Review of Modified Hemoglobin Research at Letterman: Attempts to Delineate the Toxicity of Cell-Free Tetrameric Hemoglobin

Abstract

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 systems were used to explore the toxicities of model hemoglobin (Hb) solutions produced in the sterile Hb production facility. Human mononuclear cells release TNFα and Il-8 when exposed to chromatographically purified human Hb (HbA₀). Mixed cultures of fetal mouse neurons and glial cells exhibit neuronal death with exposure to HbA₀ in a dose and time dependent manner while the glial cells are not injured. Isolated 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 rabbits HbA₀ and human Hb cross-linked with bis (3,5-dibromosalicyl) fumarate (ααHb) caused hypertension and pulmonary arteritis. In swine, HbA₀ and ααHb caused systemic and pulmonary hypertension 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. Acute renal failure seen after administration HbA₀, did not appear after ααHb. Infusion of cyanomet-ααHb did not cause the increased vascular resistance seen after ααHb. The infusion of 1-arginine or nitroglycerine with ααHb did not prevent the increased vascular resistance and decreased cardiac output or allow the increased oxygen carrying capacity provided by Hb in the plasma from translating into improved oxygen delivery or improved oxygen consumption.