Abstract

Successful application of lung transplantation is hampered by inadequate lung preservation techniques and the frequent development of lung allograft reperfusion injury. This injury is mediated by neutrophils. Inhibition of neutrophil adherence by modulating levels of nitric oxide and prostaglandin metabolites reduces ischemia reperfusion injury in the lung, improves lung graft function, decreases morbidity and mortality and reduces costs. Transfer of genetic material to lung grafts is feasible under circumstances consistent with clinical lung transplantation. The first specific aim of this proposal is to determine ideal circumstances for efficient gene transfer to lung grafts.
In Specific Aim II, neutrophil adherence and lung reperfusion injury will be reduced by modulation of nitric oxide and prostaglandin E2 and prostacyclin. This will be accomplished by augmentation of lung graft levels of genes encoding for inducible nitric oxide synthase and prostaglandin synthase. These studies will be conducted in a sequential series of in vitro rat and canine lung transplant models.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL041281-07A2
Application #
2693320
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1990-09-01
Project End
2001-06-30
Budget Start
1998-08-01
Budget End
1999-07-31
Support Year
7
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
Washington University
Department
Surgery
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130

  Publications

Huang, Howard J; Sugimoto, Seiichiro; Lai, Jiaming et al. (2011) Maintenance of IKK? activity is necessary to protect lung grafts from acute injury. Transplantation 91:624-31
Ray, M; Dharmarajan, S; Freudenberg, J et al. (2007) Expression profiling of human donor lungs to understand primary graft dysfunction after lung transplantation. Am J Transplant 7:2396-405
Okazaki, M; Kreisel, F; Richardson, S B et al. (2007) Sphingosine 1-phosphate inhibits ischemia reperfusion injury following experimental lung transplantation. Am J Transplant 7:751-8
Ishiyama, Takaaki; Dharmarajan, Sekhar; Hayama, Makio et al. (2005) Inhibition of nuclear factor kappaB by IkappaB superrepressor gene transfer ameliorates ischemia-reperfusion injury after experimental lung transplantation. J Thorac Cardiovasc Surg 130:194-201
Dharmarajan, Sekhar; Hayama, Makio; Kozlowski, James et al. (2005) In vivo molecular imaging characterizes pulmonary gene expression during experimental lung transplantation. Am J Transplant 5:1216-25
Krupnick, Alexander Sasha; Gelman, Andrew E; Barchet, Winfried et al. (2005) Murine vascular endothelium activates and induces the generation of allogeneic CD4+25+Foxp3+ regulatory T cells. J Immunol 175:6265-70
Suda, Takashi; Daddi, Niccolo'; Tagawa, Tsutomu et al. (2005) Recipient intramuscular cotransfection of transforming growth factor beta1 and interleukin 10 ameliorates acute lung graft rejection. J Thorac Cardiovasc Surg 129:926-31
Kuo, Elbert; Bharat, Ankit; Dharmarajan, Sekhar et al. (2005) Animal models for bronchiolitis obliterans syndrome following human lung transplantation. Immunol Res 33:69-81
Tagawa, Tsutomu; Kozower, Benjamin D; Kanaan, Samer A et al. (2004) Gene transfer of tumor necrosis factor inhibitor improves the function of lung allografts. J Thorac Cardiovasc Surg 127:1558-63
Tagawa, Tsutomu; Dharmarajan, Sekhar; Hayama, Makio et al. (2004) Endobronchial gene transfer of soluble type I interleukin-1 receptor ameliorates lung graft ischemia-reperfusion injury. Ann Thorac Surg 78:1932-9; discussion 1939

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