Direct inhibition of arginase attenuated airway allergic reactions and inflammation in a Dermatophagoides farinae-induced NC/Nga mouse model

Abstract

The expression of arginase I has been a focus of research into the pathogenesis of experimental asthma, because arginase deprives nitric oxide synthase (NOS) of arginine and therefore participates in the attenuation of bronchodilators such as nitric oxide (NO). The present study used an intranasal mite-induced NC/Nga mouse model of asthma to investigate the contribution of arginase to the asthma pathogenesis, using an arginase inhibitor, N -hydroxy-nor-L-arginine (nor-NOHA). The treatment with nor-NOHA inhibited the increase in airway hyperresponsiveness (AHR) and the number of eosinophils in bronchoalveolar lavage fluid. NOx levels in the lung were elevated despite suppressed NOS2 mRNA expression. Accompanied by the attenuated activity of arginase, the expression of arginase I at both the mRNA and protein level was downregulated. The levels of mRNA for T helper 2 cytokines such as IL-4, IL-5, and IL-13, and for chemotactants such as eotaxin-1 and eotaxin-2, were reduced. Moreover, the accumulation of inflammatory cells and the ratio of goblet cells in the bronchiole were decreased. The study concluded that the depletion of NO caused by arginase contributes to AHR and inflammation, and direct administration of an arginase inhibitor to the airway may be beneficial and could be of use in treating asthma due to its antiinflammatory and airway-relaxing effects, although it is not clear whether the anti-inflammatory effect is direct or indirect. experimental asthma; arginase inhibitor; nor-NOHA

Increased arginase activity contributes to airway remodelling in chronic allergic asthma

“…The expression of arginase is strongly induced by Th2 cytokines, including IL-13 [35]; ABH markedly attenuated the allergen-induced increase in IL-13 in our model, indicating that the increased arginase activity and the inhibitory effect of ABH thereon may result from changes in IL-13. This is consistent with a recent finding in a mouse model of acute asthma, showing that intranasal application of the arginase inhibitor N v -hydroxy-nor-arginine (nor-NOHA) prevents house dust mite-induced increases in Th2 cytokine expression and arginase activity in the lung [38]. It is tempting to speculate that the previously observed anti-allergic effect of inhaled ABH [19] underlies the reduction of Th2 cytokine release and subsequent arginase induction.…”

“…Thus, allergeninduced inflammatory responses are attenuated in mice that overexpress endothelial NOS [49] and are elevated in iNOS -/-mice [50] compared with wild-type mice. Consistent with our observations, treatment with the arginase inhibitor nor-NOHA reduced inflammatory cell numbers in the bronchoalveolar lavage (BAL) of allergen-challenged mice [38,50]. However, the arginase inhibitor S-(2-boronoethyl)-L-cysteine did not affect inflammatory cell numbers or cytokine levels in BAL, and even further enhanced peribronchiolar and perivascular inflammation in another mouse model of acute allergic asthma [51].…”

Arginase Inhibition Prevents Inflammation and Remodeling in a Guinea Pig Model of Chronic Obstructive Pulmonary Disease

“…This results in decreased production of bronchodilatory NO as well as increased synthesis of proinflammatory and procontractile peroxynitrite, which contribute to the development of allergen-induced airway hyperresponsiveness (Meurs et al, 2002;Maarsingh et al, 2006Maarsingh et al, , 2009a. Treatment with inhaled arginase inhibitors protected against allergeninduced airway obstruction, airway hyper-responsiveness, and airway inflammation in guinea pig (Maarsingh et al, 2008b) and mouse (North et al, 2009;Takahashi et al, 2010) models of acute allergic asthma. Using repeatedly allergen-challenged guinea pigs, we recently demonstrated that increased arginase activity also has a major role in airway remodeling in chronic asthma, as indicated by effective inhibition of these features by inhalation of the specific (Baggio et al, 1999) arginase inhibitor 2(S)-amino-6-boronohexanoic acid (ABH) .…”

Mechanisms of 2,4-Dinitrochlorobenzene-induced acute inflammation in Human Papillomavirus type 16 E7 oncoprotein expressing skin

“…In mouse models of asthma, arginase-1 mediated allergic inflammatory response in lung epithelial cells through the modulation of NFκB signaling pathway (120,121). Furthermore, treatment with arginase specific inhibitor, 2(S)-amino-6-boronohexonic acid (ABH), significantly ameliorated pulmonary inflammation and airway fibrosis in guinea pigs repeatedly exposed to LPS.…”

“…In line with these findings, arginase-1 produced by macrophages has been shown to be responsible for the pathophysiology of asthma which is a complex disease manifested by allergic airway inflammation and airway hyperreactivity. In mouse models of asthma, arginase-1 drives allergic inflammatory response in lung epithelial cells through the modulation of NFκB signaling pathway (120,121). Furthermore, treatment with an arginase specific inhibitor, ABH, significantly ameliorated pulmonary inflammation and airway fibrosis in guinea pigs repeatedly exposed to LPS.…”