Abstract

Previous studies have provided evidence that lung tissue subjected to period of decreased perfusion undergoes increased damage during reperfusion (ischemia-reperfusion injury). The hypothesis is that injury results from an increased rate of generation of oxidizaing free radicals associated with reoxygenation of tissue. This study will utilize the isolated perfused rat lung to develop a model for ischemia-reperfusion injury. Injury will be assessed by measurments of lipid peroxidation, protein oxidation, energy and redox state, and cellular ionic composition. Sp.
Aim 1 is the development of the model which emphasis on the roles of hypoxia, pH, and substrate in the genesis of injury. The lung is especially amenable to manipulation of these variables since the perfusate and alveolar gas composition can be varied independently. We will also evaluate the role of alveolar O2 tension during the reperfusion period. Our preliminary studies with this model have indicated lipid peroxidation during ischemia/reperfusion. Sp.
Aim 2 will evaluate the role of oxidants in generation of the injury. We will study Fe chelators, an inhibitor of xanthine oxidase, and vit. E and selenium (glutathione peroxidase) deficiencies. Sp.
Aim 3 will separately evaluate epithelial and endothelial components for ischemia-reperfusion injury. Ion composition (Na, K, Cl, Ca, Mg) in cytoplasm and mitochondria will be evaluated with electron probe microanalysis. Function of epithelium and endothelium will be evaluated through B-agonsit stimulated surfactant secretion and serotonin clearance, respectively. Sp.
Aim 4 will attempt to modify ischemia-reperfusion injury through delivery of liposome encapsulated antioxidant enzymes (SOD, catalase) by endotracheal or perfusate administration. These studies will establish the basic parameters for production of ischemia-reperfusion injury and will provide insights into possible prevention of this form of injury in lungs subjected to ischemia as, for example, after a pulmonary embolism.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL041939-05
Application #
3359800
Study Section
Special Emphasis Panel (SRC (SB))
Project Start
1988-09-30
Project End
1994-04-21
Budget Start
1992-08-01
Budget End
1994-04-21
Support Year
5
Fiscal Year
1992
Total Cost
Indirect Cost

  Institution

Name
University of Pennsylvania
Department
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104

  Publications

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
Chatterjee, Shampa; Chapman, Kenneth E; Fisher, Aron B (2008) Lung ischemia: a model for endothelial mechanotransduction. Cell Biochem Biophys 52:125-38
Fisher, A B (2004) Reactive oxygen species and cell signaling with lung ischemia. Undersea Hyperb Med 31:97-103
Fisher, Aron B; Al-Mehdi, Abu B; Manevich, Yefim (2002) Shear stress and endothelial cell activation. Crit Care Med 30:S192-7
Al-Mehdi, A B; Zhao, G; Tozawa, K et al. (2000) Depolarization-associated iron release with abrupt reduction in pulmonary endothelial shear stress in situ. Antioxid Redox Signal 2:335-45
Fisher, A B; Al-Mehdi, A B; Muzykantov, V (1999) Activation of endothelial NADPH oxidase as the source of a reactive oxygen species in lung ischemia. Chest 116:25S-26S
Tozawa, K; al-Mehdi, A B; Muzykantov, V et al. (1999) In situ imaging of intracellular calcium with ischemia in lung subpleural microvascular endothelial cells. Antioxid Redox Signal 1:145-54
Wei, Z; Costa, K; Al-Mehdi, A B et al. (1999) Simulated ischemia in flow-adapted endothelial cells leads to generation of reactive oxygen species and cell signaling. Circ Res 85:682-9
Atochina, E N; Balyasnikova, I V; Danilov, S M et al. (1998) Immunotargeting of catalase to ACE or ICAM-1 protects perfused rat lungs against oxidative stress. Am J Physiol 275:L806-17
Al-Mehdi, A B; Zhao, G; Fisher, A B (1998) ATP-independent membrane depolarization with ischemia in the oxygen-ventilated isolated rat lung. Am J Respir Cell Mol Biol 18:653-61

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