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Special Feature: Oral Presentations

MECHANOPROTECTIVE VS CYTOPROTECTIVE HYPOTHESES: PULMONARY APPLICATIONS OF PERFLUOROCHEMICALS

Wolfson, Marla R.

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This presentation provided a theoretical paradigm supported by in vitro and in vivo experimental data to address the dual hypotheses of mechanoprotective and cytoprotective mechanisms for perfluorochemical protection of the lung. Physicochemical properties of perfluorochemical liquids were reviewed. In vitro and in vivo experimental data were presented to demonstrate the effect of vapor pressure and lipid solubility of the PFC, and physiological properties of surface area, lipid content, blood flow, and blood components on uptake of PFC. Evidence was presented to demonstrate mechanoprotective and cytoprotective effects of PFC as a function of the physicochemical properties and cell-specific protection. Examples of information presented demonstrated cell-specific difference in perfluorochemical (PFC) entrance and functional impact. The ability of the PFC PP2/PP9: 25%/75% to accumulate in alveolar epithelium was determined both in vitro and in vivo. When confluent monolayer of A549 cells were incubated with PP2/PP9 for 2 h, then fixed and examined by electron microscopy, PFC was evident in vacuoles and lamellar bodies. This demonstrates that PFCs can enter a non-phagocytic cell. For in vivo studies, a rAd. LacZ was suspended in either PFC or saline and was instilled into mouse lungs and activity assessed at 72h. PP2/PP9 (25%/75%) increased viral transduction activity throughout the entire lung. ß-gal expression was observed in the alveolar epithelium, particularly type II cells, whereas little to none is seen in the alveoli of the saline controls. These data strongly suggest that PFC assisted the rAd into alveolar type II cells allowing for increased expression. We have also assessed the effect of the PFC FC-75 on lymphocytes and monocytes. When PFC is used as a ventilation strategy, macrophages internalize the compounds resulting in “foamy” morphology. This has two implications. First, that the accumulation of PFC in theses cells would moderate their ability to secrete cytokines. Indeed, PFC does: (1) accumulate and leaves the cell over time as the PFC volalitizes out of the lung, and (2) moderates basal and induced secretion of cytokines. Second, a lower dose of PFC should have a greater impact on macrophages compared to epithelial cells. Finally, using the Calu-3 cell line and air-liquid interface system described in C2b, the effect of PFC (perflubron) on the hyperoxic TER response was evaluated (ref)*. Once cells developed TER ≥ 300 ohm.cm2, PFC was added to the apical surface to completely submerge the monolayer; PFC was replenished daily. Cells grown in an air-liquid interface served as control. TER of the PFC exposed cells was significantly greater than controls demonstrating PFC protective effects against hyperoxia-induced cell injury. Taken together these data demonstrate that as a delivery vehicle, PFC supports homogenous distribution, and suggest that it facilitates intracellular deposition and moderates cellular responses to hyperoxia.

Copyright © 2006 by the American Society for Artificial Internal Organs