Using DNA microarray analysis, we were struck by the upregulation of specific genes involved in arginine metabolism during induction of experimental asthma. In particular, the genes for the arginine transporter (cationic amino acid transporter [CAT]2) and arginase I and II were strongly induced. In situ mRNA hybridization revealed strong expression of arginase I primarily in myeloid cells (macrophages) associated with inflammatory sites in the lung. In further preliminary in-vivo experiments, lung arginase I was shown to be markedly induced by IL-4 and IL-13 in a signal-transducer-and-activator-of-transcription [STAT]6 dependent manner. Interestingly, the products of arginase, polyamines and proline, regulate cell growth and connective tissue remodeling, respectively, two processes involved in the pathophysiology of asthma. Indeed, preliminary studies demonstrated increased levels of putrescine in the asthmatic lung, and inhibition of polyamine production with difluoromethylornithine (DFMO) blocked a specific pathological feature associated with experimental asthma. The main hypothesis of this grant application is that metabolism of arginine via arginase I has an important role in the pathophysiology of allergic airway responses. We propose three aims designed to dissect the regulation, expression, and relevance of arginase I in allergic airway inflammation.
In Aim I, we will study the regulation of lung arginase I expression.
In Aim II, we will study the functional consequences of arginase-mediated downstream pathways on the outcome of experimental asthma.
In Aim III, we propose a series of translational studies aimed at examining the expression of arginase I in human lung tissue. The proposed experiments will dissect critical properties of arginine metabolism via arginase in allergic lung responses in mice and man. The pathway examined has not been previously studied in relationship to asthma, providing innovation to the proposal. It is anticipated that the proposed studies will shed new light on the pathogenesis of experimental asthma and provide a rationale for possible novel therapeutic and diagnostic interventions in asthma.
