Déterminants nutritionnels et endocriniens de la réaction inflammatoire.

Abstract

L' organisme agresse repond par une hyperproduction locale et systemique de cytokines declenchant la cascade des reactions inflammatoires. Une secretion accrue d' hormone de croissance, de cortisol, de glucagon et de catecholamines induit une resistance generale a l' insuline. La mise au repos de l' axe hypothalamo-hypophyso-thyroidien, avec inhibition de l' enzyme 5'-desiodase (5'-DA), renforce la situation hypometabolique. Le foie et les tissus leses s' adaptent selon des voies metaboliques deconnectees des systemes de controle centraux. Les cytokines entrainent un rearrangement transcriptionnel des priorites de synthese hepatique avec surproduction des marqueurs inflammatoires et effondrement des proteines refletant l' etat nutritionnel. Agissant comme des reservoirs pro-hormonaux, la transthyretine (TTR) et la proteine vectrice du retinol (RBP) liberent, du fait de leur chute, des concentrations croissantes de T4 et de retinol libres. Ces ligands liberes sont convertis par la 5'-DA et le recepteur C-RBP-I intra-hepatiques en mediateurs nucleaires actifs stimulant les reactions dependantes de T4 et du retinol. TTR et RBP jouent donc un role central dans cette evolution en modulant les effets induits par les cytokines. La capacite pour l' organisme agresse de mettre en place des reponses adequates est conditionnee par l' etat nutritionnel preexistant.

The injured body manifests a cascade of cytokine-induced metabolic responses aiming at developing defense mechanisms and tissue repair. Rising concentrations of counterregulatory hormones (cortisol, glucagon, catecholamines) and of growth hormone (GH) generate a stage of insulin resistance in healthy tissues, due to an acquired insulin post-receptor defect. The depression of both pituitary-thyroid axis and IGF-I production by the liver accounts for the slackening of energy and anabolic processes as the entire body economy is moving towards lipid dependency. The liver and damaged tissues react along pathways disconnected from central regulatory systems. Cytokines promote the hepatic transcriptional synthesis of acute-phase reactants at the expense of acute-booster reactants, notably transthyretin (TTR), retinol binding protein (RBP) and transcortin (CBG). Working as prohormonal reservoirs, TTR and RBP release substantial amounts of thyroxine and of retinol in the free from, allowing the overstimulation of ligand-dependent processes. The enzymatic cleavage of CBG and TBG by activated neutrophils, and that of the main carrier-protein (BP3) of IGF-I in the bloodstream allows peak endocrine and mitogenic influences at the site of inflammation. Energy supply of the injured territory is insured by glycolytic anaerobiosis. Healthy tissues and damaged territory thus manifest divergent patterns of response to stressful agents. This adaptive dichotomy is strongly influenced by the preexisting nutritional status as assessed by TTR and RBP blood values. Following the free hormonal concept, the amplitude of thyro- and retinol-induced processes are determined by the fluxes of ligands released in free from, meaning proportionate to the decrement of their specific carrier-proteins. The review provides further insight into the molecular mechanisms whereby malnourished patients with low TTR and RBP blood concentrations display inappropriate responses and incur the risk of higher mortality rates.