The broad, long-term objective of the proposed research is to lessen the effects of pulmonary barotrauma in ventilated patients. These include, in addition to pneumothorax, progressive impairment of pulmonary mechanics, alveolar cell dysfunction, and changes in lung fluid balance and blood-gas barrier permeability. The overall hypothesis is that mechanical ventilation which results in large lung volumes (in contrast to pressure) produced either dynamically or statically, can result in large deformations of the alveolar epithelial lining with subsequent alveolar cell injury.
In specific aim one lung volume of rats will be related to alveolar epithelial surface area by morphometric techniques. From these measurements the range of strains applied to the alveolar epithelial surface will be calculated.
In Aim 2, cultured alveolar epithelial cells (both type II cells and cells maintained in culture exhibiting characteristics of type I cells) will be subjected to patterns of biaxial deformation spanning and exceeding physiologic ranges. Changes in cell viability will be measured by LDH assays, cell metabolic activity by ATP assays and, for the so-called type I cells, changes in monolayer permeability by changes in transepithelial resistance and short circuit current.
In specific aim three rats will be ventilated with frequencies and at volumes which should subject the lung and particularly the epithelium to small, medium, and large deformations. Alterations in wet-dry ratio will be considered an index of extravascular water. Alveolar fluid volume measured by the dilution of dextran in BAL fluid and alveolar concentration of fluorescein labeled albumin in blood will be used as indices of alveolar edema and permeability to large molecules respectively.
| Song, Min Jae; Davidovich, Nurit; Lawrence, Gladys G et al. (2016) Superoxide mediates tight junction complex dissociation in cyclically stretched lung slices. J Biomech 49:1330-1335 |
| Song, M J; Davis, C I; Lawrence, G G et al. (2016) Local influence of cell viability on stretch-induced permeability of alveolar epithelial cell monolayers. Cell Mol Bioeng 9:65-72 |
| Yehya, Nadir; Xin, Yi; Oquendo, Yousi et al. (2015) Cecal ligation and puncture accelerates development of ventilator-induced lung injury. Am J Physiol Lung Cell Mol Physiol 308:L443-51 |
| Davidovich, N; Huang, J; Margulies, S S (2013) Reproducible uniform equibiaxial stretch of precision-cut lung slices. Am J Physiol Lung Cell Mol Physiol 304:L210-20 |
| Dipaolo, Brian C; Davidovich, Nurit; Kazanietz, Marcelo G et al. (2013) Rac1 pathway mediates stretch response in pulmonary alveolar epithelial cells. Am J Physiol Lung Cell Mol Physiol 305:L141-53 |
| Davidovich, Nurit; DiPaolo, Brian C; Lawrence, Gladys G et al. (2013) Cyclic stretch-induced oxidative stress increases pulmonary alveolar epithelial permeability. Am J Respir Cell Mol Biol 49:156-64 |
| Davidovich, N; Chhour, P; Margulies, S S (2013) Uses of Remnant Human Lung Tissue for Mechanical Stretch Studies. Cell Mol Bioeng 6:175-182 |
| Yehya, Nadir; Yerrapureddy, Adi; Tobias, John et al. (2012) MicroRNA modulate alveolar epithelial response to cyclic stretch. BMC Genomics 13:154 |
| Cohen, Taylor S; DiPaolo, Brian C; Lawrence, Gladys Gray et al. (2012) Sepsis enhances epithelial permeability with stretch in an actin dependent manner. PLoS One 7:e38748 |
| DiPaolo, Brian C; Margulies, Susan S (2012) Rho kinase signaling pathways during stretch in primary alveolar epithelia. Am J Physiol Lung Cell Mol Physiol 302:L992-1002 |
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