Anti-inflammatory properties of rapamycin on leukocyte-endothelial cell interactions following profound hypoperfusion

Aims: We studied the translation inhibitor Rapamycin on its ability to modulate leukocyte-endothelial cell interactions following ischemia and reperfusion. During the inflammatory response, leukocyte rolling, adherence, and subsequent transmigration through the endothelial wall in the microcirculation are key steps in the inflammatory cascade and lead to further tissue injury.

Methods: The effects of the rapamycin on inflammatory response were observed by intravital microscopy in the rat mesenteric microcirculation and immunohistochemical analysis. The inflammatory cascade (leukocyte rolling, firm adherence, and transmigration) was studied by thrombin (0.5U/ml) superfusion of the microcirculation or hemorrhage with low perfusion (60min) followed by reperfusion (90min).

Results: Systemic bolus administration of rapamycin (10µg/kg) 5min prior to reperfusion significantly reduced leukocyte rolling from 49±10 to 8.3±2.3 cells/min (p<0.001) and adherence from 11.3±2.8 to baseline conditions (p<0.05) along the venular endothelium of the rat mesentery during reperfusion. Similar, rapamycin decreased leukocyte endothelium interaction following local inflammatory stimulation of the mesenteries with thrombin. Moreover, myeloperoxidase activity in ischemic reperfused mesenteries, a marker of neutrophil accumulation was significantly reduced following rapamycin treatment.

Conclusions: These data demonstrate that rapamycin can potently inhibit the recruitment of leukocytes in the microvasculature, and proved to be a potent endothelium protective agent in clinically relevant doses. Thus, rapamycin treatment may be useful agent for primary prevention of inflammatory tissue injury mediated by ischemia-reperfusion like shock, trauma, open heart surgery, or other large vascular surgery.