While mechanical ventilation is a life-saving therapy in patients with respiratory complications, the application of large pressures and volumes can result in pathological changes in lung function. The overall hypothesis of this dissertation is that the alveolar epithelial lining of the lung, which is crucial to efficient gas exchange and edema clearance, is vulnerable to large deformations which occur when regional or global lung over-inflation occurs.

In order to characterize the range of alveolar epithelial deformations which occur over the vital capacity of the lung, rat lungs fixed by perfusion were examined morphometrically using electron microscopy, and the surface area of the alveolar epithelial basement membrane was determined. The resulting relationship between lung volume and epithelial surface area was used in subsequent studies to relate in vitro deformation-induced injury to in situ changes in lung volume.

To investigate the tolerance of alveolar epithelial cells to deformation, primary type II pneumocytes were isolated from rats, and seeded onto elastic membranes. In vitro deformation studies were carried out using a multi-well cell stretching device which subjects cells to quantifiable, equi-biaxial deformations. Cellular injury was quantified microscopically using a fluorescent cell viability assay. Vulnerability to deformation-induced injury decreased significantly between one and five days after seeding, decreased with increasing seeding density, increased with the number of deformation cycles, and increased non-linearly with deformation magnitude. Dramatic increases in deformationinduced injury occurred when deformations exceeded those associated with inflation to total lung capacity.

To relate these findings to the clinical situation, a static pressure-volume model of the lung was created. This model incorporates the isolated pressure-volume properties of the major load bearing components of the lung, and includes non-communicating and regional variations in distending pressure to represent the heterogeneity frequently found in patients with acute lung injury. The model demonstrates that regional volume can exceed total lung capacity even when overall lung pressure and volume are well below threshold levels previously associated with injury.

Taken together, these investigations demonstrate the mechanical fragility of the alveolar epithelial barrier, and the need to evaluate patient-specific measures of heterogeneity to prevent regional over-inflation and epithelial injury during mechanical ventilation.