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Increased Cholinergic Signaling leads to Respiratory distress/arrest
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Acetylcholinesterase inhibition leading to acute mortality||adjacent||High||Low||Dan Villeneuve (send email)||Under Development: Contributions and Comments Welcome||Under Development|
Life Stage Applicability
Key Event Relationship Description
Respiratory distress as a result of increased cholinergic signalling due to AChE inhibition occurs through combined peripheral and central cholinergic effects.
Evidence Collection Strategy
Evidence Supporting this KER
The link between increased cholinergic signalling and respiratory distress/failure is based on respiratory manifestations observed in many organisms and what is well-understood about cholinergic signalling, which is mediated by both muscarinic and nicotinic receptors.
1. Nicotinic Respiratory paralysis (Wadia 1974),
2. Muscarinic- Central respiratory depression (Costa, Peter 2014), rhinorrhea, bronchorrhea, bronchospasm (Peter 2014), increased bronchial secretions (Costa, Buels 2012), bronchoconstriction (Costa, de Candole 1953, Buels 2012), neuromuscular block at the diaphragm, potentially leading to inability to regulate movements of the diaphragm (de Candole 1953).
Nicotinic acetylcholine receptors (nAChRs) are expressed in brain and spinal cord regions in control of breathing, and mediate central cholinergic regulation of respiration. Activation of nAChRs in the the preBötzinger Complex (preBötC), an essential site for normal respiratory rhythm generation in mammals, modulates excitatory glutamatergic neurotransmission and depolarizes preBötC inspiratory neurons, leading to increases in respiratory frequency. nAChRs are also present in motor nuclei innervating respiratory muscles. Activation of post- and/or extra-synaptic alpha4* nAChRs on hypoglossal (XII) motor neurons depolarizes these neurons, potentiating tonic and respiratory-related rhythmic activity (Shao 2009).
In humans, early acute mixed central and peripheral respiratory failure. Early respiratory failure in humans involves depression of central respiratory drive from the respiratory center in the ventrolateral medulla, respiratory muscle weakness, and direct pulmonary effects such as bronchospasm and bronchorrhea. (Eddleston 2007).
The first signs of OP poisoning to appear are usually muscarinic, followed by nicotinic signs. Early respiratory failure may not display clear cut symptoms (Costa). A study of neurological signs in humans exposed to OP compounds found impaired consciousness in 10%, fasciculations in 27%, convulsions in 1%, toxic delirium in 50%, and paralysis in 26%. Type 1 signs were present on admission, while type 2 signs appeared later. Type 1 signs, such as impaired consciousness and bilateral pyramidal tract signs, respond to atropine. Of 36 cases with type 2 signs (proximal limb weakness, areflexia, and cranial nerve palsies), 15 died from respiratory paralysis after a variable period of artificial respiration (Wadia 1974).
A study of OP poisoning in humans found that of 376 patients, 90 (24%) required intubation: 52 (58%) within 2 h of admission while unconscious with cholinergic features. Twenty-nine (32%) were well on admission but then required intubation after 24 h while conscious and without cholinergic features. These two syndromes were not clinically distinct and had much overlap. In particular, some patients who required intubation on arrival subsequently recovered consciousness but could not be extubated, requiring ventilation for up to 6 days (Eddleston 2006).
In animal models, ventilation can be impaired through bronchoconstriction, neuromuscular block, and central respiratory failure, with central failure being the predominant factor (De Candole 1953, Peter 2014). Disruption of the normal firing pattern of medullary respiratory-related neurons is followed by changes in phrenic nerve activity, diaphragm EMG, diaphragm contraction and airflow (Rickett 1986).
In fish, reduced uptake of oxygen by the gills due to reduced respiratory surface area, as a result of direct toxicant effects on the gills. Inhibition of AChE in the gills would result in continuous stimulation of neural-muscular junctions and cause sphincters at the base of the efferent filamental arteries to constrict, reducing blood flow through the secondary lamellae (McKim 1987).
Uncertainties and Inconsistencies
- There is abundant evidence that increased cholinergic signalling leads to respiratory failure in many organisms. There is one area of uncertainty, which relates to how the balance of nicotinic and muscarinic effects lead to respiratory failure. It is unclear which mechanism predominates and greater understanding of these mechanisms could help inform therapeutic intervention strategies.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
- Cats - see Rickett 1986, cited above
Buels, K.S., Fryer, A.D. 2014. Muscarinic Receptor Antagonists: Effects on Pulmonary Function. Handb Exp Pharmacol. 2012; (208): 317–341.
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Eddleston M, Mohamed F, Davies JO, Eyer P, Worek F, Sheriff MH, Buckley NA. 2006. Respiratory failure in acute organophosphorus pesticide self-poisoning. QJM. 99(8):513-22.
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