Airway collapse and reopening due to mechanical ventilation exerts mechanical stress on airway walls and injures surfactant-compromised lungs. The reopening of a collapsed airway was modeled experimentally and computationally by the progression of a semi-infinite bubble in a narrow fluid-occluded channel. The extent of injury caused by bubble progression to pulmonary epithelial cells lining the channel was evaluated. Counterintuitively, cell damage increased with decreasing opening velocity. The presence of pulmonary surfactant, Infasurf, completely abated the injury. These results support the hypotheses that mechanical stresses associated with airway reopening injure pulmonary epithelial cells and that pulmonary surfactant protects the epithelium from this injury. Computational simulations identified the magnitudes of components of the stress cycle associated with airway reopening (shear stress, pressure, shear stress gradient, or pressure gradient) that may be injurious to the epithelial cells. By comparing these magnitudes to the observed damage, we conclude that the steep pressure gradient near the bubble front was the most likely cause of the observed cellular damage.

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Proactive, "next generation" dental/orthopedic biomaterials must be designed rationally to elicit specific, timely, and desirable responses from surrounding cells/tissues; for example, such biomaterials should support and enhance osteoblast adhesion (a crucial function for anchorage-dependent cells). In the past, integrin-binding peptides have been immobilized on substrates to partially control osteoblast adhesion; the present study focused on the design, synthesis, and bioactivity of the novel peptide sequence Lys-Arg-Ser-Arg that selectively enhances heparan sulfate-mediated osteoblast adhesion mechanisms. Osteoblast, but not endothelial cell or fibroblast, adhesion was enhanced significantly (p < 0.05) on substrates modified with Lys-Arg-Ser-Arg peptides, indicating that these peptides may be osteoblast- or bone cell specific. Blocking osteoblast cell-membrane receptors with various concentrations of soluble Arg-Gly-Asp-Ser peptides did not inhibit subsequent cell adhesion on substrates modified with Lys-Arg-Ser-Arg peptides, providing evidence that osteoblasts interact with Arg-Gly-Asp-Ser and with Lys-Arg-Ser-Arg peptides via distinct (i.e., integrin- and proteoglycan-mediated) mechanisms, each uniquely necessary for osteoblast adhesion. The present study constitutes an example of rational design/selection of bioactive peptides, confirms that osteoblast adhesion to substrates can be controlled selectively and significantly by immobilized peptides, and elucidates criteria and strategies for the design of proactive dental/orthopedic implant biomaterials.

The reduction of tidal volume during mechanical ventilation has been shown to reduce mortality of patients with acute respiratory distress syndrome, but epithelial cell injury can still result from mechanical stresses imposed by the opening of occluded airways. To study these stresses, a fluid-filled parallel-plate flow chamber lined with epithelial cells was used as an idealized model of an occluded airway. Airway reopening was modeled by the progression of a semi-infinite bubble of air through the length of the channel, which cleared the fluid. In our laboratory's prior study, the magnitude of the pressure gradient near the bubble tip was directly correlated to the epithelial cell layer damage (Bilek AM, Dee KC, and Gaver DP III. J Appl Physiol 94: 770-783, 2003). However, in that study, it was not possible to discriminate the stress magnitude from the stimulus duration because the bubble propagation velocity varied between experiments. In the present study, the stress magnitude is modified by varying the viscosity of the occlusion fluid while fixing the reopening velocity across experiments. This approach causes the stimulus duration to be inversely related to the magnitude of the pressure gradient. Nevertheless, cell damage remains directly correlated with the pressure gradient, not the duration of stress exposure. The present study thus provides additional evidence that the magnitude of the pressure gradient induces cellular damage in this model of airway reopening. We explore the mechanism for acute damage and also demonstrate that repeated reopening and closure is shown to damage the epithelial cell layer, even under conditions that would not lead to extensive damage from a single reopening event.