Abstract
Oxidative stress plays an important role in the pathogenesis of falciparum malaria, a disease still claiming close to 1 million deaths and 200 million new cases per year. Most frequent complications are severe anemia, cerebral malaria, and immunodepression, the latter being constantly present in all forms of malaria. Complications are associated with oxidative stress and lipoperoxidation. Its final product 4-hydroxynonenal (4-HNE), a stable yet very reactive and diffusible molecule, forms covalent conjugates with proteins, DNA, and phospholipids and modulates important cell functions at very low concentrations. Since oxidative stress plays important roles in the pathogenesis of severe malaria, it appears important to explore the role of 4-HNE in two important malaria complications such as malaria anemia and malaria immunodepression where oxidative stress is considered to be involved. In this review we will summarize data about 4-HNE chemistry, its biologically relevant chemical properties, and its role as regulator of physiologic processes and as pathogenic factor. We will review studies documenting the role of 4-HNE in severe malaria with emphasis on malaria anemia and immunodepression. Data from other diseases qualify 4-HNE both as oxidative stress marker and as pathomechanistically important molecule. Further studies are needed to establish 4-HNE as accepted pathogenic factor in severe malaria.
Highlights
In malaria pathophysiology, oxidative stress plays an important role in many fatal endpoints of the disease [1, 2].Imbalance in redox metabolism may be important under two aspects
The impaired cell cycle and reduced receptor expression decreased the total cell yield and the yield of differentiated erythroid cells [69]. These results reconfirm the inhibitory role of HZ, identify 4-HNE as HZ-generated inhibitory molecule for proliferation and differentiation, and describe molecular targets of 4-HNE in erythroid progenitors possibly involved in the inhibition of erythropoiesis in malaria anemia
This study indicates that impaired monocyte motility may contribute to the immune depression and the frequent occurrence of secondary infections observed in malaria patients [71]
Summary
Oxidative stress plays an important role in many fatal endpoints of the disease [1, 2].Imbalance in redox metabolism may be important under two aspects. 4-HNE has received little attention by malariologists as yet, elevated levels of free, unconjugated 4-HNE had been described in RBCs of P. vinckei-infected mice as early as 1988 [41]; one study reported the growth inhibition of in vitro cultured parasites by 4-HNE [42], and the general presence of oxidative stress in malaria was detected long ago [43,44,45,46]. The onset of hemoglobin degradation and HZ formation at young trophozoite stage coincided with a significantly enhanced formation of 4-HNE and 4-HNE-membrane protein conjugates in parasitized RBCs, compared to nonparasitized control RBCs. The progressive HZ generation during parasite growth was accompanied by the increase of 4-HNE conjugates up to 15-fold higher levels in HZ-rich schizonts compared to young HZ-free ring-forms (Figure 3).
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