Project 461568

According to the 2018 Global Asthma Report, 339 million people have asthma worldwide, causing 1000 deaths daily. Asthma is an inflammatory disease resulting in airway narrowing due to excessive airway smooth muscle (ASM) contraction. Several factors trigger the production of inflammatory mediators that enhance ASM contraction. Asthmatic ASM has always been considered hypercontractile but demonstrating its specific dysfunction has been challenging. We previously showed in both horse and human asthma that exposure of ASM to inflammatory mediators for 24 hours leads to increased ASM velocity of shortening whereas in chronic asthma, we reported increased force of contraction. To understand the development of the changes in ASM mechanics induced by exposure to inflammation, we devised with an industrial partner, an automated multi-muscle strip mechanics measurement apparatus housed in an incubator. In the current application, we propose to exploit this cutting edge instrument to determine the mechanical impact of acute exposure to various inflammatory mediators that act directly on ASM. We will also test the best combination of inhibitors to block these mechanical changes. Approach: We will study the changes in ASM mechanics in asthmatic and normal control lungs from human donors, post-mortem, when exposed acutely to inflammatory cells purified from the spleens of the same donors. We will use our cutting edge muscle mechanics device to measure contractility changes several times a day, for up to 4 days. We will also study ASM protein expression at time points of the observed mechanical changes. Significance: Because ASM hypercontractility is the ultimate problem in asthma, and because of the numerous inflammatory mediators present in asthma, understanding the relative effects of inflammatory mediators that act directly on the ASM should lead to the best therapies.