Characterization of local inflammatory response in an isolated lung perfusion model

Background: Current phase I trials of isolated lung perfusion for treatment of pulmonary metastases have an arbitrarily determined length of perfusion. Our objective was to examine the temporal course of the local and distant inflammatory response as a function of the length of perfusion (ischemia) and subsequent reperfusion in an equivalent animal model. Methods: Sixty male Fischer 344 rats were randomized into four groups (n = 15). Each group underwent left isolated lung perfusion with buffered Hespan for 10, 30, 60, or 90 minutes. Subsequently, two subgroups of five animals within each group were allowed to reperfuse for 1 or 3 hours, respectively. Non-perfused right lung was used as control. At each time point, lung specimens were assayed for TNF-alpha by ELISA and histologic sections were examined. Results: There was no significant difference between the left and right lung tissue levels of TNF-alpha at the termination of the ischemic period. However, on reperfusion, the left lung TNF-alpha levels increased significantly above the ischemia baseline in all groups, with a greater magnitude of rise in the groups with 60 and 90 minutes of preceding ischemia (12757 +/- 1985 vs. 3524 +/- 494 pg/g, and 16914 +/- 1657 vs. 6530 +/- 1104 pg/g, respectively; p < 0.05). There was no significant elevation in tissue levels of TNF-alpha in the right lung. Histologic changes consistent with early pulmonary edema were first detected at 12 hours following onset of reperfusion. Conclusions: Reperfusion following prolonged pulmonary ischemia during isolated lung perfusion results in a significant elevation of local tissue levels of TNF-alpha and may render the perfused lung vulnerable to the adverse effects of the inflammatory cascade.