The long-term objectives of this Program Project application are to evaluate basic mechanisms and develop new treatments for acute lung injury. High concentrations of oxygen and septic lung injury are the primary models that will be evaluated. The proposed program consists of four projects and three core units. Project 1 will evaluate the efficacy of small molecular weight catalytic antioxidants in the treatment of both hyperoxic and LPS + sepsis-initiated lung injury. This project will also develop new antioxidant mimetics and explore their relationships with the antioxidant properties of heme oxygenase (HO). Project 2 will test the hypothesis that activation of extrinsic coagulation and disordered fibrin turnover are central elements in hyperoxic and septic lung injury. The efficacy of specific blockade of the initiating steps of extrinsic coagulation in reducing inflammation and acute lung injury will be tested using two new anticoagulant drugs that block tissue factor (TF) function and do not cause bleeding. Project 3 will evaluate the regulation and function of the extracellular superoxide dismutase (EC-SOD) in acute lung injury and determine the impact of cleavage of the C-terminal """"""""heparin binding"""""""" domain of this enzyme in determining its distribution and function. Project 4 will evaluate control of metabolic pathways and upregulation of lung cell glycolysis in modulating responses to acute injury. This project will test the hypothesis that adaptation to oxidant stress in the lung requires elevated expression of hexokinase (HK), a rate limiting step in glycolysis in the lung. The overall rationale for the Program Project is to use an interdisciplinary approach to define the cellular pathways and cellular adaptive responses involved in acute lung injury and to test new strategies for pharmacologic therapy that can be extended to the treatment of humans with ARDS and sepsis.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
National Jewish Health
United States
Zip Code
Jungsuwadee, Paiboon; Weaver, Michael R; Gally, Fabienne et al. (2012) The metalloporphyrin antioxidant, MnTE-2-PyP, inhibits Th2 cell immune responses in an asthma model. Int J Mol Sci 13:9785-97
Wang, Wei; Zolty, Einath; Falk, Sandor et al. (2008) Endotoxemia-related acute kidney injury in transgenic mice with endothelial overexpression of GTP cyclohydrolase-1. Am J Physiol Renal Physiol 294:F571-6
Petersen, Steen V; Valnickova, Zuzana; Oury, Tim D et al. (2007) The subunit composition of human extracellular superoxide dismutase (EC-SOD) regulates enzymatic activity. BMC Biochem 8:19
Due, Anne V; Petersen, Steen V; Valnickova, Zuzana et al. (2006) Extracellular superoxide dismutase exists as an octamer. FEBS Lett 580:1485-9
Sutherland, E Rand; Crapo, James D; Bowler, Russell P (2006) N-acetylcysteine and exacerbations of chronic obstructive pulmonary disease. COPD 3:195-202
Wang, Wei; Zolty, Einath; Falk, Sandor et al. (2006) Pentoxifylline protects against endotoxin-induced acute renal failure in mice. Am J Physiol Renal Physiol 291:F1090-5
Welty-Wolf, Karen E; Carraway, Martha S; Ortel, Thomas L et al. (2006) Blockade of tissue factor-factor X binding attenuates sepsis-induced respiratory and renal failure. Am J Physiol Lung Cell Mol Physiol 290:L21-31
Kachadourian, Remy; Day, Brian J (2006) Flavonoid-induced glutathione depletion: potential implications for cancer treatment. Free Radic Biol Med 41:65-76
Day, Brian J; Kariya, Chirag (2005) A novel class of cytochrome P450 reductase redox cyclers: cationic manganoporphyrins. Toxicol Sci 85:713-9
Park, Jong Woong; Qi, Wen-Ning; Liu, John Q et al. (2005) Inhibition of iNOS attenuates skeletal muscle reperfusion injury in extracellular superoxide dismutase knockout mice. Microsurgery 25:606-13

Showing the most recent 10 out of 145 publications