Heme oxygenase-1 in lesions of human cerebral malaria

Human cerebral malaria is a life threatening complication of Plasmodium falciparum infection. The cascades of signaling events resulting in tissue trauma, lesion formation, coma or resolution of lesions are only slowly becoming unraveled. Understanding the generation of local tissue protective cellular reactions might pave the way for generation of novel drugs limiting the formation of cerebral malaria lesions. Heme oxygenase-1 (HO-1) is an inducible enzyme degrading heme into the gaseous mediator carbon monoxide (CO) and biliverdin, a local antioxidant. Expression of HO-1 is considered a protective reaction against inflammatory and other insults to the brain. We have localized HO-1 to Durck's granulomas, typical lesions of advanced cerebral malaria. Here, activated monocytic cells and ramified microglia in direct vicinity to the lesions express HO-1. The striking association of HO-1 expression with areas of bleedings suggests that released hemoglobin and heme - known inducers of HO-1 - are mainly responsible for induction of monocytic HO-1 expression. HO-1 is expressed rather late to play a protective role in lesion formation and appears to have only a major role in Durck's granulomas. Further, generation of the gaseous mediator CO might contribute to the neurological derangements of advanced cerebral malaria. a crucial mechanism generating damage to the vascular endothelial lining. Adaptive cellular antioxidative mechanisms might limit local tissue destruction. In addition, the typical petechial bleedings result in the liberation of hemoglobin and heme, a powerful oxidant. Heme oxygenases degrade heme to CO, Fe and biliverdin, which is then further reduced to bilirubin. Biliverdin and bilirubin are both powerful antioxidants [35]. Heme oxygenases protect cells from the deleterious, immunostimulatory and oxidative effects of free heme [21, 42] and we have therefore analyzed the localization of HO-1 (heat-shock protein hsp-32) in human CM.