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

Abstract

Liver efficiently restores function after damage induced during malarial infection once the parasites get 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 an antimalarial, α/β-arteether to clear parasites from the blood and subsequently restoration of liver function was followed. Liver function tests clearly indicated that complete recovery of liver function occurred after 25 days of parasite clearance. The analysis of pro-inflammatory gene expression and neutrophil infiltration further indicated that hepatic inflammation, which was induced immediately after parasite clearance from the blood got reduced gradually. Moreover, the inflammation in liver after parasite clearance was found to be positively correlated with oxidative stress and hepatocyte apoptosis. We investigated the role of HO-1 in the restoration of liver function after malaria because heme oxygenase 1 (HO-1) normally renders protection against inflammation, oxidative stress and apoptosis under various pathological conditions. The expression as well as the activity of HO-1 was found to be significantly increased after parasite clearance. We even found that chemical silencing of HO-1 by zinc protoporphyrin enhanced inflammation, oxidative stress, hepatocyte apoptosis and liver injury. In contrast, stimulation of HO-1 by cobalt protoporphyrin alleviated liver inflammation, reduced oxidative stress, hepatocyte apoptosis and associated tissue injury. Therefore, we propose that selective induction of HO-1 in liver would be beneficial for the restoration of liver function after parasite clearance.