Mouse Models of Asthma: Can They Give Us Mechanistic Insights into the Role of Nitric oxide?

Abstract

New clinical practice guidelines for patients with asthma include the recommendation to monitor exhaled breath nitric oxide (NO) levels. NO concentrations in exhaled breath are increased in asthmatics and increased NO levels correlate with worsening airway inflammation and asthma symptoms. The multiple roles of NO in the lung have not been delineated clearly. Clinical trials are being performed presently that test the apparently conflicting hypotheses that either donors or inhibitors of NO in the lung are effective strategies for treating asthma. These strategies evolved, in part, from results of pre-clinical studies performed in mice and other animal models. This review evaluates the existing literature with regard to mouse models of asthma and explores the often conflicting data on the role of NO, the nitric oxide synthase (NOS) enzymes, and the arginase enzymes in allergic airway inflammation. While we will emphasize the ovalbumin exposure mouse model, we will also examine other models. Where inconsistencies are identified among the studies, we attempt to determine whether such inconsistencies arise from methodological differences or alternative mechanisms. Ultimately, we address whether the allergen-exposed mouse is a suitable model for identifying promising new drugs for the treatment of human asthma. While a consensus is building that NO is beneficial or protective in subsets of asthmatics, results from studies using mouse models to investigate the individual roles of NO and the NOS enzymes in airway inflammation are often contradictory. Further research efforts with this model will allow us to distinguish which asthma patients may benefit best from NO donors and which may benefit from NO inhibitors.

Reciprocal regulation of iNOS and PARP-1 during allergen-induced eosinophilia

“…iNOS-associated protein nitration and tissue damage are partially responsible for allergen-induced eosinophilia following exposure Although the role of iNOS in the pathogenesis of allergeninduced airway inflammation has yet to be fully elucidated [25], it is widely accepted that the potential mechanism by which iNOS contributes to disease pathogenesis is through the mediation of tissue damage as a result of the excessive production of NO and its by-product ONOO -. Accordingly, the present study began by addressing the association between iNOS-mediated tissue damage and airway inflammation.…”

“…Clinically, however, the level of exhaled NO has been reliably associated with severity of disease symptoms in asthmatics [3]. A few reports show a direct role for iNOS in the process of eosinophil recruitment in that inhibition of iNOS, either pharmacologically or by a gene knockout, reduces airway infiltration by inflammatory cells, especially eosinophils, in models of allergen-induced lung inflammation (reviewed in [25]). Furthermore, two very recent reports showed that polymorphisms in the iNOS gene may be important for asthma protection or susceptibility [11,12].…”

“…This difference may be associated with the level of NO produced rather than its cellular or molecular source. Despite the clear induction of iNOS expression in the airways after allergen exposure, its role in the pathogenesis of asthma in animal models of the disease has been challenged by several studies (for a detailed review, see [25]). The current study provides evidence for a close relationship between PARP-1 and iNOS during airway inflammation.…”

Increased mitochondrial arginine metabolism supports bioenergetics in asthma

“…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.…”

Arginase in Asthma – Recent Developments in Animal and Human Studies~!2009-11-12~!2010-03-23~!2010-05-04~!

“…Moreover, allergen-induced airway inflammation and AHR were more pronounced in NOS2 knock-out mice than in wild type animals [74], although unchanged AHR [75] and inflammation [75,76] as well as reduced inflammation [77,78] have also been reported (for a comprehensive review on the role of NOS isoforms in asthma, see Mathrani et al [79]). …”