| Acute lung injury refers to a non-specific response of the lung to a plethora of precipitating events and factors. Despite intensive research for decades, many of the fundamental mechanisms in the initiation and progression of acute lung injury are poorly understood. Abnormal mechanical forces due to mechanical ventilation and pathological changes in pulmonary function and structure have been hypothesized to influence acute lung injury. The main objective of the research described in this dissertation was to investigate the responses of pulmonary epithelial cells to mechanical stimulation in vitro in relationship to acute lung injury. This dissertation presents the first in vitro model of airway reopening that incorporates living pulmonary epithelial cells. In the model, the progression of a semi-infinite bubble in a narrow channel lined with pulmonary epithelial cells inflicts significant injury to epithelial cell population. The presence of pulmonary surfactant (Infasurf, ONY, Inc., Buffalo, NY) in sufficient quantity (1 mg/mL) effectively abates this injury, verifying its protective role in airway collapse and reopening. The complex hydrodynamics of the bubble progression in this model influence the degree of injury. A computational analysis demonstrated that the most mechanically-damaging element of the stress cycle associated with bubble progression was the steep pressure gradient near the perimeter of the bubble cap. The cellular injury that was observable immediately following “reopening” was found to be lethal for individual cells, but survivable for the population as whole. The tissues of the lung are exposed to a variety of physical forces. Motivated by the distension of the airways and alveoli during normal breathing and mechanical ventilation, cellular stretch has been assumed to be the predominant physical force that influences pulmonary epithelial function. This dissertation explores influences of mechanical stimuli other than substrate stretch on the biological function of pulmonary epithelial cells, namely the production of pulmonary surfactant, cytokines, and nitric oxide. Taken as a group, the findings suggest that physical stresses, such as transmural pressure and fluid shear stress, may impact acute lung injury by altering the function of the pulmonary epithelium. |
