Capturing the in situ behavior of airway smooth muscle in human bronchi using an ex vivo system that simulates breathing maneuvers

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The physiologic function of airway smooth muscle (ASM) within the lung is unknown. The lack of ascribed function of such an elaborated structure, which is present in every airway from the trachea to the respiratory bronchioles, perplexes a lot of investigators. We believe that this puzzlement arises from the methods and techniques that are traditionally used to study ASM contraction. An improved ex vivo setting that simulates more accurately the in vivo conditions in which ASM operates may be required to capture its in situ behavior and to decipher its role in the mechanics of breathing.The force deployed by ASM relies on a balance between a myriad of both spasmogen (e.g. acetylcholine) and bronchodilators (e.g. nitric oxide), which collectively determine the level of ASM activation. However, the force deployed by ASM is not only a function of its level of activation. The length at which ASM operates also significantly affects its capacity to generate force. To gain valuable insights into the physiologic function of ASM in vivo, it is thus imperative to study ASM at in situ length.We recently described how ASM can be studied at in situ length ex vivo (within an organ bath). We demonstrated that the in situ length of ASM is surprisingly far from the optimal length (i.e. the length at which maximal force occurs). However, these experiments were performed in static conditions. Although our findings represented significant advance to the understanding of ASM biology, our ex vivo setting can be improved to emulate in vivo conditions even more closely.The length at which ASM is called to operate in vivo is not static. The lung is a dynamic organ that requires substantial and continuous changes of volume to fulfill its ventilatory function. These changes of volume impose oscillatory changes in the length of ASM. Thus, in addition of being set at in situ length, ASM needs to be studied during changes of length that simulate the changes of lung volume that occur in vivo. The goal of this program is to determine the role of ASM in the mechanics of human bronchi within an ex vivo setting that recreates the dynamic environment in which ASM operates in vivo.This research program aims to:1-Determine the length-force relationship of ASM in human bronchi at different levels of ASM activation during dynamic and repetitive cycles of lengthening and shortening within a range of lengths that ASM can experience in vivo.2-Determine whether the rate of length change, within a range of rates that can occur in vivo, affects ASM length-force relationship. 3-Determine whether the choice of spasmogen used to activate ASM influences the response.4-Fit these experimental data into a computational model to estimate the influence of changing ASM activation and length on ASM shortening, airway narrowing and resistance to airflow in individual airways of different sizes. This project will determine the amount of force generated by ASM of human bronchi at different levels of activation during physiological range and rate of length changes. It will also predict how length and ASM activation combine to affect ASM shortening, airway narrowing and resistance to airflow. Ultimately, it will determine how all these factors interact to affect lung function. We believe that a better characterization of the length-force relationship of ASM in a dynamic system that simulates the perpetual changes of lung volume that occur in vivo is a prerequisite to understand the physiologic function of ASM. This program will provide highly qualified personnel (HQP) with cutting edge expertise in respiratory physiology, biomechanics, tissue biology, pharmacology and computational modeling analyses.