Tempol, an Intracellular Antioxidant, Inhibits Tissue Factor Expression, Attenuates Dendritic Cell Function, and Is Partially Protective in a Murine Model of Cerebral Malaria

Francischetti, Ivo M.B.; Gordon, Emile B.; Bizzarro, Bruna; Gera, Nidhi; Andrade, Bruno B.; Oliveira, Fabiano; Ma, Dongying; Assumpção, Teresa C.F.; Ribeiro, José M. C.; Peña, Mirna; Chen, Qi; Diouf, Ababacar; Moretz, Samuel E.; Long, Carole A.; Ackerman, Hans; Sá-Nunes, Anderson; Waisberg, Michael

doi:10.1371/journal.pone.0087140

Cited by 39 publications

(32 citation statements)

References 139 publications

(219 reference statements)

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“…To address whether this dynamic expression of surface markers was confounding our interpretation of which monocyte subset expresses TF in response to LPS, we sorted the three major monocyte subsets based on the dichotomous surface expression of CD14 and CD16 (CD14 ++ CD16 - , CD14 + CD16 + and CD14 dim CD16 + ), stimulated each subset with LPS and then examined TF expression in cell lysates and measured TF functional activity by a colorimetric assay which quantifies the formation of the coagulation factor Xa (27) (Figure 1E). In unstimulated conditions, TF protein expression and functional activity by each monocyte subset was uniformly low in cultures (Figure 1E).…”

Section: Resultsmentioning

confidence: 99%

Inflammatory monocytes expressing tissue factor drive SIV and HIV coagulopathy

et al. 2017

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In human immunodeficiency virus (HIV) infection, persistent inflammation despite effective antiretroviral therapy (ART) is linked to increased risk of non-infectious chronic complications such as cardiovascular and thromboembolic disease. A better understanding of inflammatory and coagulation pathways in HIV infection is needed to optimize clinical care. Markers of monocyte activation and coagulation independently predict morbidity and mortality associated with non-AIDS events. In this study, we identified a specific subset of monocytes that express tissue factor (TF), persist after virological suppression and trigger the coagulation cascade by activating factor X. This subset of monocytes expressing TF had a distinct gene signature with upregulated innate immune markers as well as evidence of robust production of multiple proinflammatory cytokines including IL-1β, TNF-α, and IL-6 ex vivo and in vitro upon LPS stimulation. We validated our findings in a nonhuman primate model, showing that TF-expressing inflammatory monocytes were associated with SIV-related coagulopathy in the progressive (pigtail macaques) but not the non-pathogenic (African Green Monkeys) SIV infection model. Lastly, Ixolaris, an anti-coagulant that inhibits the TF pathway, was tested and potently blocked functional TF activity in vitro in HIV and SIV infection without affecting monocyte responses to toll-like receptor (TLR) stimulation. Strikingly, in vivo treatment of chronically infected PTMs with Ixolaris was associated with significant decreases in D-dimer and immune activation. These data suggest that TF expressing monocytes are at the epicenter of inflammation and coagulation in chronic HIV and SIV infection and may represent a potential therapeutic target.

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Section: Resultsmentioning

confidence: 99%

Inflammatory monocytes expressing tissue factor drive SIV and HIV coagulopathy

et al. 2017

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“…Tempol (Tmp) is a SOD-mimetic drug that efficiently neutralizes ROS [43]. These drugs were administered daily by gavage.…”

Section: Resultsmentioning

confidence: 99%

Resveratrol Reverses Functional Chagas Heart Disease in Mice

et al. 2016

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Chronic chagasic cardiomyopathy (CCC) develops years after acute infection by Trypanosoma cruzi and does not improve after trypanocidal therapy, despite reduction of parasite burden. During disease, the heart undergoes oxidative stress, a potential causative factor for arrhythmias and contractile dysfunction. Here we tested whether antioxidants/ cardioprotective drugs could improve cardiac function in established Chagas heart disease. We chose a model that resembles B1-B2 stage of human CCC, treated mice with resveratrol and performed electrocardiography and echocardiography studies. Resveratrol reduced the prolonged PR and QTc intervals, increased heart rates and reversed sinus arrhythmia, atrial and atrioventricular conduction disorders; restored a normal left ventricular ejection fraction, improved stroke volume and cardiac output. Resveratrol activated the AMPK-pathway and reduced both ROS production and heart parasite burden, without interfering with vascularization or myocarditis intensity. Resveratrol was even capable of improving heart function of infected mice when treatment was started late after infection, while trypanocidal drug benznidazole failed. We attempted to mimic resveratrol’s actions using metformin (AMPK-activator) or tempol (SOD-mimetic). Metformin and tempol mimicked the beneficial effects of resveratrol on heart function and decreased lipid peroxidation, but did not alter parasite burden. These results indicate that AMPK activation and ROS neutralization are key strategies to induce tolerance to Chagas heart disease. Despite all tissue damage observed in established Chagas heart disease, we found that a physiological dysfunction can still be reversed by treatment with resveratrol, metformin and tempol, resulting in improved heart function and representing a starting point to develop innovative therapies in CCC.

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“…Rather, we next tested TPL, an SOD mimetic that has been shown to cross biological membranes (39) and effectively scavenge superoxide (55–58). A recent study in experimental cerebral malaria showed TPL slightly increased survival in treated mice (59). Similar to that model, i.p.…”

Section: Discussionmentioning

confidence: 99%

Oxidative Stress: A Potential Therapeutic Target in Placental Malaria

et al. 2017

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Placental malaria, characterized by sequestration of Plasmodium falciparum in the maternal placental blood space and associated inflammatory damage, contributes to poor birth outcomes and ~200,000 infant deaths annually. Specific mechanisms that contribute to placental damage and dysfunction during malaria are not completely understood. To investigate a potential role for oxidative stress, antioxidant genes and markers for oxidative damage were assessed by quantitative PCR and immunohistochemistry in Plasmodium chabaudi AS-infected pregnant mice. Widespread evidence of lipid peroxidation was observed and was associated with higher antioxidant gene expression in conceptuses of infected mice. To assess the extent to which this oxidative damage might contribute to poor birth outcomes and be amenable to therapeutic intervention, infected pregnant mice were treated with N-acetylcysteine, a free radical scavenger, or tempol, an intracellular superoxide dismutase mimetic. The results show that mice treated with N-acetylcysteine experienced malaria induced–pregnancy loss at the same rate as control animals and failed to mitigate placental oxidative damage. In contrast, tempol-treated mice exhibited subtle improvement in embryo survival at gestation day 12. Although lipid peroxidation was not consistently reduced in the placentas of these mice, it was inversely related to embryo viability. Moreover, reduced IFN-γ and CCL2 plasma levels in treated mice were associated with midgestational embryo viability. Thus, although oxidative stress is remarkable in placental malaria and its mitigation by antioxidant therapy may improve pregnancy outcomes, the underlying mechanistic basis and potential therapeutic strategies require additional investigation.

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Tempol, an Intracellular Antioxidant, Inhibits Tissue Factor Expression, Attenuates Dendritic Cell Function, and Is Partially Protective in a Murine Model of Cerebral Malaria

Cited by 39 publications

References 139 publications

Inflammatory monocytes expressing tissue factor drive SIV and HIV coagulopathy

Inflammatory monocytes expressing tissue factor drive SIV and HIV coagulopathy

Resveratrol Reverses Functional Chagas Heart Disease in Mice

Oxidative Stress: A Potential Therapeutic Target in Placental Malaria

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