.Adrenomedullin and adrenomedullin-binding protein-1 downregulate inflammatory cytokines and attenuate tissue injury after gut ischemia-reperfusion

Background. Recent studies have shown that adrenomedullin. (AM) and AM-binding protein-1 (AMBP-1) possess anti-inflammatory properties in sepsis. We hypothesized that administration of AMI AMBP-1 after gut ischemia-reperfusion (I/R) downregulates inflammatory crytokines and attenuates tissue injury. Methods. Male Sprague-Dawley rats (275-325 g) were used. Gut ischemia was induced by placing a microvascular clip across the superior mesenteric artery (SMA) for 90 minutes. Upon release of the SMA clamp, the animals were treated by AM (12 mu g per kilogram of body weight) and AMBP-1 (40 mu g per kilogram of body weight) in combination, or vehicle (1 mL 0.9% NaCl) over 30 minutes via a femoral vein catheter. The animals urdergoing sham operation or ischemia for 90 minutes only did not receive AM/AMBP-1 treatment. At 60 minutes after the completion of the treatment (ie, 90 minutes (after reperfusion), blood samples were collected. Plasma AM and AMBP-1 were measured by radioimmunoassay and Western, blot. analysis, respectively. Serum levels of TNF-alpha, interleukin (IL)-1 beta, IL-6, IL-10, transaminases (ie, alanine aminotransaminase, aspartate aminotransaminase), lactate, and creatinine were determined with the use of enzyme-linked immunosorbent assay and other standard. methods. In additional groups of animals, the 10-day survival rate was recorded after gut I/R. Results. Ischemia alone was sufficient to downregulate both AM rind AMBP-1. Unlike AMBP-1 that remained decreased, AM levels increased, significantly after reperfusion. I/R but not ischemia alone significantly increased serum levels of inflammatory cytokines. Moreover, I/R-induced tissue injury was evidenced by increased levels of transaminases, lactate, and creatinine. Administration of AM/AMBP-1 after ischemia, however, markedly reduced cytokine levels, attenuated tissue injury, and improved survival. Conclusions. AM/AMBP-1 may be a novel treatment to attenuate the reperfusion injury after gut ischemia.