Idiopathic pneumonia syndrome (IPS) defines a clinical entity characterized by a subacute non-infectious lung injury following autologous bone marrow transplantation (ABMT) related treatment protocols. Successful therapeutic strategies for treating primary breast cancer utilizing induction chemotherapy followed by consolidation chemotherapy and ABMT have been severely limited by the subsequent development of IPS. In this project, they hypothesize that IPS is caused by a relative increase in extracellular oxidant species and a relative decrease of extracellular antioxidant enzymes and nonenzymatic compounds. To test the hypothesis that this major nonenzymatic extracellular antioxidant is depleted in these patients, they will characterize broncho-alveolar lavage (BAL) lung levels of reduced glutathione (GSH). The major extracellular antioxidant enzyme in the lung is extracellular superoxide dismutase (EC-SOD). Its gene expression is markedly down regulated by cytokines such as TNF-alpha and TGF-beta. They will test their hypothesis that the generation of these cytokines in vivo results in decreased EC-SOD expression. This will be accomplished by directly measuring BAL levels of specific cytokines throughout the treatment program and studying these cytokine effects on EC-SOD gene expression using pulmonary cells grown in cell culture, BAL alveolar macrophages, and by in situ hybridization in mouse models of IPS. To further test the critical role of EC-SOD in these processes, they will use both transgenic mice which overexpress EC-SOD in the lung and EC-SOD knock-out mice to specifically probe the role of EC-SOD in the protection from and development of IPS in their mouse model. Previously identified biomarkers which predict pulmonary toxicity (MCP-1, prothrombin fragment Fl.2, D-Dimer, and TGF- beta) will be evaluated for their sensitivity and specificity for predicting the development of IPS. This project has been designed to critically evaluate the role of extracellular oxidants and antioxidants in the development of IPS following high-dose chemotherapy with autologous bone marrow support. Analysis of data generated from this project can be used to identify patients at highest risk for developing pulmonary toxicity and to formulate novel pharmacologic strategies to protect against the development of IPS, thus, potentially allowing for more effective treatment programs for breast cancer patients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL055166-03
Application #
2519531
Study Section
Special Emphasis Panel (ZHL1-CSR-M (M2))
Project Start
1995-09-15
Project End
1999-08-31
Budget Start
1997-09-01
Budget End
1998-08-31
Support Year
3
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705
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
Park, Jong Woong; Qi, Wen-Ning; Cai, Yongting et al. (2005) Skeletal muscle reperfusion injury is enhanced in extracellular superoxide dismutase knockout mouse. Am J Physiol Heart Circ Physiol 289:H181-7
Zelko, Igor N; Folz, Rodney J (2005) Extracellular superoxide dismutase functions as a major repressor of hypoxia-induced erythropoietin gene expression. Endocrinology 146:332-40
Bhagat, Rajesh; Rizzieri, David A; Vredenburgh, James J et al. (2004) Pulmonary sarcoidosis following stem cell transplantation: is it more than a chance occurrence? Chest 126:642-4
Zelko, Igor N; Folz, Rodney J (2004) Sp1 and Sp3 transcription factors mediate trichostatin A-induced and basal expression of extracellular superoxide dismutase. Free Radic Biol Med 37:1256-71
Nepluev, Igor; Folz, Rodney J (2003) PACS RT-PCR: a method for the generation and measurement of any poly(A)-containing mRNA not affected by contaminating genomic DNA. Methods Mol Biol 221:161-8
Zelko, Igor N; Folz, Rodney J (2003) Myeloid zinc finger (MZF)-like, Kruppel-like and Ets families of transcription factors determine the cell-specific expression of mouse extracellular superoxide dismutase. Biochem J 369:375-86
Garantziotis, Stavros; Bhalla, Karan S; Long, Gwynn D et al. (2002) Fatal re-expansion pulmonary edema associated with increased lung IL-8 levels following high-dose chemotherapy and autologous stem cell transplant. Respiration 69:351-4
Bhalla, Karan S; Folz, Rodney J (2002) Idiopathic pneumonia syndrome after syngeneic bone marrow transplant in mice. Am J Respir Crit Care Med 166:1579-89
Zelko, Igor N; Mariani, Thomas J; Folz, Rodney J (2002) Superoxide dismutase multigene family: a comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3) gene structures, evolution, and expression. Free Radic Biol Med 33:337-49

Showing the most recent 10 out of 23 publications