5-Lipoxygenase plays a role in the control of parasite burden and contributes to oxidative damage of erythrocytes in murine Chagas’ disease

Abstract

Chagas' disease is accompanied by severe anemia and oxidative stress, which may contribute to mortality. In this study, we investigated the role of 5-lipoxygenase (5-LO) in the control of parasitism and anemia associated with oxidative damage of erythrocytes in experimental Trypanosoma cruzi infection. Wild-type C57BL/6, 129Sv mice treated or not with nordihydroguaiaretic acid (NDGA, 5-LO inhibitor), mice lacking the 5-LO enzyme gene (5-LO(-/-)) and inducible nitric oxide synthase gene (iNOS(-/-)) were infected with the Y strain of T. cruzi. Impairment of 5-LO resulted in increased numbers of trypomastigote forms in the blood and amastigote forms in the heart of infected mice. We assessed oxidative stress in erythrocytes by measuring oxygen uptake, induction time and chemiluminescence following treatment with tert-butyl hydroperoxide (TBH). Our results show that 5-LO metabolites increased lipid peroxidation levels in erythrocytes during the early phase of murine T. cruzi infection. NDGA treatment reduced oxidative damage of erythrocytes in C57BL/6 T. cruzi-infected mice but not in C57BL/6 iNOS(-/-) infected mice, showing that the action of NDGA is dependent on endogenous nitric oxide (NO). In addition, our results show that 5-LO metabolites do not participate directly in the development of anemia in infected mice. We conclude that 5-LO products may not only play a major role in controlling heart tissue parasitism, i.e., host resistance to acute infection with T. cruziin vivo, but in the event of an infection also play an important part in erythrocyte oxidative stress, an NO-dependent effect.

The Acute Phase ofTrypanosoma cruziInfection Is Attenuated in 5-Lipoxygenase-Deficient Mice

“…These results corroborate our in vivo findings that 5-LO −/− mice are more efficient at controlling parasitemia, but contrasts with previous in vitro findings showing LTs foster intracellular parasite killing [26, 38]. However, it is suggested in 5-LO −/− mice that an oxidative stress occurs by a leukotriene-independent pathway, since an increase in erythrocyte oxidative stress was observed in these animals [39]. Differences in experimental design between our study and previously published investigations warrant discussion.…”

“…Despite the relevance of LTs in T. cruzi killing by macrophages in vitro as well as in controlling blood parasite numbers in vivo [26, 37, 38], the oxidative balance in 5-LO −/− T. cruzi infected mice has been related to be 5-LO-pathway independent [39]. Different results for NO and cytokines productions were observed during the acute phase of T. cruzi Y strain infection of 5-LO −/− mice and it has been related to resistance [40] or susceptibility [41].…”

Characterization of the abomasal transcriptome for mechanisms of resistance to gastrointestinal nematodes in cattle

“…In addition, products of the 5-lipoxygenase pathway, a part of AA metabolism, are important mediators of inflammation. 5-lipoxygenase plays a major role in controlling parasite burden of Trypanosoma cruzi in mice [44]. Detailed link between lipid metabolism and the development of protective immunity and host resistance to parasitic infections in cattle is worthy of further investigation.…”

Kinetics of Serum and Local Leukotriene B<sub>4</sub> Response in Experimental Intravaginal Trichomoniasis by <i>T. vaginalis</i> Isolates from Symptomatic and Asymptomatic Women

“…However, some protozoan parasite as T. gondii may inhibit LTB 4 production whereas exogenous LTB 4 promoted intracellular killing of ingested T. gondii in human monocytes [59]. By using of LTB 4 receptor antagonist and genetic approaches (5-LO-deficient mice), researchers have demonstrated increased parasitemia in mice infected with T. cruzi [60] [61]. In Chagas disease, LTB 4 control parasite differentiation and proliferation in the infected host cells allowing the infection to progress to a chronic state.…”