Understanding risk in asymptomatic carotid stenosis

Abstract

Drug delivery by inhalation is used to maximize the therapeutic effect in the lung while minimizing systemic exposure. However, to achieve the best possible treatment we need to understand where a targets is expressed in the lung and assure retention of drugs at the relevant location. Currently, our models regard the lung as a uniform unit and do not distinguish between different tissue structures and hence we need to increase our understanding of what structures are targeted by inhalation and if all benefit from inhaled delivery equally. In the present study, we used RNAscope in-situ hybridization to systemically examine how the administration route influences which part of the lung respond to fluticasone propionate (FP). Together with an automated image analysis, developed specifically to adress the different sub-compartments of the lung, we were able to measure mRNA expression of Zbtb16 in epithelium, sub-epithelium, alveolar bed and blood vessels. Spleenic Zbtb16 expression, measured by qPCR, was used to assess systemic responses. The results show that inhaled and i.v. administration give different distinct spatial responses. Inhalation of FP provides superior targeting of the airway epithelium and sub-epithelium regions but not alveolar space or vasculature compared to systemic administration. Finally, the analysis shows that exclusive targeting of lung epithelium by inhalation can be achieved with very low doses of FP.