Lutter contre le paludisme en réduisant sa transmission? Présentation de la controverse

Abstract

La place de la lutte antivectorielle dans la lutte antipaludique en zone de forte ou moyenne endémie palustre (soit essentiellement en Afrique tropicale rurale) est actuellement l’objet d’une controverse. Le suivi à court terme des interventions ayant réduit la transmission, par exemple par pulvérisation intradomiciliaire d’insecticides ou par utilisation de moustiquaires imprégnées de pyréthrinoïde, montre une réduction importante de la morbidité et de la mortalité palustres. A l’opposé, la comparaison de plusieurs situations où les niveaux de transmission diffèrent, suggère que, sur le long terme, l’abaissement du niveau de transmission n’a pas d’autre conséquence que de retarder l’âge moyen de survenue des accès palustres sans modifier l’importance globale de la morbidité et de la mortalité dues au paludisme. L’apparente contradiction entre les résultats observés reflète des approches différentes. Elle est avant tout révélatrice de l’importance des défis que soulève la lutte contre le paludisme.

The main function of vascular smooth muscle tissue is the regulation of blood pressure through changes in the vascular tone. Two main factors regulate the contraction and relaxation of vascular smooth muscle cells: the cytosolic free Ca2+ concentration ([Ca2+](i)) and the Ca2+ sensitivity of the contractile elements. Schematically, constrictors increase [Ca2+](i) and the Ca2+ sensitivity of contractile apparatus while relaxant agonists have opposite effects. The sources of Ca2+ are both extracellular and intracellular. The sarcoplasmic reticulum (SR) is the physiological intracellular source of Ca2+. The Ca2+ storage capacity of SR involves intraluminal Ca2+ binding protein such as calsequestrin and calreticulin. Ca2+ is released from SR to the cytosol through InsP3 and ryanodine receptors for (InsP3-induced Ca2+ release and Ca2+-induced CA2+ release). During relaxation, the [Ca2+](i) is reduced in part by Ca2+ pumping into the SR by Ca2+-ATPase (SERCA). Several isoforms of SERCA are expressed in vascular smooth muscle. Ca2+ enters into vascular smooth cells through Ca2+ permeable ion channels. The capacitative Ca2+ entry and ligand-gated channels (P(2x)-purcinoceptors) allow extracellular Ca2+ to flow into the cytosol. However, voltage-dependent Ca2+ channels represent the main route for Ca2+ entry which is essentially modulated by the membrane potential. Ca2+-activated channels such as Cl- (Cl(Ca)) or K+ (K(Ca)) channels play a key role in the modulation of membrane potential. Activated Cl(Ca) channels depolarize whereas activated K(Ca) channels hyperpolarize the membrane thus causing increase and decrease in the vascular tone, respectively. Modulation of the force at constant [Ca2+](i) results from changes in the activities of kinases and phosphatases, acting on the regulatory light chain of myosin (MLC20) phosphorylation. Intracellular messages such as arachidonic acid or protein kinase modulate the activity of the MLC20 phosphatase and thus, the Ca2+ sensitivity. G protein-coupled Ca2+ sensitization also involves inhibition of the MLC20 phosphatase. Trimeric as well as monomeric G proteins (Rho p21, Ras p21) seem to be responsible for this mechanism. Recent studies, by identifying new regulatory mechanisms, provide a better understanding of the fundamental mechanisms regulating contractile properties of vascular smooth muscle and open new way for the treatment of vascular diseases. [References: 58]