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  • br Asthma The chronic airway inflammatory disease asthma

    2024-09-14


    Asthma The chronic airway inflammatory disease Calpain Inhibitor XII is associated with enhanced levels of exhaled NO generated by iNOS in the airway epithelium [12]. In asthmatic patients local and systemic changes in iNOS, peroxynitrite, arginase, ADMA and arginine levels have been observed and are associated with i.a. lung function and asthma severity [5•, 10, 13]. In support, gene association studies in asthmatic patients [14] and different animal models of allergic asthma [15•, 16] show a key role for arginase in different aspects of the disease. Allergic rhinitis is a frequent co-morbidity of asthma [17]. Allergic rhinitis patients show increased nasal arginase and iNOS expression [18, 19], and changes in nitrite/nitrate and nitrite serum levels during symptomatic periods [20, 21]. Furthermore, peroxynitrite plays a likely role in nasal blockage after allergen encounter [22]. Interestingly, the role of arginase in allergic rhinitis has not much been studied. Treatment of allergic rhinitis patients with the leukotriene antagonist montelukast, leads to decreased arginase serum levels compared to the control group [23], indicating that in allergic rhinitis, arginase may be affected by mast-cell mediator release, leading to a reduced bioavailability of l-arginine for NOS. Psychological disorders such as depression and anxiety are important co-morbidities of both asthma and COPD [17, 24]. Major depressed patients show a positive correlation between arginase activity and disease severity [25] and elevated ADMA and decreased SDMA concentration [26]. A significant decrease in arginase levels, an increase in l-arginine/ADMA ration and a trend for increased global arginine bioavailability is observed after first improvement at hospital discharge [26]. In addition, patients with major depression have lower levels of platelet NOS activity and NO metabolites in plasma [27]. Antidepressants have normalizing effects on plasma NO levels [28]. Several studies have looked into the effect of NOS isoenzymes and inhibition on various brain areas during stress, however these show contrasting results [29]. After viral and bacterial respiratory infection, common causes of asthma exacerbation [30], toll like receptor stimulation upregulates arginase in lung myeloid cells [31••, 32]. In response, iNOS is upregulated in lung macrophages and polymorphonuclear leukocytes shortly after infection, leading to an increase in NO production, NO metabolites and ADMA levels [33, 34, 35] promoting inflammation. T-cells can replenish l-arginine levels through the conversion of l-citrulline [], thereby supporting the anti-viral or anti-bacterial response. Inhibition of arginase with 2(S)-amino-6-boronohexanoic acid (ABH), leads to a similar increase in l-arginine [35]. Nasal obstruction, an increased upper airway collapsibility and a decrease in pharyngeal cross-sectional area in asthma patients can promote symptoms of obstructive sleep apnea syndrome (OSAS) [36]. In OSAS patients, serum NO levels are reduced compared to control subjects [37, 38]. In line, serum arginase activity is increased [38]. This might be induced by intermittent hypoxia that can also cause upregulation of pulmonary arginase and pulmonary arterial hypertension [39]. Moreover, concentrations of ADMA are found to be increased [40]. Two independent studies showed that, plasma NO levels can be increased by treatment with continuous positive airway pressure [37, 41]. Whether OSAS treatment also decreases arginase activity has not been investigated. In contrast, granulocytes and plasma of allergic dermatitis patients show a decreased arginase activity compared to controls [42]. iNOS expression is found to be upregulated in skin biopsies of allergic dermatitis patients [43]. This finding is supported by two different mouse models of allergic dermatitis, where it is shown that iNOS possibly induces α-melanocyte-stimulating hormone, leading to exacerbation of symptoms [44] and an increase in protein-bound nitrotyrosine in eosinophils in skin lesions due to a disrupted NO-balance [45].