Adaptive Cytoprotection and the Brain-Gut Axis

Abstract

Adaptive cytoprotection is a concept to counteract against the gastric mucosal injury caused by stress, strong irritants and drugs such as non-steroidal anti-inflammatory drugs. The process is mediated through diverse mediators and mechanisms. Studies on adaptive cytoprotection began from the discovery of prostaglandin (PG)-dependent and PG-independent pathways, followed by the investigation on the types and concentrations of mild irritants to be used. Upon the confirmation on the importance of the vagus nerve and the vago-vagal pathway in regulating the mucosal protective actions of the mild irritants, individual participating mediators for the neuronal modulatory processes were explored, including peptide neurotransmitters such as calcitonin gene-related peptide and substance P. Further correlation with the sympathetic nervous system, the sensory afferent neurons and the enteric nervous system of the gastric mucosa had been made. A close working relationship between the hypothalamic-pituitary-adrenal axis, the autonomic nervous system and the enteric nervous system was then proposed, with concurrent regulation of PG, nitric oxide and sensory neuropeptides by different mild irritants. Apart from these conventional concepts, there are now contemporary ideas on newer forms of adaptive cytoprotection such as ischemic preconditioning and heat-shock proteins, which will cast new light to novel approaches in facilitating gastric mucosal protection.

Moderate ethanol ingestion and cardiovascular protection: From epidemiologic associations to cellular mechanisms

“…Subsequent studies directed at examining the mechanisms whereby low concentrations of ethanol confer protection against noxious perturbations in the stomach have revealed an important role for prostaglandins, especially PGE 2 acting via EP1 receptors [171-180]. Other work has implicated a co-regulatory relationship between NO and prostaglandins, increased glutathione, activation of gastric dopamine or β2-adrenergic receptors, improved mucosal blood flow, enhanced mucus secretion, stimulation of the internal enteric reflex, increased salivary secretions, prevention of intracellular calcium accumulation, and the formation of a protective layer of surface debris in the development of the defensive phenotype induced by ethanol exposure [176-179,181]. In addition to these mechanisms, antecedent ethanol exposure has been shown to limit the production of proinflammatory mediators such as leukotriene C4, an effect which may limit disturbances in microcirculatory function that otherwise would produce severe mucosal injury during subsequent exposure to necrotizing stimuli [176].…”

“…Other work has implicated a co-regulatory relationship between NO and prostaglandins, increased glutathione, activation of gastric dopamine or β2-adrenergic receptors, improved mucosal blood flow, enhanced mucus secretion, stimulation of the internal enteric reflex, increased salivary secretions, prevention of intracellular calcium accumulation, and the formation of a protective layer of surface debris in the development of the defensive phenotype induced by ethanol exposure [176-179,181]. In addition to these mechanisms, antecedent ethanol exposure has been shown to limit the production of proinflammatory mediators such as leukotriene C4, an effect which may limit disturbances in microcirculatory function that otherwise would produce severe mucosal injury during subsequent exposure to necrotizing stimuli [176]. The latter observation led Dinda and coworkers [182] to propose that ethanol-induced adaptive cytoprotection is due to inhibition of neutrophil infiltration.…”

“…The mechanisms underlying ethanol-induced adaptive cytoprotection in the small bowel also appear to involve the production of prostaglandins [176,179,182]. However, it is important to emphasize that the intraluminal ethanol levels (20-100% ethanol) to which the small intestine was exposed in these studies, while relevant to the stomach, far exceeded those present in downstream segments of the gastrointestinal tract following oral intake.…”

Role of Vagus Nerve in Gastroduodenal Adaptation and Cytoprotection

“…In addition, the afferent nerve shutdown is accompanied by a decrease of adaptive reactions in microvascular circulation and mucusbicarbonate barrier (protection). So toxic agents diffusion (including hydrochloric acid) induces a rapid increase of the local blood flow due to the afferent nerves stimulation [10]. This effect is caused by the afferent releasing calcitonin gene-related peptide (CGRP) and substance P in the area of arterioles and so resulting in vasodilation.…”

“…The intensity of cerebral phase depends on multiple settings: activation of conditioned reflexes by the sense of smell and taste receptors of the tongue, and mechanical stimulation of the stomach and intestine chemoreceptors. Afferents activation of the gastroduodenal mucosa leads to the switching on of local (intramural) and vago-vagal (or extramural) reflexes that impact on the motility, mucus and secretion of the digestive juices and cytoprotection in GDA [10]. However, what signals determine the activation of afferent nerve fibers, and how does local protective system responses against the effects of aggressive exogenous and endogenous factors?…”