Clinical studies in human lung transplantation have demonstrated that, despite short ischemic times and well-functioning grafts after implantation, up to 34% of graft cells undergo cell death, predominantly by apoptosis, or programmed cell death. Studies in experimental ischemia-reperfusion injury have shown that while the total amount of cell death remains near 30%, the mode of cell death is switched from apoptosis to necrosis. This switch is thought to be an important part of the pathogenesis of I/R injury, as necrotic cell death, as opposed to apoptosis, results in a significant inflammatory response. The transcription factor nuclear factor-kappa B (NF-kappaB) is a critical regulator of apoptosis. The activation of NF-kB 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 promoting a switch in cell death from apoptosis to necrosis in I/R injury following experimental lung transplantation and the mechanism by which overexpression of IL-10 alters these events. An orthotopic rodent left lung transplantation model has been developed and proved to be a productive and reliable in vivo model for this investigation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32HL074687-02
Application #
6793203
Study Section
Special Emphasis Panel (ZRG1-F10 (20))
Program Officer
Colombini-Hatch, Sandra
Project Start
2003-08-06
Project End
2005-06-24
Budget Start
2004-08-06
Budget End
2005-06-24
Support Year
2
Fiscal Year
2004
Total Cost
$46,244
Indirect Cost
Name
Washington University
Department
Surgery
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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
Dharmarajan, Sekhar; Schuster, Daniel P (2005) Molecular imaging of the lungs. Acad Radiol 12:1394-405
Dharmarajan, Sekhar; Schuster, Daniel P (2005) Molecular imaging of pulmonary gene expression with positron emission tomography. Proc Am Thorac Soc 2:549-52, 514-6