THE EARLY RELEASE OF INTERLEUKIN-2, TUMOR NECROSIS FACTOR-α AND INTERFERON-γ AFTER ISCHEMIA REPERFUSION INJURY IN THE LUNG ALLOGRAFT

Abstract

A period of cold and warm ischemia is obligatory when performing lung transplantation. Subtle ischemia-reperfusion injury induced in the course of transplantation can pass undetected or cause a short phase of reversible lung dysfunction. We hypothesized that ischemia-reperfusion injury may result in the local release of cytokines that have the capability to mediate acute lung injury early following transplantation. To test this hypothesis, 10 mongrel dogs were subjected to left lung allotransplantation. As performed in the clinical setting, donor lungs were preserved with Eurocollins solution and stored at 4°C for 4 hr, which was followed by 1 hr of warm ischemia. Recipients received standard immunosuppression of cyclosporine, azathioprine, and low dose steroids. Bronchoalveolar lavage (BAL) and open lung biopsies were performed before operation and at approximately 1 hr, 4 hr, 24 hr, and 1 week after transplantation. A significant increase in BAL IL-2 levels was observed 4 hr after surgery (0 hr: 349±138 pg/ml; 4 hr: 757±284 pg/ml) (mean ± SEM) (P<0.05) which subsequently decreased 24 hr (320±168 pg/ml) after transplantation. BAL TNF-α levels were significantly increased 1 hr after transplantation (P<0.05) (0 hr: 3.4±0.65 pg/ml; 1 hr: 13.3±8.0 pg/ ml) returning to baseline after 24 hr (5.8±2.8 pg/ml). BAL IFN-γ levels also significantly increased 1 and 4 hr after transplantation (0 hr: 7.2±2.1 pg/ml; 1 hr: 68.2±49.2 pg/ml; 4 hr: 301±131 pg/ml) (P<0.05). This decreased back to baseline after 24 hr and 1 week (5.2±1.2 pg/ml and 9.7±7.9 pg/ml, respectively). There were no changes detected in plasma levels of cytokines. Histology showed evidence of grade 1–2 rejection after 1 week. We conclude that subjection of a lung allograft to standard periods of cold-warm ischemia will result in a temporary early elevation of IL-2, TNF-α, and IFN-γ detectable only in the bronchoalveolar compartment. Such local increase in cytokines in the lung allograft may play an important role in the development of early allograft dysfunction.