Regulation of Apoptosis in Lung Transplantation

Washington University, Saint Louis MO

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Abstract

DESCRIPTION (provided by applicant): 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.