Dr.Bogdan Paltineanu*,Dr.Flory Revnic**,Dr.Cristian Romeo Revnic***
*UMF Tg.Mures
**NIGG”Ana Aslan”
***Ambroise Pare`Hospital,University of Medicine, Paris VI, France
Rezumat
Aceasta lucrare este o trecere in revista a literaturii de specialitate care prezinta date recente despre implicarea barierei mucoasei gastrice potrivit carora, in absenta mucusului gastric, nu exista protectie. In timp ce acidul clorhidric, pepsina si H.pylori sunt considerate a fi factorii majori in fiziopatologici gastritei, importanta sistemului de aparare a fost de asemenea subliniata. Citoprotectia gastrica se refera la reducerea ori preventia eroziunilor hemoragice induse chimic de catre compusi precum prostaglandinele (PG) si derivatii SH fara inhibarea secretiei de acid la rozatoare. Intrucat conceptul de citoprotectie a fost introdus, s-a acordat o atentie sporita in privinta efectului medicatiei asupra mecanismelor de aparare ale mucoasei gastrice. Cu toate ca mecanismele exacte ale sistemului de aparare ale mucoasei gastrice nu sunt cunoscute, acesta implica unul sau mai multi factori de aparare precum metabolismul mucusului. Pentru estimarea functiei gastroprotectoare au fost investigate multe medicamente pentru activitatea acestora de a proteja mucoasa gastrica de o varietate de agenti necrozanti precum alcoolul si acidul clorhidric. Informatii considerabile au fost acumulate cu privire la functia gastroprotectoare a mucusului care acopera suprafata mucoasei stomacale.
Cuvinte cheie: mucoasa gastrica, citoprotectia, gastrita
Abstract
This review of literature data presents recent insights into the implication of the gastric mucus barrier as “no mucus, no protection”.While acid, pepsin, and H. pylori are thought to be major factors in the pathophysiology of gastritis, the importance of the mucosal defense system has also been emphasized. Gastric‘cytoprotection’ refers to a reduction or prevention of chemically induced acute hemorrhagic erosions by compounds such as prostaglandin (PG) and SH derivatives without inhibiting acid secretion in rodents (Robert, 1979; Szabo et al., 1981). Since the concept of ‘cytoprotection’ was introduced, increasing attention has been paid to the effect of medications on the gastric mucosal defensive mechanisms. Although the exact mechanisms of the mucosal defense system are unknown, it involves one or more of the naturally occurring gastric mucosal defensive factors such as mucus metabolism. For estimation of the gastroprotective function, many drugs have been investigated for their activity to protect the gastric mucosa from a variety of necrotizing agents such as ethanol and HCl. Considerable information has accumulated about the gastroprotective function of the mucus that covers the mucosal surface of the stomach.
Key words: gastric mucosa, cytoprotection, gastritis
Introduction
It is well known that gastric mucosa is continuously exposed to many noxious factors and substances. The gastric epithelium must also resist damage from extrinsic agents, including Helicobacter pylori (H.pylori) and noxious ingestions such as ethanol and nonsteroidal anti-inflammatory drugs (NSAIDs). The luminal surface of the stomach is covered by a viscoelastic mucus gel layer that acts as a protective barrier against the harsh luminal environment. The structural characteristics of this barrier are primary indicators of its physiological function and changes of its composition have been identified in gastrointestinal pathologies.
Since 200 years ago, clinicians and investigators have been concerned about finding out How the gastric mucosa maintains structural integrity and resists auto-digestion by substances such as acid and pepsin. The gastric epithelium must also resist damage from extrinsic agents, including Helicobacter pylori (H.pylori) and noxious ingestions such as ethanol and nonsteroidal anti-inflammatory drugs(NSAIDs). The luminal surface of the stomach is covered by a viscoelastic mucus gel layer that acts as a protective barrier against the harsh luminal environment. The structural characteristics of this barrier are primary indicators of its physiological function and changes of its composition have been identified in gastrointestinal pathologies.
Structure of second-generation H2-blockers
The H2-blockers are widely used these days in the treatment of gastritis. All the known H2-blockers comprise an aromatic ring with a flexible chain joined to a polar group. Despite considerable diversity, these compounds can be grouped into two main series according to the nature of the aromatic rings, namely five-membered and six-membered aromatic ring series. Cimetidine and ranitidine belong to the conventional group characterized by a five membered aromatic ring. Recently, some of the newer H2-blockers (so-called secondgeneration H2-blockers) have been reported to promote the gastric mucosal defense mechanisms [1,2,3]. Second-generation H2-blockers contain a six-membered aromatic ring, instead of a five-membered heterocyclic ring.
