Abstract

Ischemia-reperfusion (I/R) injury continues to cause significant morbidity and mortality in lung transplantation. Two important pathways which significantly contribute to ischemia-reperfusion injury are the inflammatory response and apoptosis. The transcription factor nuclear factor-kappa B (NF-KappaB) is critical for the maximal expression of many pro-inflammatory mediators. NF-KappaB is also a critical regulator of apoptosis, or programmed cell death. The activation of NF-KappaB is important in the pathogenesis of acute lung injury typical of I/R injury. The overexpression of the anti-inflammatory cytokine Interleukin-10 (IL-10) in experimental lung grafts is effective in significantly ameliorating I/R injury.
The aim of this proposal is to study the role of NF-KappaB activation in I/R injury following experimental lung transplantation and the mechanisms by which the overexpression of IL-10 alters these events. An orthotopic rodent left lung transplantation model has proved to be a productive and reliable in vivo model for this investigation. Adenoviral gene transfer of IL-10 by the endobronchial route is an efficient means of establishing IL-10 overexpression in experimental lung grafts.
The first aim of this project is to examine the role of NF-KappaB activation in I/R injury.
The second aim of this project is to investigate the mechanisms by which gene transfer of IL-10 ameliorates I/R injury.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL041281-12
Application #
6920767
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Reynolds, Herbert Y
Project Start
1990-09-01
Project End
2007-07-31
Budget Start
2005-08-01
Budget End
2006-07-31
Support Year
12
Fiscal Year
2005
Total Cost
$382,500
Indirect Cost

  Institution

Name
Washington University
Department
Surgery
Type
Schools of Medicine
DUNS #
068552207
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
Kuo, Elbert; Bharat, Ankit; Dharmarajan, Sekhar et al. (2005) Animal models for bronchiolitis obliterans syndrome following human lung transplantation. Immunol Res 33:69-81
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
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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