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Packed red blood cells (PRBCs) transfusion is associated with immune suppression, but these mechanisms are incompletely understood. PRBCs contain arginase, an enzyme that converts arginine to ornithine, and is known to limit arginine availability and suppress cellular immunity. We sought to determine whether PRBC arginase causes arginine depletion, potentially contributing to immunosuppression.A model of transfusion was designed by adding either centrifuged acellular supernatant from the PRBC unit (plasma) or total fluid from the unit (plasma+RBC [red blood cells]) to cell culture media. Through an institutional review board-approved protocol, PRBC units were isolated and processed by an accredited blood bank and stored at 4°C. Leukoreduced PRBCs or supernatant aliquots were withdrawn every 5 days to 7 days for 42 days. Cell cultures were created with standard Roswell Park Memorial Institute media, controlling the arginine level at 80 μmol/L (approximating human serum), and adding 20% plasma or plasma+RBC. An irreversible arginase blocker (nor-N-ω-OH-l-arginine) was added to selected cultures. After 24 hours, culture arginase activity was measured by ornithine synthesis, and amino acid levels were measured using mass spectroscopy.Culture arginase activity was increased by both plasma and plasma+RBC, but with plasma+RBC this did not reach statistical significance. Arginine levels were decreased and ornithine levels increased in cultures containing either supernatant or PRBC, as compared with control media. Addition of nor-N-ω-OH-l-arginine significantly decreased cell culture arginase activity, restored arginine levels, and diminished ornithine synthesis.Arginase is present in PRBC units and causes arginine depletion. Depletion of arginine by PRBC arginase is a potential novel mechanism for immunosuppression.