We plan to characterize the responses of alveolar pneumocytes to deforming stress. Motivation for this work stems from our interest in ventilator-induced lung injury (VIM). The long-term goal of our effort is the pharmaco-protection of the lung from deformation injury. The proposed experiments build on key observations we have made during the past funding period, namely: a) stretching of alveolar epithelial cells in culture triggers a vigorous lipid trafficking response; b) the trafficking response is vesicular in nature, varies with strain rate and amplitude, is temperature and energy dependent and can be pharmacologically manipulated; c) inhibition of deformation induced lipid trafficking (DILT) increases the risk of plasma membrane (PM) stress failure and lowers the likelihood of subsequent PM repair; d) cell wounding and resealing as distinct from cell necrosis can be readily demonstrated and quantified in whole living lungs. These observations suggest that DILT is integral to the maintenance of sublytic PM tensions. Experiments are organized along 3 specific aims: 1) to measure the effects of pH and pCO2 on the separate probabilities of mechanical ventilation associated PM wounding and repair in whole living rat lungs; 2) to characterize in primary rat alveolar pneumocytes the effects of deforming stress on PM integrity and the uptake, sorting and recycling of sphingolipids; 3) to measure the effects of intra- and extracellular acid-base balance on DILT, on the susceptibility to stretch-related PM wounding and on the probability of subsequent wound repair. The proposed studies will expand our knowledge of intended and unintended consequences of permissive hypercapnia; will establish mechanistic relationships between alveolar epithelial phenotype, deformation induced sphingolipid trafficking and the susceptibility of alveolar pneumocytes to PM stress failure; and will suggest molecular targets for DILT and cell repair directed therapeutic interventions.
| Hubmayr, Rolf D; Oeckler, Richard A (2014) The hidden consequences of ventilator management decisions. Respir Care 59:1302-5 |
| Hubmayr, Rolf D; Malhotra, Atul (2014) Still looking for best PEEP. Anesthesiology 121:445-6 |
| Suki, Béla; Hubmayr, Rolf (2014) Epithelial and endothelial damage induced by mechanical ventilation modes. Curr Opin Crit Care 20:17-24 |
| Hubmayr, Rolf D (2014) Regional lung strain and the metabolic signature of injury*. Crit Care Med 42:1745-6 |
| Hubmayr, Rolf D (2013) Volutrauma and regional ventilation revisited. Am J Respir Crit Care Med 188:1388-9 |
| Hussein, Omar; Walters, Bruce; Stroetz, Randolph et al. (2013) Biophysical determinants of alveolar epithelial plasma membrane wounding associated with mechanical ventilation. Am J Physiol Lung Cell Mol Physiol 305:L478-84 |
| Hubmayr, Rolf D (2012) Does oxygen tune cellular mechanotransduction? Am J Physiol Lung Cell Mol Physiol 302:L1233-4 |
| Plataki, Maria; Hubmayr, Rolf D (2011) Should mechanical ventilation be guided by esophageal pressure measurements? Curr Opin Crit Care 17:275-80 |
| Godin, Lindsay M; Vergen, Jorge; Prakash, Y S et al. (2011) Spatiotemporal dynamics of actin remodeling and endomembrane trafficking in alveolar epithelial type I cell wound healing. Am J Physiol Lung Cell Mol Physiol 300:L615-23 |
| Belete, Hewan A; Hubmayr, Rolf D; Wang, Shaohua et al. (2011) The role of purinergic signaling on deformation induced injury and repair responses of alveolar epithelial cells. PLoS One 6:e27469 |
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