Of the four H2-blockers, lafutidine and roxatidine have a stimulant effect on mucin biosynthesis in the rat gastric mucosa. In contrast, first-generation H2-receptor antagonists such as cimetidine, ranitidine and famotidine, failed to stimulate mucin biosynthesis[3]. Second-generation H2-blockers,lafutidine and roxatidine, have been reported to prevent the formation of gastric mucosal lesions induced by necrotizing agents in rats [1,4], and this effect may be due not only to the inhibition of aggressive factors such as acid, but also to the maintenance of defensive factors such as mucus. On the other hand, many reports have indicated that cimetidine and ranitidine lack a protective effect against necrotizing agent-induced gastric mucosal damage in the rat [4,5].
It has been clarified that the second-generation H2-blockers have a unique structure, and not only inhibit acid secretion but also enhance the protective mechanisms of the gastric mucosa. This should stimulate new interest in the chemical analysis of these drugs to determine the structural requirements for their gastroprotective actions.
Compared with the structural requirements of the acid-inhibitory mechanisms of the H2-blockers, only a few detailed analyses have been reported of the structural aspects of their gastroprotective actions [3,6] because of the complicated mechanisms of mucosal protection. However, the cardinal chemical features of lafutidine that determine its mucin biosynthetic activity, as a quantitative index of its gastroprotective action, were identified by considering the structural analogs of this drug using an rat stomach organ culture system [3]. Compounds A, B and C bear the pyridine ring and compounds D and E bear the furan ring, which are commonly present in the structure of lafutidine. Mucin biosynthetic activity was increased by the addition of two pyridine derivatives, lafutidine and compound A. In contrast, compounds D and E, lacking a pyridine ring, failed to stimulate mucin biosynthesis. Similar results were obtained for compounds B and C, which have a pyridine ring but lack an amide structure. These results indicate that pyridine-based compounds containing an amide structure may be essential for activating the gastroprotective function. Furthermore, comparison with the H2-receptor antagonistic activities of these compounds suggests that H2-receptor antagonism is not directly correlated with lafutidine-induced stimulation of mucin biosynthesis.
A more detailed analysis has been performed using roxatidine and its structural analogs to reveal the structural requirements of second-generation H2-blockers for the stimulant effect on rat gastric mucin biosynthesis, particularly with regard to whether the cardinal features of roxatidine are only the six-membered aromatic ring and amide structure, and its relation to H2-receptor antagonism [7]. Of six compounds containing both a benzene ring and an amide structure, analogs A and B, but not C, stimulated mucin biosynthesis in a manner similar to that of roxatidine.
The mucin produced by human gastric gland mucus cells appears to function as a natural antibiotic, protecting the host from H. pylori [8].
Mechanisms of gastroprotective actions
Although the exact mechanisms that underlie the gastroprotective activity of the second generation H2-receptor antagonists are not well understood, recent findings suggest that the activation of capsaicin-sensitive sensory neurons is associated with their maintenance of gastric mucosal integrity[1,9,10,11].
The gastrointestinal tract is known to possess a rich neural network, among which afferent neurons of extrinsic origin are reported to operate as the emergency protective system. The discovery of these sensory neuron functions was made possible by capsaicin, a pharmacological tool with which the activity of certain primary afferent neurons can be manipulated selectively. Capsaicin is an excitotoxin that acutely stimulates a group of afferent neurons with unmyelinated (C) or thinly myelinated (Aδ) nerve fibers. This excitotoxic action is restricted to neurons with C- and Aδ-fibers because only these cells express receptor-binding sites (vanilloid receptor type 1: VR1) for capsaicin and structurally related ligands. The mammalian stomach, particularly the submucosa, is densely innervated with capsaicin-sensitive afferent neurons. These neurons not only serve a sensory and afferent role, but also display a local effector function initiated by the release of neuropeptide transmitters, such as calcitonin gene-related peptide (CGRP) and substance P, from their peripheral nerve endings. CGRP is reported to exhibit significant mucosal protective roles in the gastrointestinal tract[13]. The action of CGRP is in part mediated by endogenous NO.
The gastroprotective effects of lafutidine are decreased by treatment with NO synthase inhibitors or NO antidotes [14], indicating the involvement of NO generation in lafutidine function. Similar results have been obtained with another second-generation H2-receptor antagonist, roxatidine [15].
Lafutidine has been shown to enhance the healing of gastrointestinal mucosal lesions in a manner independent of its antacid secretory action [16,17].
Several studies show that luminal lafutidine stimulates capsaicin-sensitive afferent nerves via presumably direct diffusion rather than after its absorption from intestine followed by via circulation, suggesting the rapid local diffusion reaching to the afferents before H2-receptor blockade from the circulation (Onodera et al., 1999b; Nagahama et al., 2003).
Second-generation H2-receptor antagonists such as lafutidine are thought to facilitate capsaicin-sensitive sensory afferent nerves and exert gastroprotective effects through CGRP and in part via NO release in the stomach.
Conclusion
The gastric mucus barrier constituted by the layer of viscous mucus is crucial to the defense of gastric mucosa. The gastroprotective effects of second-generation H2-blockers may be of physiological relevance. Enhanced understanding of the mechanisms of gastric mucosal defense and injury provides new insight into potential therapeutic targets, which contributes towards the development of more well tolerated and more effective therapies.
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