Acute lung injury and its more severe form, acute respiratory distress syndrome (ARDS), are devastating illnesses with high rates of incidence and high mortality rates. Patients with acute lung injury are typically provided supplemental oxygen using positive pressure mechanical ventilation, but this can lead to additional injury, termed ventilator induced lung injury (VILI). The long term objective of this proposal is to improve understanding of the mechanisms by which overdistention (or stretch) of pulmonary epithelial cells contributes to ventilator-induced lung injury. The central hypothesis is that overdistention contributes both to the initiation of epithelial injury through loss of cell adhesion and to inhibition of repair mechanisms through decreased cell migration. Mechanisms of the initiation of VILI will be investigated using rats exposed to acid injury or surfactant depletion and direct visualization of airspace mechanics by microfocal Xray imaging. A combination of in vitro, in vivo, and ex vivo approaches will be used to investigate the hypothesis that mechanical stretch causes loss of cell adhesion and inhibition of repair mechanisms through focal adhesion kinase (FAK) signaling. These approaches include primary cultures of rat alveolar type II (AT2) epithelial cells isolated from rats following mechanical ventilation, exposure of cells to mechanical stretch in vitro, and confocal microscopy of isolated rat lungs. Finally, atomic force microscopy will be used to test the hypothesis that localized changes in mechanical stiffness regulate the repair mechanisms of AT2 cells in culture. The proposed studies will investigate the mechanisms that contribute to lung injury during mechanical ventilation and provide new insights into mechanotransduction, the process of converting mechanical signals to biological signals.

Public Health Relevance

Acute lung injury is a devastating illness that results in significant loss of life and substantial economic impact due to extended stays in the intensive care unit. The proposed studies will investigate the mechanisms that contribute to lung injury during mechanical ventilation and will identify potential targets for therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL094366-03
Application #
8044736
Study Section
Special Emphasis Panel (ZRG1-RES-B (02))
Program Officer
Harabin, Andrea L
Project Start
2009-04-03
Project End
2013-03-31
Budget Start
2011-04-01
Budget End
2012-03-31
Support Year
3
Fiscal Year
2011
Total Cost
$519,524
Indirect Cost
Name
University of Tennessee Health Science Center
Department
Physiology
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
Michael, Christie F; Waters, Christopher M; LeMessurier, Kim S et al. (2017) Airway Epithelial Repair by a Prebiotic Mannan Derived from Saccharomyces cerevisiae. J Immunol Res 2017:8903982
Andrews, Kelly; Ghosh, Manik C; Schwingshackl, Andreas et al. (2016) Chronic hypersensitivity pneumonitis caused by Saccharopolyspora rectivirgula is not associated with a switch to a Th2 response. Am J Physiol Lung Cell Mol Physiol 310:L393-402
Roan, Esra; Wilhelm, Kristina R; Waters, Christopher M (2015) Kymographic Imaging of the Elastic Modulus of Epithelial Cells during the Onset of Migration. Biophys J 109:2051-7
RĂ¡palo, Gabriel; Herwig, Josh D; Hewitt, Robert et al. (2015) Live Cell Imaging during Mechanical Stretch. J Vis Exp :e52737
Samak, Geetha; Gangwar, Ruchika; Crosby, Lynn M et al. (2014) Cyclic stretch disrupts apical junctional complexes in Caco-2 cell monolayers by a JNK-2-, c-Src-, and MLCK-dependent mechanism. Am J Physiol Gastrointest Liver Physiol 306:G947-58
Schwingshackl, Andreas; Teng, Bin; Makena, Patrudu et al. (2014) Deficiency of the two-pore-domain potassium channel TREK-1 promotes hyperoxia-induced lung injury. Crit Care Med 42:e692-701
Toutounchian, Jordan J; Steinle, Jena J; Makena, Patrudu S et al. (2014) Modulation of radiation injury response in retinal endothelial cells by quinic acid derivative KZ-41 involves p38 MAPK. PLoS One 9:e100210
Roan, Esra; Waters, Christopher M; Teng, Bin et al. (2014) The 2-pore domain potassium channel TREK-1 regulates stretch-induced detachment of alveolar epithelial cells. PLoS One 9:e89429
Wilhelm, Kristina R; Roan, Esra; Ghosh, Manik C et al. (2014) Hyperoxia increases the elastic modulus of alveolar epithelial cells through Rho kinase. FEBS J 281:957-69
Schwingshackl, Andreas; Teng, Bin; Ghosh, Manik et al. (2013) Regulation of interleukin-6 secretion by the two-pore-domain potassium channel Trek-1 in alveolar epithelial cells. Am J Physiol Lung Cell Mol Physiol 304:L276-86

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