Papel da heme oxigenase 1 na malária gestacional: estudo em três tempos gestacionais usando um modelo murino

Abstract

Malaria in pregnancy is a serious public health problem. Thousands of cases of newborns with low birth weight due to maternal infection by Plasmodium species are registered each year. Furthermore, the infection is capable of inducing other complications such as anemia, maternal death, abortion and premature birth. Heme oxygenase 1 (HO-1) is an enzyme that catalyzes the degradation of heme into biliverdin, iron and carbon monoxide and whose activity has been shown to be protective in several contexts, including pregnancy, although its induction has also been related to be harmful. However, the effect of HO-1 modulation on gestational malaria had not been previously described. For this reason, the role of HO-1 in Plasmodium berghei ANKA infection in early, mid and late gestation in BALB/c mice was evaluated in the present study. For this purpose, the mRNA expression levels of the enzyme at the maternal-fetal interface after infection and the effect of treatment of infected pregnant mice with an inducer (CoPPIX) or an inhibitor (ZnPPIX) of the enzyme's activity were evaluated. The results showed that the infection induces anemia, hypoglycemia, elevated heme levels, embryonic loss and decreased fetal weight. The expression of HO-1 mRNA in uterus/placenta increased in early and late gestation compared to uninfected controls in these gestational periods. An increase in iron deposition at implantation sites of the females on day 8 of gestation and 7 of infection was also observed. Inhibition of HO-1 led to an improvement in adverse pregnancy outcomes caused by the infection, especially in early pregnancy, in which there was a reduction in parasitism, iron deposition, oxidative stress and local levels of TNF, as well as an increase in the number of uterine NK cells, maternal hemoglobin and blood glucose levels. Although there is no induction of HO-1 in mid-pregnancy in response to infection, treatment with ZnPPIX decreases the rate of abnormal implantation sites and parasitemia levels, as well as increasing hemoglobin levels compared to infected females treated with vehicle. In late gestation, the beneficial effects of HO-1 inhibition were restricted to higher fetal weight, whereas HO-1 induction led to a decrease in placental IFN-γ levels. The protective effects of HO-1 inhibitor treatment diminished as pregnancy progressed. In conclusion, the expression of HO-1 seems to contribute to the adverse outcomes caused by infection during pregnancy and its modulation seems to be necessary to guarantee gestational success, especially in early pregnancy.