Hemoglobin-Endotoxin Interactions

Abstract

Toxicities of hemoglobin (Hb) solutions, which have been demonstrated in numerous animal resuscitation models, prominently include fever, hypertension, thrombocytopenia, activation of the complement and coagulation cascades, disseminated intravascular coagulation with parenchymal organ damage, reduced tolerance to sepsis, susceptibility to bacterial infections, reticuloendothelial cell blockade and lethal toxicity (Bolin et al. 1983, Bornside, Bouis, and Cohn 1970, Brandt, Frank, and Lichtman 1951, Feola et al. 1988a and 1988b, Feola et al. 1990, Marks et al. 1989, Savitsky et al. 1978, Smith et al. 1990, White et al. 1986a). In addition, recent clinical trials of cross-linked Hb have been associated with production of hypertension and gastrointestinal dysmotility. Of particularly great current interest is the recent demonstration that injection of non-lethal doses of gram-negative bacteria into animals produced 50% and 100% mortality when the animals had been pre-infused with either native or cross-linked preparations of cell-free Hb, respectively (Griffiths et al. 1995). In vitro Hb has been shown to stimulate tissue factor production by mononuclear cells (Smith and Winslow 1992), cause endothelial cell injury (Feola et al. 1989) and to activate complement (Smith and Winslow 1992). These in vivo and in vitro effects are characteristic of bacterial endotoxins (lipopolysaccharide, LPS). Investigations of the possibility that LPS may contribute to the observed side effects of Hb infusions have been a major focus of our laboratory during the past several years, and a significant role for LPS in Hb toxicity has been suggested by our studies.