REVIEW OF MODIFIED HEMOGLOBIN RESEARCH AT LETTERMAN - ATTEMPTS TO DELINEATE THE TOXICITY OF CELL-FREE TETRAMERIC HEMOGLOBIN

In the final two years, June 1991 to June 1993, of the Letterman Army Institute of Research, a variety of cell, tissue, organ, and animal sy stems were used to explore the toxicities of model hemoglobin (Hb) sol utions produced in the sterile Hb production facility. Human mononucle ar cells release TNF alpha and I1-8 when exposed to chromatographicall y purified human Hb (HbA(0)). Mixed cultures of fetal mouse neurons an d glial cells exhibit neuronal death with exposure to HbA(0) in a dose and time dependent manner while the glial cells are not injured. Isol ated perfused rabbit hearts were used to explore the reversibility of coronary vasoconstriction after Hb and cyanomet-Hb administration, and deferoxamine was shown to partially protect that reversibility. In ra bbits HbA(0) and human Hb cross-linked with bis(3,5-dibromosalicyl) fu marate (alpha alpha Hb) caused hypertension and pulmonary arteritis. I n swine, HbA(0) and alpha alpha Hb caused systemic and pulmonary hyper tension and a doubling of the vascular resistance that was equivalent to that seen with inhibition of nitric oxide synthesis. Elevations of creatine kinase and lactic dehydrogenase activity were observed after Hbs were infused, but not after blockade of nitric oxide synthesis. Ac ute renal failure seen after administration HbA(0), did not appear aft er alpha alpha Hb. Infusion of cyanomet-alpha alpha Hb did not cause t he increased vascular resistance seen after alpha alpha Hb. The infusi on of 1-arginine or nitroglycerine with alpha alpha Hb did not prevent the increased vascular resistance and decreased cardiac output or all ow the increased oxygen carrying capacity provided by Hb in the plasma from translating into improved oxygen delivery or improved oxygen con sumption.