Hepatic inflammatory responses to αα-cross-linked hemoglobin infusion in rats

• Published in: The Journal of laboratory and clinical medicine 1998, Vol.131 (5), p.432-441
• Main Authors: Przybocki, Joan M., McCalden, Thomas A., Collier, John M., Billings, Ruth E.
• Format: Article
• Language: English
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Biological and medical sciences; Blood. Blood and plasma substitutes. Blood products. Blood cells. Blood typing. Plasmapheresis. Apheresis; Medical sciences; Transfusions. Complications. Transfusion reactions. Cell and gene therapy
• ISSN: 0022-2143; 1532-6543
• DOI: 10.1016/S0022-2143(98)90144-5

Cross-linked hemoglobin (αα-Hb) may be a useful red blood cell substitute if it can be administered safely. However, cell-free hemoglobin has inherent properties that may cause oxidant-mediated toxicity. We investigated whether αα-Hb induces oxidative or inflammatory responses that lead to liver damage. αα-Hb (0.5 or 1.0 gm/kg) was infused into rats, and indices of liver injury, inflammation, and oxidative stress were examined. Although focal hepatic necrosis was noted at 24 hours, plasma alanine aminotransferase activity was not increased and lesions were resolved by 48 hours. Modest neutrophil accumulation in hepatic vessels, but not sinusoids, occurred at 24 hours. Heme oxygenase-1 (HO-1) protein and activity were induced in a dose- and time-dependent manner, with maximal induction at 24 hours. Plasma tumor necrosis factor-α levels were not significantly increased. Additional cytokine- and oxidant-mediated events such as nuclear transcription factor-κB activation and nitric oxide synthase induction were not observed. These results suggest that αα-Hb-derived products such as heme and ferric iron (Fe 3+), potent inducers of HO-1, are responsible for increasing HO-1. HO-1 induction may be a protective response by the liver to metabolize excess heme and Fe 3+, thereby providing antioxidative products to counter the potentially damaging oxidants produced by Fe 3+-catalyzed reactions.