Impact of Fluid versus Solid Stresses on Air-Blood Integrity

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DESCRIPTION (provided by applicant): Mechanical ventilation is a crucial therapy for patients with acute respiratory distress syndrome (ARDS); however, improper ventilation has been shown to promote further cellular-level injury, leading to an exacerbation of ARDS-like symptoms, termed ventilator-induced lung injury (VILI). Cellular-level damage found in VILI is hypothesized to result from a combination of cyclic and fluidic mechanical stresses generated as atelectactic alveoli collapse and re-open. Solid mechanical stress (volutrauma) occurs as epithelial cells are exposed to the cyclic stretching and relaxation of the alveolus during over-expansion and contraction. The role of fluid mechanical stress in the breakdown of air-blood barrier integrity has been suggested based upon observations during liquid ventilation treatment. In liquid ventilation the alveolus is completely filled with perfluorocarbons, effectively eliminating the air-liquid interface responsible for most fluid mechanical stresses. These in vivo studies suggest that volutrauma alone is not sufficient to cause damage to the degree of air-blood barrier damage seen in VILI, but the lack of in vitro models capable of replicating fluid mechanical stress has limited research on fluid stress in ARDS-pathology. Recent advances in microfluidic fabrication have allowed in vitro study on the role fluid mechanical stress in the development of airway injuries. Similarly, as fluid is redistributed within an edematous alveolus, we hypothesize that high fluid mechanical stresses will be generated at the resulting air-liquid interface. This air-liquid interface moves in a cyclic fashion as alveolar pressure gradients are generated during mechanical ventilation. The small size of alveolar sacs and ducts enables shearing conditions at the air-liquid interface to cause cellular damage and death. The impact of these fluid mechanical stresses independently and in combination with cyclic stretching (solid mechanical) has been suggested by in vivo studies but has not been confirmed. What is required is a systematic study of the effect on alveolar epithelial cells of fluid mechanical stresses individually and in combination with solid mechanical stresses (stretch). Current systems lack the ability to simultaneously study the effects of both stretch and shear. This project will fill this gap by creating a micro- tissue engineered alveoli with a cellular air-blood interface where physiological fluid mechanical events can be recreated over the alveolar epithelial cells in a highly controlled in vitro format. As an initial application of this micro-engineered alveoli, I will study the effects of fluid flow and cyclic stretch independently and in combination. This proposal will specifically test the hypothesis that fluid mechanical stress damages the integrity of the air-blood barrier through a mechanism independent of mechanical cell stretching.