Grant: Project Grant

Two million Canadians suffer from uncontrolled asthma (Asthma Society of Canada www.asthma.ca, 2016). Asthma is an inflammatory disease resulting in airway narrowing due to excessive smooth muscle contraction. Several factors trigger the production of inflammatory mediators that presumably in turn enhance the contraction of the airway smooth muscle. The current treatments for asthma are either very specific but cannot cope with all the possible inflammatory mediators or broad-spectrum like the corticosteroids but have undesired side effects. We propose to examine the effect of inflammation on airway smooth muscle in order to develop new and more specific treatment strategies targeting the smooth muscle directly. Goal: The goal of this proposal is to determine what alterations in airway muscle contractility are produced by exposure to the inflammatory mediators found in human asthma and identify the underlying mechanisms that lead to these alterations in order to develop more specific therapies. Approach: We will study the mechanisms of airway muscle hypercontractility in asthmatic lungs from human donors, post-mortem. We have developed a unique technique to study the muscle from human lung small airways so we will be able to address the contractility of the affected tissues directly. With these tissues, and the inflammatory cells purified from the donors' spleen, we will reproduce in vitro, the environment that the airway muscle bathes in. With state-of-the-art biophysical measurement equipment, we will measure the contractility changes, and the mechanisms behind those changes, of the airway smooth muscle when exposed to the inflammatory cells observed in the asthmatic airways. Significance: Considering the multiple inflammatory mediators present in asthma, this study will identify the specific dysfunctions of the final effector of the disease, the airway smooth muscle, thus yielding a more specific downstream therapeutic target.