Sepsis and CIP
CIP is a pathology often observed in patients hospitalized in intensive care units. Its incidence varies according to the diagnostic criteria which are used: 25% on clinical criteria, but more than 50% in the case of electromyographic exploration. The CIP is characterized by muscular atrophy, weakness and a muscle hypoexcitability particularly affecting the appendicular muscles (distal muscles) but also the diaphragm. The diaphragmatic attack mainly leads to a difficulty of weaning from mechanical ventilation (increase in the length of hospitalization and additional costs). In the most severe cases (septic shock), heart failure can be observed with a possible fatal issue. The incidence of this neuromuscular pathology is increasing for 40 years because of the ageing of the population and associated co-morbidities. It is responsible for more or less debilitating late effects secondary to the seriousness of the initial infringement. Different factors are involved in the triggering of this pathology: sepsis, systemic inflammatory response with release of cytokines, prolonged bed rest and muscle disuse are the most often cited factors. Chronic murine sepsis model by induced peritonitis that reproduced the weakness and the muscle hypoexcitability observed in patients is used in our lab to study some aspects of the pathophysiology of the CIP.
Immunostaining of myofibrillar ATPases
Effect of sepsis on contraction and muscle excitability
Sepsis causes a decrease in contractile force related to muscle atrophy and an evolution towards a faster profile as well as an increase in the muscle fatigability. At the level of the motor unit (basic functional unit ofthe contraction), we showed that the synaptic delay was increased without an alteration of the electromechanical delay or of the speed of conduction. We have also evidenced that sepsis induced an alteration of the fast voltage gated sodium channels (NaV) responsible for this delay but also decreased the excitability of the sarcolemma.
Preliminary work showed that sepsis induced a decrease in ventilatory efficiency related in part to a reduction in force and an increase in fatigue of diaphragm by preferential recruitment of the fast fibres.
During chronic sepsis, it has been also observed an overexpression of the mRNA and protein of the channel NaV1.4, which contributes to the muscle membrane hypoexcitability.
Role of cytokines on muscle excitability
Cytokines released in the early hours of the sepsis also play a role in the decrease of the muscle membrane excitability during the initial phase of sepsis by a post-traductionnal mechanism. Indeed, a study performed in vitro on isolated muscle fibers showed rapid effects of TNFa (Tumor necrosis factor a) on the sodium currents, namely a fast but incomplete and reversible inhibition. This effect was related to the activation of the PKC and the phosphorylation of sites located on the sodium channel alpha subunit. TNFa also increases the resting potential of the muscle fiber. Both effects contribute to the muscle hypoexcitability.
Ongoing works are intended to establish the responsibility of TNF a in the early heart failure observed in septic shock. On a model of isolated-perfused heart, TNFa decreases the cardiac contractile force both by coronary flow reduction but also by direct effect on cardiomyocytes. The cardiac effects of TNFa are fast and reversible. The mechanisms of action of TNFa on myocardial infarction and coronary flow are subject to current work.
Considering the sepsis, it is accepted that an anti-inflammatory response takes place during the early phase with release of IL-13, IL-10... Preliminary results show a beneficial but inconstant effect of IL-13 according to the muscle or the type of fiber: increase of the sodium current, reduction in fatigability. The intracellular pathways involved in opposing and/or variables of these cytokines remain to be elucidated. One of the possibilities is the interrelation between redox status/oxygen species and cytokines.
Effects of biomolecules from a plant with antioxidant and anti-inflammatory activity
In collaboration with the University of Tunis (laboratory of extremophiles, Pr R. Ksoury), we test the anti-inflammatory and antioxidant extracts of halophytes properties or chemical compounds isolated on cell models or animals. The goal is to detect biomolecules of therapeutic interest capable of partly reducing the muscle catabolism involved in muscle atrophy and mitochondrial dysfunction.
UFR Sciences et Techniques, Université de Bretagne Occidentale
6 Av. Le Gorgeu - CS 93837
29238 BREST Cedex 3 - FRANCE
Directrice : C.MOISAN (+332.98.01.62.63)
Directrice adjointe: M-A.GIROUX-METGES(+332.98.01.80.67)