Severe malaria pathogenesis involves both overproduction of inflammatory cytokines and cytoadherence of parasitized erythrocytes to the microvasculature, leading to local obstruction and hypoxia. Hypoxia and cytokines stimulate endothelial cells to produce endothelin-1 (ET-1), a vasoconstrictor peptide that, in turn, regulates the inflammatory response and, in pregnancy, is involved in pre-eclampsia. Active ET-1 derives from BigEndothelin-1 after processing by endothelin converting enzymes (ECE). To investigate whether, beyond parasite killing, antimalarial drugs could also play an anti-intlammatory role, the effects of quinolines and artemisinins antimalarials on the in vitro production of ET1 and inflammatory cytokines was tested. Human microvascular endothelial cell line (HMEC) treated with quinolines or arremisinin derivatives under normoxia or hypoxia were analyzed for the production of ET-1 and cytokines (IL-6, lL-8) by RT PCR and ELISA. The inhibition of constitutive or hypoxia-induced ET1 secretion by HMEC in the presence of quinolines or artemisinins was dose and time-dependent, and not due to direct toxicity. However, the mechanism of inhibition was different: quinolines, including chloroquine, inhibited the processing by ECE, but not the production, of the precursor Big-ET1 to active ET1. Activity was dependent upon the weak base properties of the drugs. On the contrary, artemisinins inhibited the synthesis of Big-ET1 indicating an effect on transcription. Modulation of cytokine secretion was also observed. These results may explain some of the pharmacological effects of antimalarial drugs such as hypotension after CQ treatment and suggest that their us in pregnancy could help preventing preeclarnpsia.

Anti-inflammatory and vasoactive properties of quinoline and artemisinins antimalarials : Modulation of endothelin-1 and cytokines production by microvascular endothelial cells / N. Basilico, S. Parapini, S. D’Alessandro, Y. Corbett, S. Finaurini, D. Taramelli. ((Intervento presentato al 5. convegno Multilateral Initiative on Malaria Pan-African Malaria Conference tenutosi a Nairobi, Kenya nel 2009.

Anti-inflammatory and vasoactive properties of quinoline and artemisinins antimalarials : Modulation of endothelin-1 and cytokines production by microvascular endothelial cells

N. Basilico
Primo
;
S. Parapini
Secondo
;
S. D’Alessandro;Y. Corbett;S. Finaurini
Penultimo
;
D. Taramelli
Ultimo
2009

Abstract

Severe malaria pathogenesis involves both overproduction of inflammatory cytokines and cytoadherence of parasitized erythrocytes to the microvasculature, leading to local obstruction and hypoxia. Hypoxia and cytokines stimulate endothelial cells to produce endothelin-1 (ET-1), a vasoconstrictor peptide that, in turn, regulates the inflammatory response and, in pregnancy, is involved in pre-eclampsia. Active ET-1 derives from BigEndothelin-1 after processing by endothelin converting enzymes (ECE). To investigate whether, beyond parasite killing, antimalarial drugs could also play an anti-intlammatory role, the effects of quinolines and artemisinins antimalarials on the in vitro production of ET1 and inflammatory cytokines was tested. Human microvascular endothelial cell line (HMEC) treated with quinolines or arremisinin derivatives under normoxia or hypoxia were analyzed for the production of ET-1 and cytokines (IL-6, lL-8) by RT PCR and ELISA. The inhibition of constitutive or hypoxia-induced ET1 secretion by HMEC in the presence of quinolines or artemisinins was dose and time-dependent, and not due to direct toxicity. However, the mechanism of inhibition was different: quinolines, including chloroquine, inhibited the processing by ECE, but not the production, of the precursor Big-ET1 to active ET1. Activity was dependent upon the weak base properties of the drugs. On the contrary, artemisinins inhibited the synthesis of Big-ET1 indicating an effect on transcription. Modulation of cytokine secretion was also observed. These results may explain some of the pharmacological effects of antimalarial drugs such as hypotension after CQ treatment and suggest that their us in pregnancy could help preventing preeclarnpsia.
Settore MED/04 - Patologia Generale
Anti-inflammatory and vasoactive properties of quinoline and artemisinins antimalarials : Modulation of endothelin-1 and cytokines production by microvascular endothelial cells / N. Basilico, S. Parapini, S. D’Alessandro, Y. Corbett, S. Finaurini, D. Taramelli. ((Intervento presentato al 5. convegno Multilateral Initiative on Malaria Pan-African Malaria Conference tenutosi a Nairobi, Kenya nel 2009.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/166726
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