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Physiopathologie de la ventilation après modulation génétique et pharmacologique du système cholinergique : mise en place d’un modèle d’analyse de la ventilation par système de pléthysmographie double chambre

Abstract : Intoxications induced by cholinesterase (ChE) inhibitors (ChEIs) like organophosphorus compounds (OPs) or carbamates can be lethal. Although these intoxications affect many physiological functions, death is usually triggered by respiratory failure. Preventing respiratory failure is therefore the immediate therapeutic priority. The respiratory failure has been widely assumed to be due to an inhibition of ChEs in the brain, leading to a perturbation of the cholinergic synapses in the respiratory centers. But some data suggested the contribution of inhibition of peripheral ChEs. We tried to establish the relative roles of central and peripheral ChEs inhibitions in the respiratory failure induced by ChEIs. Using a double chamber plethysmograph to measure various respiratory parameters before and during the intoxications, we found that the development of long “end inspiratory pauses” (EIP) was a major cause of the depressed breathing during most intoxications. Comparing the effects of two ChEIs (paraoxon, physostigmine) which both cross the blood brain barrier with those of a ChEI which does not (pyridostigmine) supported the classical view that inhibition of central ChEs plays a major role in respiratory failure. However, the analysis of the effects of ChEIs on mice in which acetylcholinesterase (AChE) had been selectively deleted from either the central cholinergic synapses (PRiMA KO mice) or from the neuromuscular junction (NMJ) (Colq KO and AChE1iRR mice) indicated that inhibition of peripheral ChEs provokes the alteration of breathing and, more particularly, the development of EIPs. We hypothesize that this role involves a spillover of acetylcholine (Ach) from the NMJ and that the consequent ACh flood reach and activate peripheral ACh receptors, and we suggest that these receptors are those identified in the afferent pathway of the reflex which triggers EIPs in physiological conditions or when irritants are inhaled. Indeed, eucalyptol, a compound acting on receptors of afferent sensory neurons and known to reduce the EIPs triggered by irritants, strongly reduced the ChEI-induced EIP. In physiological conditions, ACh released at the NMJ is prevented from reaching the afferent pathways by two sets of ChEs, those of the NMJ and those of the blood and peripheral tissues. EIPs appear when both systems are blocked by ChEIs. Thus, in the treatment of ChEIs intoxications, exogenous AChE or butyrylcholinesterase (BChE) used as scavenger of OPs could also serve to clear neuronal ACh which could reach non-synaptic receptors normally activated by non-neuronal ACh.
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https://tel.archives-ouvertes.fr/tel-02469635
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  • HAL Id : tel-02469635, version 1

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Aurélie Nervo. Physiopathologie de la ventilation après modulation génétique et pharmacologique du système cholinergique : mise en place d’un modèle d’analyse de la ventilation par système de pléthysmographie double chambre. Neurosciences [q-bio.NC]. Université Sorbonne Paris Cité, 2018. Français. ⟨NNT : 2018USPCB230⟩. ⟨tel-02469635⟩

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