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L‐Arginine Prevents Heme‐Induced Acute Lung Injury (ALI) in a Rat Model of Trauma/Hemorrhage and Resuscitation with Transfusion

Resuscitation with long (> 28 days) stored packed red blood cells (PRBC) promotes acute lung injury (ALI) in our rat model of trauma/hemorrhage. Low nitric oxide (NO) production has been implicated in the development of ALI. Arginase can decrease NO production by decreasing L‐arginine availability for endothelial NO synthase (eNOS). We found that arginase, released from red blood cells (RBC) during prolonged storage, contributes to ALI in our rat model of trauma/hemorrhage. Prolonged storage also increases levels of free hemoglobin (Hb). Heme, a breakdown product of Hb, is metabolized by heme oxygenase to form carbon monoxide (CO). We were the first to report that heme‐derived CO inhibits endothelial nitric oxide (NO) synthase and promotes vasoconstriction in a manner that can be prevented by L‐arginine administration. This study tests the hypothesis that the hemolysis product, heme, promotes ALI in our rat model of trauma/hemorrhage and resuscitation with transfusion in a manner that is exacerbated by limited L‐arginine availability. Fresh PRBC were prepared from rat whole blood. Male Lewis rats were implanted with femoral arterial and venous catheters (trauma), subjected to a 30% hemorrhage and resuscitated with crystalloids and fresh PRBC containing heme alone or with L‐arginine or L‐lysine (competitive inhibitor of L‐arginine uptake). ALI was assessed by pulmonary protein leak (Evans blue dye ‐ EBD) and cytokine‐induced neutrophil chemoattractant‐1 (CINC‐1; rat homologue of human interleukin (IL)‐8) accumulation in bronchoalveolar lavage fluid (BALF). Heme alone caused a 5.6‐fold increase in pulmonary protein leak and 3.5‐fold increase in CINC‐1 accumulation. Co‐administration of L‐arginine decreased heme‐induced pulmonary protein leak by 77% and CINC‐1 accumulation by 32.4%. In contrast, L‐lysine, a competitive inhibitor of L‐arginine uptake, increased heme‐induced pulmonary protein leak by 102% and CINC‐1 accumulation by 106.4%. These data show that the Hb breakdown product, heme, promotes ALI in our rat model of trauma/hemorrhage and resuscitation with transfusion. L‐Arginine co‐administration protects against heme‐induced ALI, while blocking L‐arginine transport by L‐lysine exacerbates heme‐induced ALI. These results suggest that the other hemolysis product, heme, also contributes to ALI in a manner that is greatly exacerbated by decreased L‐arginine bioavailability. We conclude that hemolysis products arginase and heme work in concert to promote ALI during trauma/hemorrhage and resuscitation with transfusion.