Pathophysiology of extracellular haemoglobin: use of animal models to translate molecular mechanisms into clinical significance

Abstract

Pathophysiology of extracellular haemoglobinuse of animal models to translate molecular mechanisms into clinical significance Smeds, Emanuel; Romantsik, Olga; Jungner, Åsa; Erlandsson, Lena; Gram, Magnus General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. AbstractThe blood's major gas-exchange is carried out by haemoglobin, a heme-protein that binds iron and oxygen and can have potentially dangerous side effects due to redox reactions.Haemoglobin is a very abundant molecule with a concentration of 150 g/L in whole blood, resulting in almost one kg haemoglobin in an adult human body. Normal turn-over of red blood cells results in significant haemoglobin release, and pathological conditions that involve haemolysis can lead to massive haemoglobin levels. To control for the potential threat of extracellular haemoglobin, several protective defence systems have evolved.Many pathological conditions, diseases as well as iatrogenic conditions, such as infusion of haemoglobin-based oxygen carriers, cerebral intraventricular haemorrhage, extracorporeal circulation and the pregnancy complication preeclampsia, involve abnormal levels of haemolysis and extracellular haemoglobin. Although quite different aetiology, the haemoglobin-induced damage often cause similar clinical sequelae and symptoms. Here we will give an overview of the pathophysiological mechanisms of extracellular haemoglobin and its metabolites. Furthermore, we will highlight the use of animal models in advancing the understanding of these mechanisms and discuss how to utilize the knowledge in the development of new and better pharmaceutical therapies.

Cell-free oxidized hemoglobin drives reactive oxygen species production and pro-inflammation in an immature primary rat mixed glial cell culture

“…In the present study, we show by exposing mixed glial cells to cell-free Hb-metabolites that oxidized Hb (constituting a mixture of Hb-metabolites with mainly Fe 3+ and some proportion of Fe 4+ , free heme, and iron) rather than oxyHb (Fe 2+ ) is responsible for the proinflammatory and oxidative response observed following IVH. In agreement with previous reports, exposure to hemorrhagic CSF and oxidized Hb induced cellular activation and pro-inflammatory, oxidative, and cytotoxic pathways [8][9][10][11][12][13]. Co-administration with Hp partially reversed the cellular damage induced, both by exposure to hemorrhagic CSF from preterm human infants with GM-IVH and pure oxidized Hb, indicating that oxidation of cell-free oxyHb (Fe 2+ ) is a critical step in the damaging pathway of IVH.…”

“…Cell-free Hb is described to be causally involved in the damaging pathway following IVH [2,[10][11][12]. It has been Fig.…”

“…Cell-free Hb is described to be causally involved in the damaging pathway following IVH [ 2 , 10 – 12 ]. It has been suggested that this is caused by affecting the redox activity of the extracellular environment and thereby exposing cells and tissues to oxidative stress [ 11 , 13 , 29 , 30 ].…”

“…The subsequent degradation results in the generation of bilirubin, carbon monoxide, and free iron. Cell-free Hb and its metabolites are known to be initiators of cytotoxic, oxidative, pro-inflammatory, and apoptotic events inducing tissue damage [8][9][10][11][12]. Although published data clearly describe the involvement of Hb in the development of brain damage [4][5][6][7], a limitation of the studies conducted up to date has been the inability to characterize the importance of the different Hb-metabolites responsible for the observed damage.…”

Extracellular Hemoglobin: Modulation of Cellular Functions and Pathophysiological Effects

“…In addition to Hp, both hemopexin and albumin act as mechanisms that limit the effects of extracellular hemoglobin [ 3 , 14 ]. These two molecules can bind free heme, maintain it in soluble form and thus prevent it from exhibiting its oxidative and proinflammatory effects [ 17 ]. Hemopexin is a plasma heme-binding glycoprotein with an affinity for heme higher than all known heme-binding proteins.…”