Induction of haem oxygenase‐1 causes cortical non‐haem iron increase in experimental pneumococcal meningitis: evidence that concomitant ferritin up‐regulation prevents iron‐induced oxidative damage

Abstract

Desferrioxamine inhibits cortical necrosis in neonatal rats with experimental pneumococcal meningitis, suggesting that iron-induced oxidative damage might be responsible for neuronal damage. We therefore examined the spatial and temporal profile of changes in cortical iron and iron homeostatic proteins during pneumococcal meningitis. Infection was associated with a steady and global increase of non-haem iron in the cortex, particularly in neuronal cell bodies of layer II and V, and in capillary endothelial cells. The non-haem iron increase was associated with induction of haem oxygenase (HO)-1 in neurones, microglia and capillary endothelial cells, whereas HO-2 levels remained unchanged, suggesting that the non-haem iron increase might be the result of HO-1-mediated haem degradation. Indeed, treatment with the haem oxygenase inhibitor tin protoporphyrin (which completely blocked the accumulation of bilirubin detected in HO-1-positive cells) completely prevented the infection-associated non-haem iron increase. The same cells also displayed markedly increased ferritin staining, the increase of which occurred independently of HO activity. At the same time, no increase in DNA/RNA oxidation was observed in infected animals (as assessed by in situ detection of 8-hydroxy[deoxy]guanosine), strongly suggesting that ferritin up-regulation protected the brain from iron-induced oxidative damage. Thus, although pneumococcal meningitis leads to an increase of cortical non-haem iron, protective mechanisms up-regulated in parallel prevent iron-induced oxidative damage. Cortical damage does not appear to be a direct consequence of increased iron, therefore.

Pharmacological and Clinical Aspects of Heme Oxygenase

“…An increase in nonheme iron was associated with the induction of HO-1 in neurons, microglia, and capillary endothelial cells whereas HO-2 levels remained unchanged, suggesting that the nonheme iron increase might be the result of HO-1-mediated heme degradation (Ren et al, 2007). Indeed, treatment with SnPP (which completely blocked the accumulation of bilirubin detected in HO-1-positive cells) prevented the infection-associated nonheme iron increase.…”

“…Ferritin has been shown to protect endothelial cells from oxidized low-densitylipoprotein (LDL) and iron-induced oxidative stress (Matsumi et al, 2002) and from UV light (Vile and Tyrrell, 1993). Ferritin has been shown to be a cytoprotective antioxidant of endothelium Ren et al, 2007), presumably due to antiapoptotic effects (Berberat et al, 2003). For a review of the role of ferritin in cell protection, see Ponka et al (1998).…”

Heme Oxygenase-1 as a Therapeutic Target in Neurodegenerative Diseases and Brain Infections

“…Thus, although pneumococcal meningitis leads to an increase of cortical non-heme iron, protective mechanisms up-regulated in parallel prevents iron-induced oxidative damage. The authors did not analyze inflammation markers [154]. However, in a related model of meningoencephalitis, consisting in infection of rat brain with the neurotropic Borna disease virus, Herden et al, analyzed the temporal changes in expression of allograft inflammatory factor-1, a novel microglial marker, and HO-1.…”

Regulation of inducible heme oxygenase and cyclooxygenase isozymes in a mouse model of spotted fever group rickettsiosis

“…Recent studies have shown increased expression of HO-1 in macrophages infected with Mycobacterium tuberculosis and regulation of bacterial ‘dormancy regulon’ by carbon monoxide, a by-product of HO activity [32]; induced expression in the liver and potent cytoprotective function in a mouse model of salmonellosis [33]; and down-regulation of placental HO-1 by Listeria monocytogenes leading to infectious abortion [34]. In contrast, abortion due to Brucella abortus infection in pregnant mice is attributed to HO-1 expression in the placenta [35] and HO-1 induction in an experimental model of pneumocoocal meningitis results in iron-mediated oxidative damage in the brain [36]. Interestingly, in a mouse model of secondary bacterial pneumonia due to Streptococcus pneumoniae after initial influenza infection, the expression of HO-1 was significantly higher in the lungs, but not in other tissues [37].…”