Gastric Fluid Aspiration-Mediated Pulmonary Allograft Failure
Since its first success in 1983, lung transplantation has become the treatment of choice for selected patients with end stage lung disease. However, long-term graft survival is relatively low compared to other solid organs, such as heart, liver and kidney. The primary factor limiting long-term survival of pulmonary allografts is obliterative bronchiolitis (OB), a form of chronic pulmonary graft rejection characterized by submucosal fibroproliferation of the small airways, which leads to luminal compromise and respiratory failure. Due to their unique anatomic location, lungs are exposed to environmental factors in the air which include potentially toxic agents. This suggests a possible importance of non-alloimmune mediated factors in the pathogenesis of pulmonary rejection in addition to alloimmunity.
Clinical reports reveal that gastroesophageal reflux disease (GERD) is commonly observed following lung transplantation, and it has been postulated that GERD after lung transplantation could accelerate the development of OB and subsequent lung allograft failure. Although clinical studies point to the importance of GERD in the survival of the transplant, the potential effects of GERD on pulmonary allografts still need to be identified. In this dissertation, the effects of GERD on pulmonary allografts, including ischemia-reperfusion (I-R) injury and the pH of the gastric fluid aspirate, are evaluated. Further, this dissertation explores the mechanisms by which GERD affects chronic lung allograft rejection, particularly the role played by mast cells in rejection.
I-R injury of the pulmonary graft has been associated with a higher risk of developing bronchiolitis obliterans syndrome (BOS) in clinical practice, and prolonged ischemic time has been correlated with poorer long-term survival after lung transplantation. To explore the relationship between GERD, I-R injury, and OB formation after lung transplantation, the effect of long and short ischemic times on WKY-to-F344 rat orthotopic left lung transplants receiving 8 weekly aspirations of gastric fluid was assessed. In this study, described in Chapter 2, long ischemic times led to significantly (p < 0.05) greater development of OB compared to short ischemic times. However, the development of OB was dependent on aspiration, as controls receiving aspiration with normal saline showed little development of OB, regardless of ischemic time (p < 0.05). The data suggest that prolonged ischemic time, while insufficient by itself to lead to OB, worked synergistically with chronic aspiration of gastric fluid to exacerbate the development of OB.
Also, it remains unknown whether pharmaceutical-induced increases in gastric pH might effectively prevent pulmonary injury associated with chronic aspiration. The hypothesis that neutralization of gastric fluid would affect the development of aspiration-associated OB was tested. The results, described in Chapter 3, revealed that the pH of the aspirated gastric fluid did not significantly affect pulmonary graft rejection. This finding suggests that clinical management of lung transplant patients with GERD should probably include more than just pharmaceutical blockage of gastric protons and/or antacid to neutralize the pH of gastric fluid.
Mast cells, the first responders of the innate defense system, might play a role in pulmonary allograft rejection due to their ability to orchestrate innate and adaptive immune responses. Correspondingly, increased mast cell numbers associated with increased rejection grade as well as the presence of OB were reported in a retrospective clinical study. Identifying how mast cells are involved with gastric fluid aspiration-associated pulmonary allograft rejection could uncover a potential method for treatment. With this in mind, cromolyn, a mast cell membrane stabilizer which prevents mast cell degranulation, was utilized to investigate the role of mast cells in the pathogenesis of pulmonary allograft failure. The results, described in Chapter 4, reveal that pulmonary allografts in rats treated with cromolyn and aspirated with gastric fluid developed significantly fewer OB lesions than those treated with gastric fluid alone (p<0.001). Further, the number of mast cells per small bronchiole significantly increased in the animals aspirated with gastric fluid regardless of the treatment of cromolyn. Therefore, cromolyn ameliorates the development of OB in pulmonary allografts, perhaps by qualitative (preventing mast cells degranulation), and not quantitative (numbers of mast cells) changes in the mast cells in the bronchioles. These findings suggest that mast cells play a substantial role in gastric fluid aspiration-mediated pulmonary allograft failure.
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