Mechanisms of haem toxicity in haemolysis and protection by the haem‐binding protein, haemopexin

Abstract

Haem (iron‐protoporphyrin IX) is vital to aerobic life. However, haemolysis generates massive amounts of free haem that can be maintained for several days. Haem is toxic because the chemical reactions of haem that occur in the presence of oxygen can destroy most biological molecules and haem activates cells of the immune system to drive inflammation. Haemopexin captures haem and disarms its chemical activity, thus protecting cells and molecules in biological fluids from haem toxicity. A surprisingly large number of disease states characterized by haemolysis or complicated by haemolysis (e.g. sickle cell disease, sepsis, haemolytic anaemias, viral haemorrhagic fevers) lack targeted therapies. Novel treatments from proof of principle studies in mice models of sickle cell disease and sepsis include replenishment therapies with haemopexin infusions or hepatic gene therapy to express haemopexin. Here, we characterize the key protective mechanisms that haemopexin instigates, explain how methaemoglobin and methemalbumin produce haem toxicity and evaluate the clinical importance of the haemopexin system in protecting against extracellular haem‐activated pathology in intravascular haemolysis. The main findings are that endocytosis of haem–haemopexin co‐regulates the safe trafficking of three redox‐active metals through subcellular compartments and, compared with the response to ‘free’ haem, uniquely activates several signalling pathways and transcription factors that induce the production of antioxidant enzymes and molecules known to maintain the intracellular redox state. Mounting evidence from patient longitudinal studies supports that impairments of haem and haemoglobin clearance are often unrecognized. Clinical data suggest that haemopexin is likely the best plasma biomarker for assessing a haem load as, unlike haptoglobin, it responds to heme and is not an acute‐phase reactant. Knowledge of the biology of haemopexin has yielded a potential novel therapeutic and also provided an impetus and means for improving diagnosis and longitudinal monitoring of patients with haemolysis.