Regulatory effects of extracellular substrate stiffness with mechanical oscillatory stretch on contractile phenotype and function of airway smooth muscle cells

The human airway is composed of many cell types including smooth muscle cells. In asthma, the airway is both thickened and overactive and narrows too much causing potentially dangerous airway obstruction. The reason for this airway narrowing in asthma is unknown, but changes in the muscle cells may be a key contributor. My laboratory has previously done experiments that examine how airway smooth muscle cells react to different substrate stiffnesses. These initial experiments suggest that the increased stiffness of thickened airways in asthma causes the muscle cells to be more active. However, the stretching of the muscle cells that normally happens during breathing may alter how the cells respond to changes in stiffness. In this project I will study how the thickening of the airway in asthma affects airway smooth muscle cells when breathing is included. To study this I will grow these cells on a flexible membrane that has variable stiffnesses to simulate normal and thickened airways. I can then simulate breathing by cyclically stretching the membrane and examining the activity of the muscle cells. I hypothesise that when breathing is simulated, the activity of airway smooth muscle cells will become more variable because the regular stretch will obstruct the way that the cells sense stiffness. By replicating these changes in stiffness and stretch that occur in asthma, we can study how the airway smooth muscle cells change both their function and signalling. A more thorough understanding of how changes in the airway occur in asthma will provide better diagnosis and treatment options.