Abstract
Mechanical ventilation (MV) is the first treatment in intensive care for acute respiratory distress syndrome to maintain adequate tissue oxygenation. However, it induces an impairment of the contractile function of the respiratory muscles, particularly the diaphragm, thereby increasing the patient's dependence on his ventilator. This acquired muscle disease have been termed ventilator induced diaphragmatic dysfunction (VIDD). The aim of this thesis is to propose, from a mouse model of mechanical ventilation, early pathophysiologic mechanisms involved in this dysfunction, to identify new therapeutic targets in preventing VIDD.We observed after 6 hours of mechanical ventilation, a mitochondrial oxidative stress which induces ryanodine receptor (RyR1) oxidation, the main calcium channel involved in the ECC. We also showed the presence after an equivalent time of mechanical ventilation, phosphorylation of RyR1, due to protein kinase activation, secondary to an adrenergic stress. Then, we have demonstrated that these post-translational modifications of RyR1 should be necessarily associated to trigger a functional impairment of RyR1 with calcium leakage from the sarcoplasmic reticulum to the cytosol, due to the loss of connection between RyR1 and the stabilizing protein KBP12. In his thesis, we also showed that these calcium homeostasis disorders, induced by 12 hours of ventilation, secondary activates the dependent proteolysis calcium and atrophy.Thus, these results show the benefit of all therapy stabilizing the connection between the RyR1 channel and the FKBP12 protein to prevent VIDD. Indeed, were observed in mice, that a specific mitochondrial anti-oxidant treatment (SS-31), or a specific beta-blocker treatment of beta2 adrenergic pathway (ICI-118551 ) or a treatment that stabilizes directly FKBP12- binding RyR1 (S107 ) prevent early disorders of calcium homeostasis and secondary appearance of proteolysis and atrophy induced by mechanical ventilation.Finally, in the last part of my work thesis, I suggest that mitochondrial ROS production may be associated with remodeling of the mitochondrial network with a preponderance of mitochondrial fission phenomenon. This remodeling could be seen as an adaptation of the mitochondria due to a sudden mismatch between energy production and consumption. Indeed, we showed that an inhibitor of the mitochondrial fission (P110), which blocks the connection between the DRP1 protein and its receptor in our animal model of mechanical ventilation, could prevent the appearance of VIDD. Thus the continuity of this last work of my thesis is to make the link between mitochondrial fission and oxidative stress underlying the disorders of calcium homeostasis. Indeed, I hope to show that this treatment during mechanical ventilation, may decrease mitochondrial ROS production, oxidation of RyR1 channel and calcium leak through the RyR1. This last work will emphasis any therapeutic which limit mitochondrial fission and its consequences, to prevent VIDD.Keywords: RyR1, mitochondria, contractile dysfunction, VIDD, oxidative stress