Association of Heme Oxygenase 1 with the Restoration of Liver Function after Damage in Murine Malaria by Plasmodium yoelii

Abstract

The liver efficiently restores function after damage induced during malarial infection once the parasites are cleared from the blood. However, the molecular events leading to the restoration of liver function after malaria are still obscure. To study this, we developed a suitable model wherein mice infected with Plasmodium yoelii (45% parasitemia) were treated with the antimalarial ␣/␤-arteether to clear parasites from the blood and, subsequently, restoration of liver function was monitored. Liver function tests clearly indicated that complete recovery of liver function occurred after 25 days of parasite clearance. Analyses of proinflammatory gene expression and neutrophil infiltration further indicated that hepatic inflammation, which was induced immediately after parasite clearance from the blood, was gradually reduced. Moreover, the inflammation in the liver after parasite clearance was found to be correlated positively with oxidative stress and hepatocyte apoptosis. We investigated the role of heme oxygenase 1 (HO-1) in the restoration of liver function after malaria because HO-1 normally renders protection against inflammation, oxidative stress, and apoptosis under various pathological conditions. The expression and activity of HO-1 were found to be increased significantly after parasite clearance. We even found that chemical silencing of HO-1 by use of zinc protoporphyrin enhanced inflammation, oxidative stress, hepatocyte apoptosis, and liver injury. In contrast, stimulation of HO-1 by cobalt protoporphyrin alleviated liver inflammation and reduced oxidative stress, hepatocyte apoptosis, and associated tissue injury. Therefore, we propose that selective induction of HO-1 in the liver would be beneficial for the restoration of liver function after parasite clearance.

Association of Heme Oxygenase 1 with Lung Protection in Malaria-Associated ALI/ARDS

“…HO-1 showed a protective role in experimental episodes of severe malaria, including cerebral malaria [15, 16, 31]. Moreover, treatment with HO-1 inhibitors such as zinc protoporphyrin IX (ZnPPIX) or tin protoporphyrin IX (SnPPIX) led to an enhancement of ALI/ARDS signals in the case of sepsis but had no effect in the cases of hyperoxia and experimental cerebral malaria [16, 24, 32].…”

Antimalarial Activity of Small-Molecule Benzothiazole Hydrazones

“…We performed animal drug testing under highly parasitemic conditions to determine the drug efficacy when the number of parasites is high enough to cause physiological stress in the host (47). Moreover, under such conditions, we were able to compare the lead molecule with the frontline antimalarial ␣/␤-arteether that is known to be effective in a similar situation (47). Compound 5f significantly suppressed the parasite growth.…”

“…Therefore, after confirming the activity of compound 5f in chloroquine-sensitive and -resistant P. falciparum strains, we used an MDR P. yoelii parasite for in vivo drug testing. We performed animal drug testing under highly parasitemic conditions to determine the drug efficacy when the number of parasites is high enough to cause physiological stress in the host (47). Moreover, under such conditions, we were able to compare the lead molecule with the frontline antimalarial ␣/␤-arteether that is known to be effective in a similar situation (47).…”

Current and innovative emerging therapies for porphyrias with hepatic involvement

“…carbon monoxide, biliverdin and bilirubin) and compromise their cytoprotective, antioxidant and antiinflammatory effects. 44,45 The livers of most patients with AHP function normally despite the specific inherited enzyme deficiencies and periodic dysregulation of haem biosynthesis. Thus, transfer of a normal copy of cDNA to hepatocytes by means of an rAAV vector is a potentially durable approach to restore the specific enzyme deficiency.…”