Ann Thorac Surg 2001;72:1171-1172
© 2001 The Society of Thoracic Surgeons
Invited commentary
John A. Kern, MDa
a TCV Surgery, University of Virginia, Lee St, Charlottesville, VA 22908, USA
e-mail: jak3r{at}virginia.edu
Despite significant advances in organ procurement and preservation techniques, transplanted lungs are unusually sensitive to ischemia-reperfusion injury. Severe early graft dysfunction has been reported in up to 20% of lung recipients, and this early dysfunction can lead to an increase in early and late morbidity and mortality. Although ischemia plays an important role in initiating early post-transplant lung injury, reperfusion mechanisms are equally important. Pulmonary ischemia-reperfusion (I/R) injury is a complex process involving many cell types and inflammatory biochemical mediators. The study by Sunose and colleagues has utilized a popular dog model of lung transplantation to evaluate the effect of a COX-2 inhibitor on subsequent graft function after 12 hours of ischemia and varying times of up to 4 hours of reperfusion. The hilum of the contralateral non-transplanted lung was ligated in order to evaluate the function of the transplanted organ and its ability to support the animal. The COX-2 inhibitor was administered to both the donor animal 15 minutes prior to lung ischemia, and to the recipient animal 15 minutes prior to reperfusion. COX-2 is an inducible protein that catalyzes arachidonic acid to several active metabolites, including pro-inflammatory thromboxane A2 (TxA2). The authors point out that COX-2 is temporarily induced in monocytes and tissue macrophages during inflammatory conditions, such as might be encountered during ischemia and reperfusion. Therefore, the authors imply that donor pulmonary macrophages may play an important early role in ischemia-reperfusion injury.
In this study, COX-2 inhibition resulted in significant improvement in graft function, as reflected hemodynamically, and in improved arterial oxygenation. PMN infiltration into the transplanted lung was significantly higher in the control (non-treated) group, and serum levels of TxB2 (a metabolite of TxA2) were significantly lower in the treated group, providing nice evidence that COX-2 inhibition was achieved. The authors provide an excellent discussion on the importance of proper balance of TxA2 and PGI2 for minimizing I/R injury, and speculate that selective inhibition of TxA2 over PGI2 may be most important for ameliorating injury. Importantly, they support the continued use of PGI2 flush during clinical lung procurement. The results of this nicely done study provide additional information into the potential time-course of cellular and biochemical events that are responsible for lung ischemia-reperfusion injury.
It appears as though there may be a bimodal response to I/R injury, with products of donor pulmonary macrophages being responsible for initiating the cascade of events that ultimately lead to neutrophil accumulation and worsening inflammation, edema, and pulmonary dysfunction. The inciting event for the resident pulmonary macrophage still is not known however. In other words, is it the ischemia or the reperfusion? In this study, the COX-2 inhibitor was given to both the transplanted lung prior to ischemia and to the recipient animal prior to reperfusion. Although protection from injury was observed in this study, it would be interesting to see if treating either just the transplanted lung or the recipient (prior to reperfusion) would achieve similar results. Additionally, although superior graft function was seen in animals that received the COX-2 inhibitor, evaluation was only carried out for 4 hours. The measured physiologic parameters did not quite reach steady state, and it is likely that other reperfusion mechanisms could have led to more profound delayed graft dysfunction. It is rare to find a single pathway responsible for such a wide complex of cellular and biochemical interactions so that one step inhibition can be achieved.
Nevertheless, these results support our own findings. We have found in an isolated blood-perfused ventilated rabbit lung model, that inhibition of donor pulmonary macrophages with gadolinium chloride improves early post I/R pulmonary function. Unfortunately, the lungs must be pretreated 24 hours prior to harvesting. We have also found that late dysfunction can best be ameliorated through neutrophil filtration, suggesting a bimodal inflammatory response to I/R. Therefore, evidence from the present study as well as from our own studies would seem to support the idea that donor pulmonary macrophages may be responsible for initiating the inflammatory cascade that leads to subsequent neutrophil accumulation and pulmonary dysfunction following lung transplantation. Whether ischemia and reperfusion together, or ischemia alone is enough to stimulate the pulmonary macrophage is an area of ongoing work. Optimal treatment of lung donors prior to organ harvest may ultimately prove to be as important as the actual harvesting technique and the subsequent treatment of the recipient. Targeting specific mediators of injury and inflammation, as demonstrated in this study, may hold significant promise for improving the early and late outcome of clinical lung transplantation.
Related Article
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Effect of a cyclooxygenase-2 inhibitor, FK3311, in a canine lung transplantation model
- Yutaka Sunose, Izumi Takeyoshi, Hirofumi Tsutsumi, Susumu Ohwada, Noboru Oriuchi, Koshi Matsumoto, and Yasuo Morishita
Ann. Thorac. Surg. 2001 72: 1165-1171.
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