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 X- ray 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 #
5R01HL094366-04
Application #
8235024
Study Section
Special Emphasis Panel (ZRG1-RES-B (02))
Program Officer
Harabin, Andrea L
Project Start
2009-04-03
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2014-03-31
Support Year
4
Fiscal Year
2012
Total Cost
$518,966
Indirect Cost
$151,900
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
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
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
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
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
Ghosh, Manik C; Gorantla, Vijay; Makena, Patrudu S et al. (2013) Insulin-like growth factor-I stimulates differentiation of ATII cells to ATI-like cells through activation of Wnt5a. Am J Physiol Lung Cell Mol Physiol 305:L222-8
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
Mishra, Jayshree; Waters, Christopher M; Kumar, Narendra (2012) Molecular mechanism of interleukin-2-induced mucosal homeostasis. Am J Physiol Cell Physiol 302:C735-47
Makena, Patrudu S; Gorantla, Vijay K; Ghosh, Manik C et al. (2012) Deletion of apoptosis signal-regulating kinase-1 prevents ventilator-induced lung injury in mice. Am J Respir Cell Mol Biol 46:461-9
Ghosh, Manik C; Makena, Patrudu S; Gorantla, Vijay et al. (2012) CXCR4 regulates migration of lung alveolar epithelial cells through activation of Rac1 and matrix metalloproteinase-2. Am J Physiol Lung Cell Mol Physiol 302:L846-56
Schwingshackl, Andreas; Teng, Bin; Ghosh, Manik et al. (2012) Regulation and function of the two-pore-domain (K2P) potassium channel Trek-1 in alveolar epithelial cells. Am J Physiol Lung Cell Mol Physiol 302:L93-L102

Showing the most recent 10 out of 18 publications