1. An intervention to reduce ischaemia-reperfusion
lung injury will be an important advance in transplant medicine. Although the mechanisms associated with producing ischaemia-reperfusion endothelial injury have not been completely elucidated, many of the injury mediators have been studied in detail. While no single pharmacological
therapy is likely to be totally effective in eliminating this complex injury, we have developed a mixture of agents that are known to block pathways involved in producing ischaemia-reperfusion-associated lung
vascular injury.2. The present study modified University of Wisconsin
solution (UW) by adding one of the
protective agents prostaglandin E1 (
PGE1),
dexamethasone (Dex) or dibutyryl cAMP (Bt2-cAMP), or a combination of these, to the perfusate of rat lungs exposed to 4 h of cold ischaemia followed by 1 h of reperfusion. Nine modified UW solutions were studied: (1) UW+Dex, (2) UW+PGE1, (3) UW+Bt2-cAMP, (4) UW+Dexx3, (5) UW+PGE1x3, (6) UW+Bt2-cAMPx3, (7) UW+Dex+
PGE1, (8) UW+Dex+Bt2-cAMP, (9) UW+
PGE1+Bt2-cAMP. These solutions were utilized in individual experiments to assess haemodynamic changes, lung
weight gain, the capillary filtration coefficient (Kfc) and pathology in all lungs.3. The results indicate that lung
weight gain and Kfc values were significantly lower than with UW alone in groups 1, 2 and 3, which contained only one additional
protective agent. In groups 4, 5 and 6, which contain three times the concentration of each
protective agent, both Kfc and lung
weight gain were similar to those measured in groups 1, 2 and 3, i.e. lungs were protected but the protection was not dose dependent. In groups 7, 8 and 9, which contained two
protective agents, lung
weight gain and Kfc were greatly reduced compared with UW alone. Histopathological studies showed similar decreases in the injury profiles of lungs.4. Although UW contains several
antioxidant protective agents such as
allopurinol and
glutathione, it did not provide effective protection in our ischaemia-reperfusion
lung injury model. UW modified with an additive of
PGE1, Dex or Bt2-cAMP attenuated ischaemia-
reperfusion injury. Furthermore, UW containing two of these
protective agents augmented the protection. Among the modified solutions, it appears that UW+
PGE1+Bt2-cAMP protects the lungs to a greater extent than all other solutions used in our study. We suggest that preservation solutions containing PGE1-Bt2-cAMP will provide additional protective effects to organs stored for
transplantation.