Preterm intraventricular haemorrhage - Effects of extracellular haemoglobin Sveinsdottir, Snjolaug

Intraventricular haemorrhage (IVH) is the most common brain lesion in preterm infants. The prognosis is dire and there is no available therapy to prevent infants from developing either post-haemorrhagic ventricular dilatation (PHVD) or serious neurological disability. Mechanisms leading to brain damage and hydrocephalus following IVH are complex and incompletely understood. Our working hypothesis is that cell-free Hb and its metabolites act as causal initiators of inflammation following IVH, constituting a critical up-stream event eventually leading to periventricular cell death. We further hypothesize that inflammation of the choroid plexus alters the ability of the epithelium to maintain CSF homeostasis contributing to the formation of post-haemorrhagic hydrocephalus. To test the hypothesis we used the rabbit pup model of preterm IVH. We found that the formation of metHb is a key up-stream event leading to inflammation following IVH and there is extensive damage to the choroid plexus epithelium, which develops over time. There is a distinct inflammatory and cellular response induced by haemoglobin metabolites and alteration of aquaporin expression, a key transmembrane protein. Injection or co-incubation with haptoglobin, a haemoglobin scavenger, reduces or reverses the effects of haemoglobin both in vivo and in vitro. In conclusion; following IVH released cell free haemoglobin, metabolized to metHb and hemin, constitutes a causal up-stream initiator of inflammation and cellular damage. Scavenging or removal of haemoglobin might be an efficient and feasible approach to reduce brain damage following preterm IVH.