Abstract
We have investigated the impact of persistent intravascular hemolysis on liver dysfunction using the mouse malaria model. Intravascular hemolysis showed a positive correlation with liver damage along with the increased accumulation of free heme and reactive oxidants in liver. Hepatocytes overinduced heme oxygenase-1 (HO-1) to catabolize free heme in building up defense against this pro-oxidant milieu. However, in a condition of persistent free heme overload in malaria, the overactivity of HO-1 resulted in continuous transient generation of free iron to favor production of reactive oxidants as evident from 2',7'-dichlorofluorescein fluorescence studies. Electrophoretic mobility shift assay documented the activation of NF-κB, which in turn up-regulated intercellular adhesion molecule 1 as evident from chromatin immunoprecipitation studies. NF-κB activation also induced vascular cell adhesion molecule 1, keratinocyte chemoattractant, and macrophage inflammatory protein 2, which favored neutrophil extravasation and adhesion in liver. The infiltration of neutrophils correlated positively with the severity of hemolysis, and neutrophil depletion significantly prevented liver damage. The data further documented the elevation of serum TNFα in infected mice, and the treatment of anti-TNFα antibodies also significantly prevented neutrophil infiltration and liver injury. Deferoxamine, which chelates iron, interacts with free heme and bears antioxidant properties that prevented oxidative stress, NF-κB activation, neutrophil infiltration, hepatocyte apoptosis, and liver damage. Furthermore, the administration of N-acetylcysteine also prevented NF-κB activation, neutrophil infiltration, hepatocyte apoptosis, and liver damage. Thus, hepatic free heme accumulation, TNFα release, oxidative stress, and NF-κB activation established a link to favor neutrophil infiltration in inducing liver damage during hemolytic conditions in malaria.
Highlights
Multiorgan failure is evident in conditions of intravascular hemolysis
We demonstrated that heme overload and oxidative stress activated the transcriptional factor NF-B, which in turn enhanced neutrophil infiltration and extravasation through the up-regulation of intercellular adhesion molecules and chemokines
We have presented evidence to support a positive correlation between intravascular hemolysis and liver damage using malaria as a model where hemolysis is prevalent
Summary
Results: Persistent intravascular hemolysis in malaria causes liver damage because of excess hepatic free heme accumulation, TNF␣ release, NF-B activation, and neutrophil infiltration. Hepatic free heme accumulation, TNF␣ release, oxidative stress, and NF-B activation established a link to favor neutrophil infiltration in inducing liver damage during hemolytic conditions in malaria. In conditions of persistent hemolysis and continuous supply of heme, HO-1 is overinduced and generated huge quantities of free iron, which may cross the limit of its ferritin sequestration This chaos or failure of the cytoprotective system leads to severe oxidative stress-mediated cell death through necrosis and apoptosis [15, 20, 21]. We provide evidence that intravascular hemolysis in malaria damages liver as a result of increased accumulation of free heme and reactive oxidants in liver, which favor neutrophil infiltration. The chelation of free iron, scavenging of reactive oxidants, and depletion of neutrophil significantly prevented liver damage during malaria in mice
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