Mechanical ventilation provides the essential respiratory functions for patients who are unable to breathe naturally. Physicians must ventilate patients using inflation volumes high enough to supply the amount of oxygen necessary for survival. However, chronic pulmonary disease and acute lung injury can alter the mechanical properties of the lungs by reducing their stiffness in a heterogeneous fashion. In this situation, lung inflation even at relatively minor volumes can potentially result in very high local strains at the injured locations. This type of regional overdistension of the lung has been shown to increase the presence of fluid and macromolecules in the alveolar airspaces, preventing adequate gas transfer and often leading to further pulmonary dysfunction or even death.

The goal of this dissertational research was to evaluate the effects of physiologically relevant strain magnitudes and rates on the paracellular permeability of the alveolar epithelium. The hypothesis of this research was that strains associated with large inflation volumes can disrupt the structure and function of the paracellular transport barrier, leading to the injuries observed in patients receiving improper mechanical ventilation. The experimental model was a monolayer o f cultured primary alveolar epithelial cells, which was subjected to well-defined mechanical deformation at usercontrolled magnitudes and frequencies. Using novel techniques, we have demonstrated that application of cyclic equibiaxial strain at high magnitudes increases the paracellular permeability of the monolayer. In addition, this strain regimen perturbs the structure of the cellular components which control the permeability of the intercellular spaces. By modeling paracellular transport through the monolayer as diffusion through a heterogeneous population of circular pores, we have shown that application of high strain alters the distribution and size of these pores, allowing larger molecules to pass through the barrier more easily. Finally, we identified two of the intracellular pathways that participate in translating the stretch into an injurious cellular response. Blocking these pathways partially ameliorates but does not completely prevent the stretch-induced permeability increase. We hope that this research enables clinicians to develop safer and more effective lung ventilatory strategies.