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Oxygen Transport Following Lung Transplantation in COPD

Institution: University of California, San Diego
Investigator(s): Moh Malek, Ph.D.
Award Cycle: 2007 (Cycle 16) Grant #: 16FT-0060 Award: $74,500
Subject Area: Pulmonary Disease
Award Type: Postdoctoral Fellowship Awards

Initial Award Abstract
Patients presenting with severe chronic obstructive pulmonary disease (COPD) are typically characterized by having shortness of breath and are thus limited in their activities of daily living which often leads to a poor quality of life. Studies demonstrate that lung transplantation improves the patient’s pulmonary mechanics and gas exchange parameters; however, exercise capacity remains substantially reduced. Although it has been suggested that skeletal muscle dysfunction may contribute to a reduced exercise tolerance postoperatively, the underlying mechanism has yet to be elucidated. While the ability to sustain aerobic exercise is multifactorial (i.e., cardiac function, muscle blood flow, and/or hemoglobin concentration), it is primarily dependent on oxygen supply and the ability of oxygen to diffuse from the red blood cells to the muscle mitochondria.

Vital to this process is the role of capillary development. Thus, the adaptation of skeletal muscle to aerobic training includes the development of new capillaries from existing capillaries in a process called angiogenesis. Studies have demonstrated that angiogenesis is initiated by vascular endothelial growth factor (VEGF) which is located on chromosome 6p21.3 in humans. VEGF165, the most common isoform, is involved in vascular permeability, endothelial cell proliferation, and angiogenesis. Thus, any examination of reduced exercise tolerance in post transplant COPD patients, must consider the role of capillary development/maintenance and specifically, VEGF.

Lung transplant patients, therefore, present a unique opportunity to examine the role of skeletal muscle dysfunction preoperatively and postoperatively as well as to test the interaction between immunosuppressives and capillary development/maintenance. The research proposed in this application is significant, because it is expected to provide that knowledge related to immunosuppressives and their interaction with capillary development/maintenance (i.e. VEGF) which is currently lacking in the literature. This is expected to have a significant positive impact on the understanding of angiogenesis in skeletal muscle of post transplant COPD patients, and as a consequence, provide insight into the skeletal muscle dysfunction observed postoperatively in COPD patients.