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Clinical lung transplantation has developed over the past several years into a viable therapeutic option for many types of end-stage lung disease. Most patients benefiting from this therapy are adults with various types of end-stage emphysema, primary pulmonary hypertension, restrictive lung disease such as pulmonary fibrosis, and cystic fibrosis. Relatively few children are in need of lung transplantation, and because of a lack of donor organs, fewer still actually undergo this life-saving surgery. In 1995, nearly one-third of children on the lung transplant waiting list died while awaiting a suitable organ. We and others have reported on the clinical application of “reduced-size” lung transplantation in which part of a more mature lung is transplanted into a smaller recipient in order to procure more organs for the pediatric population.
Studies from our laboratory and studies from other investigators have reported evidence of lung growth of mature lobar transplants. Measured parameters of lung growth have included changes in lobar weight and fixed volume but minimal changes in functional volumes. A modest increase in alveolar number has also been seen. Most recently, we have demonstrated dividing pneumocytes in porcine mature lobar transplants implanted into an immature host. The origin and potential of these dividing pneumocytes remains unknown. In addition, the stimulus for pneumocyte division also is unknown. Our continuing research will verify our preliminary results and explore the molecular and cellular biology of lung growth following reduced-size transplants. In addition, we aim to identify molecular mediators of lung growth which may also be active in the growth of transplanted mature lobes.
Basic Science Model
The MHC-Defined minipig is used for our experiments involving mature porcine lobar transplantation into immature swine. Previous experience in our lab using wild-type domestic swine in survival studies of lung transplantation have been complicated by a significant and unpredictable degree of acute and chronic allograft rejection. Since even moderate degrees of rejection can markedly affect lung function, data scatter can be readily introduced if extreme care is not taken to exclude data from those allografts demonstrating any degree of rejection. However, by using the genetically inbred MHC-defined minipig, we can hold the degree of genetic mismatch constant, and minimize pig to pig variability in the frequency and severity of rejection. By continuing triple drug immunosuppression (the pigs are not genetically identical), the frequency of rejection in ongoing preliminary studies has been nil.
