Abstract
Heme oxygenase 1 (HO-1) is an essential enzyme induced by heme and multiple stimuli associated with critical illness. In humans, polymorphisms in the HMOX1 gene promoter may influence the magnitude of HO-1 expression. In many diseases including murine malaria, HO-1 induction produces protective anti-inflammatory effects, but observations from patients suggest these may be limited to a narrow range of HO-1 induction, prompting us to investigate the role of HO-1 in malaria infection. In 307 Gambian children with either severe or uncomplicated P. falciparum malaria, we characterized the associations of HMOX1 promoter polymorphisms, HMOX1 mRNA inducibility, HO-1 protein levels in leucocytes (flow cytometry), and plasma (ELISA) with disease severity. The (GT)n repeat polymorphism in the HMOX1 promoter was associated with HMOX1 mRNA expression in white blood cells in vitro, and with severe disease and death, while high HO-1 levels were associated with severe disease. Neutrophils were the main HO-1-expressing cells in peripheral blood, and HMOX1 mRNA expression was upregulated by heme-moieties of lysed erythrocytes. We provide mechanistic evidence that induction of HMOX1 expression in neutrophils potentiates the respiratory burst, and propose this may be part of the causal pathway explaining the association between short (GT)n repeats and increased disease severity in malaria and other critical illnesses. Our findings suggest a genetic predisposition to higher levels of HO-1 is associated with severe illness, and enhances the neutrophil burst leading to oxidative damage of endothelial cells. These add important information to the discussion about possible therapeutic manipulation of HO-1 in critically ill patients.
Highlights
Heme oxygenase (HO) is the rate limiting enzyme that catabolizes free heme into carbon monoxide (CO), ferrous iron, and biliverdin/bilirubin [1]
Nine of the ten deaths occurred in children who were classified as having severe respiratory distress (SRD), defined as lactic acidosis, that has been recognized as the single most important determinant of mortality in severe malaria [45]
Inspired by elegant studies in murine malaria models clearly demonstrating that the induction of Heme oxygenase 1 (HO-1) helps prevent severe forms of malaria [9,10], and the intriguing possibility either to manipulate HO-1 activity pharmaceutically [71,72] or to mimic its effect by administering CO [20], we explored the role of HO-1 in children with severe and uncomplicated P. falciparum infection
Summary
Heme oxygenase (HO) is the rate limiting enzyme that catabolizes free heme into carbon monoxide (CO), ferrous iron, and biliverdin/bilirubin [1]. While HO-2 is constitutively produced by most cells, HO-1 protein is induced by its substrate heme and a broad array of acute stress stimuli, many of which are associated with critical illnesses [2]. HO-1 induction produces cytoprotective and anti-inflammatory effects by reducing intracellular heme availability, through generation of CO and bilirubin, through stimulation of ferritin synthesis [3], and possibly, by heme-independent mechanisms of transcriptional regulation [4]. HO-1 is an essential enzyme in humans and mice; deficiency in humans is deleterious, predominantly affecting endothelial cells and the reticuloendothelial system, and results in a greatly reduced life expectancy [5]. The impact of HMOX1 over- or under-expression, silencing or knockout and the concomitant changes in protein levels in a physiological or homeostatic context [6] or in humans [7] is less clear
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