Date of Award

1-1-2017

Embargo Period

1-1-2022

Document Type

Thesis

Degree Name

Master of Science (MS)

Department

Microbiology and Immunology

College

College of Graduate Studies

First Advisor

Carl Atkinson

Second Advisor

Satish Nadig

Third Advisor

Laura Kasman

Fourth Advisor

Timothy Whelan

Abstract

Ever since the first lung transplant, in 1963, survival rates have suffered greatly. Approximately 50 years later, around 83% of patients survive one-year post transplant, and an even lower 65% survive 3-years after surgery. The majority of these patients’ cause of death is chronic rejection, which is unresponsive to current immunosuppressive therapies. Although there is no shortage of immunosuppressant drugs, the standard protocol for administration of these drugs comes too late to prevent early organ damage. The donor organ is subjected to stress and inflammation due to the transplantation process, which causes the organ to fail. We propose that a pre-treatment of the donor organ with a neutrophil elastase inhibitor, Alpha-1 Antitrypsin, will lessen the immune response seen early post-transplant, and therefore implement improved patient outcomes. A major complication that increases the chances of early organ failure and death after transplantation is ischemia-reperfusion (IR)-induced lung injury. Severe IR-induced lung injury occurs in around 25% of all lung transplant recipients and is characterized by poor oxygenation, tissue damage, and pulmonary edema. During the transplantation process, IR causes an acute inflammatory response which in turn causes the release of inflammatory mediators, neutrophil infiltration and activation, and cell death. This leads to the injury of the tissue and an overall decline in lung function. Mechanisms of inflammation and cell injury have been studied, but there remains no drug to lessen or prevent IR-induced lung injury. The protein we will use in addition to the preservation solution is Alpha-1 Antitrypsin (A1AT). A1AT is a neutrophil elastase inhibitor in the lung. It is synthesized by a number of different cell types including, hepatocytes, macrophages, monocytes, pulmonary epithelial cells, neutrophils, and endothelial cells. For in vitro studies, to mimic cold storage, BEAS-2b cells were exposed to cold hyperoxic conditions with Perfadex solution or Perfadex plus A1AT, and NAC for 18hrs at 4oC, prior to reperfusion with normal media for 24 hrs. Supernatants were analyzed for pro-inflammatory cytokine secretion using ELISA.

Rights

All rights reserved. Copyright is held by the author.

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