooth muscle relaxation, decreased inflammation via inhibition of the nuclear factor-kB (NF-kB) pathway, activation of antioxidant pathways via activation of Nrf-2, and increased mucin clearance (Nozik-Grayck et al, 2002Que et al, 2005;Sanghani et al, 2009;Wu et al, 2010;Kelleher et al, 2011;Foster et al, 2012;Ferrini et al, 2013).…”

“…Together, these considerations have suggested that SPL-334 may provide a multifactorial approach to the treatment of ILD as an inducer of antioxidant enzymes to limit oxidant damage (Chen and Kunsch, 2004), as an anti-inflammatory agent (Sanghani et al, 2009;Ferrini et al, 2013), and as a bronchodilator (Ferrini et al, 2013). To assess this possibility of a protective and curative effect of SPL-334 on ILD, we have tested preclinically the preventive and therapeutic effects of SPL-334 in vivo in the bleomycin (BLM) lung injury mouse model.…”

Recent developments in the role of reactive oxygen species in allergic asthma

“…Moreover, decreased glutathione levels have been suggested to induce changes in T H 1 to T H 2 cell differentiation. Under these circumstances, the oxidant and antioxidant balance is lost and AHR is induce by the synthesis of S-nitrosoglutathione and a corresponding shift in NO metabolism (58,59).…”

“…The role of LTC 4 in allergic asthma has been extensively evaluated (85). LTC 4 is produced in mast cells by assembly of a biosynthetic complex at the nuclear envelope, consisting of cytosolic phospholipase A2 (cPLA2), (64) Oxi-CaMKII inhibitor KN-93 KN-93 significantly decreased goblet cell hyperplasia, bronchial epithelial thickness, airway eosinophilia, the eosinophil chemoattractant molecule, Ccl-11, and NF-κB activity in allergic asthma (61) Leukotriene C4 (LTC 4 ) inhibitor A LTC 4 inhibitor reduced NOX4 levels and attenuated cell death (32) Galangin Galangin demonstrated decreased airway remodeling, angiogenic activity, and ASMC proliferation through the TGF-β1-ROS-MAPK pathway (65)(66)(67) Astragalin Astragalin suppressed LPS-induced ROS production and eotaxin-1 expression in epithelial cells through the TLR4-PKCγ1-PKCβ2-NADPH signaling pathway (68,69) Glutathione GSH balances Th1/Th2 responses, alters nitric oxide metabolism and inhibits ROS (55,59,70) SOD SODs protects against the harmful effects of ROS and airway inflammation (71)(72)(73) Glutathione peroxidases Glutathione peroxidases prevent airway inflammation and alveolar destruction (74)(75)(76) Vitamins C and E Vitamins C and E reduce AHR, inflammation, and oxidative stress (77)(78)(79) TLR7, toll-like receptor 7; Oxi-CaMKII, oxidative-CaMKII; SOD, superoxide dismutase; AHR, airway hyper-reactivity; Nrf2, nuclear factor E2-related factor 2; Cu/Zn SOD, copper/zinc superoxide dismutase; ROS, reactive oxygen species; NOX4, NADPH oxidase 4; LPS, lipopolysaccharide; Th2, type 2 helper T.…”