Redox side reactions of haemoglobin and cell signalling mechanisms

Cell-free chemically modified or recombinant haemoglobins developed as oxygen therapeutics are designed to correct oxygen deficit caused by ischaemia in a variety of clinical settings. Oxidative processes, which are in some cases enhanced when modifications are introduced that lower oxygen affinity, can limit the safety of these proteins. Direct cytotoxic effects associated with haemoglobins have been ascribed to the redox reactions between haemoglobin and biological peroxides [i.e. hydrogen peroxide (H2O2), lipid peroxides (LOOH) and peroxynitrite (ONOO-)]. Biochemical changes at the cellular, tissue and organ levels have been documented to occur in response to haemoglobin oxidative reactions. These peroxides have been implicated as regulators of redox sensitive cell signalling pathways. The effects of reactions between haemoglobin and biologically relevant peroxides may be more subtle than oxidative damage and may thus involve perturbation of redox sensitive signalling pathways. In this review, a brief outline of the role of cell-free haemoglobin in oxidative and cell-signalling pathways and the implications of these reactions on the safety and efficacy evaluation of haemoglobin-based oxygen carries are presented.