Asthmatic airway inflammation was alleviated by limiting the level of lung extracellular ATP

Abstract

Abstract Asthma is a chronic respiratory disease characterized by recurrently attacks of breathlessness and wheezing. ATP accumulation in bronchoalveolar lavage fluid (BALF) of asthmatic subjects indicates that extracellular ATP (eATP) and downstream responses are involved. The level of eATP is tightly controlled by its release and degradation in healthy tissues. Pannexin-1 is a channel contributing to ATP release, and CD39 is membrane bound apyrase contributing to ATP degradation. Cellular stress or inflammatory stimulation leads increased release of ATP and accompanied with the reduction of CD39. The recombinant adeno-associated virus (rAAV) vectors have been developed for efficient gene transfer with low toxic and difference tissue tropisms. Thus, we generated rAAV-CD39 and rAAV-s10Panx1 and examined their efficacy in OVA-mediated asthmatic mice model. The mice were sensitized intraperitoneally and challenged intratracheally with OVA and treated with the vectors three days before OVA challenge. At the end of procedure, some asthmatic and inflammatory cardinal features were examined. Elevated ATP level either in stimulated-culture supernatant and BALF of OVA-sensitized mice was determined. These two treatments downregulated the levels of ATP in BALF. Several asthmatic features, such as eosinophilia, Th2 cytokine production and AHR were decreased in the treatment groups. These treatments altered the T cell response by targeting the danger signal eATP and its metabolites. Taken together, these approaches are able to downregulate the asthma symptoms with the reduction of inflammatory responses in the lungs. Based on these results, eATP can be considered as a potential gene therapy target for asthma.