This project will evaluate mechanisms for generation of partially reduced oxygen species (ROS) by pulmonary endothelium during lung ischemia. The studies are currently supported by an R-01 grant which will be relinquished if the SCOR is funded. Our primary experimental model is the isolated, perfused rat lung that is continuously ventilated in order to maintain tissue oxygenation and ATP during global ischemia +/- reperfusion. Additional studies utilize cultured endothelial cell preparations. During our present period of grant support, we have demonstrated generation of ROS and oxidative injury to lung that occurs during the ischemic period and have provided evidence for a new mechanism of ROS production, i.e., ROS production in association with endothelial cell membrane depolarization. ROS generation also was demonstrated in cultured bovine pulmonary artery endothelial cells and in the perfused lung in the presence of membrane depolarizing solutions (high K+) and with anoxia/reoxygenation produced by ventilating lungs with N2 and then 02. Studies with metabolic inhibitors indicated that ROS production with lung ischemia and with anoxia/reoxygenation occurred through different pathways and indicated a role for NADPH oxidase in lung ischemic injury.
The specific aims of the present proposal are to: 1) evaluate endothelial generation of ROS through the use of fluorescence imaging in situ and to determine the temporal sequence between endothelial depolarization, changes in intracellular Ca++ and FE2+/3+ and ROS generation; 2) develop an artificial capillary system for the in vitro evaluation of the role of shear stress and shear stress adaptation on endothelial ROS generation with ischemia; and 3) evaluate the role of the NADPH oxidase pathway as the source of ROS and endothelium using inhibitors, a knock-out mouse model, and antisense technology. This project will provide new information concerning a mechanism for initiation of lung oxidative injury and will document the presence of NADPH oxidase in endothelium and a possible pathophysiologic role in lung ischemia injury. This mechanism is of potential importance in ARDS as a source of ROS generation in association with focal capillary obstruction.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Specialized Center (P50)
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University of Pennsylvania
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Ferguson, Jane F; Meyer, Nuala J; Qu, Liming et al. (2015) Integrative genomics identifies 7p11.2 as a novel locus for fever and clinical stress response in humans. Hum Mol Genet 24:1801-12
Reilly, John P; Meyer, Nuala J; Shashaty, Michael G S et al. (2014) ABO blood type A is associated with increased risk of ARDS in whites following both major trauma and severe sepsis. Chest 145:753-761
Chatterjee, Shampa; Nieman, Gary F; Christie, Jason D et al. (2014) Shear stress-related mechanosignaling with lung ischemia: lessons from basic research can inform lung transplantation. Am J Physiol Lung Cell Mol Physiol 307:L668-80
Reilly, John P; Bellamy, Scarlett; Shashaty, Michael G S et al. (2014) Heterogeneous phenotypes of acute respiratory distress syndrome after major trauma. Ann Am Thorac Soc 11:728-36
Shashaty, Michael G S; Kalkan, Esra; Bellamy, Scarlett L et al. (2014) Computed tomography-defined abdominal adiposity is associated with acute kidney injury in critically ill trauma patients*. Crit Care Med 42:1619-28
Meyer, Nuala J; Feng, Rui; Li, Mingyao et al. (2013) IL1RN coding variant is associated with lower risk of acute respiratory distress syndrome and increased plasma IL-1 receptor antagonist. Am J Respir Crit Care Med 187:950-9
Shashaty, Michael G S; Meyer, Nuala J; Localio, A Russell et al. (2012) African American race, obesity, and blood product transfusion are risk factors for acute kidney injury in critically ill trauma patients. J Crit Care 27:496-504
Christie, Jason D; Wurfel, Mark M; Feng, Rui et al. (2012) Genome wide association identifies PPFIA1 as a candidate gene for acute lung injury risk following major trauma. PLoS One 7:e28268
Holena, Daniel N; Netzer, Giora; Localio, Russell et al. (2012) The association of early transfusion with acute lung injury in patients with severe injury. J Trauma Acute Care Surg 73:825-31
Meyer, Nuala J; Daye, Zhongyin John; Rushefski, Melanie et al. (2012) SNP-set analysis replicates acute lung injury genetic risk factors. BMC Med Genet 13:52

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