Aspirin-induced Mucosal Damage Research Articles

Omeprazole taken once every other day can effectively prevent aspirin-induced gastrointestinal mucosal damage in rats

BackgroundProton-pump inhibitors (PPIs) prevent aspirin-associated gastric and duodenal mucosal damage. However, long-term use of PPIs can lead to various adverse reactions, such as gastric polyps and enterochromaffin-like cell hyperplasia. Current research indicates that the abovementioned adverse reactions are mainly related to hypergastrinemia. We investigated whether low-frequency administration of omeprazole could effectively repair aspirin-induced mucosal damage and reduce the increase in gastrin levels associated with long-term use of PPIs.MethodsSprague‒Dawley rats were divided into four treatment groups: daily aspirin, daily aspirin and omeprazole once every day (qd), daily aspirin and omeprazole once every other day (qod), and daily aspirin and omeprazole once every three days (1/d3). After 15 days of feeding, blood samples were collected, and the stomachs of sacrificed rats were subjected to macroscopic, histological, and immunohistochemical studies. Moreover, in clinical practice, patients with peptic ulcers caused by aspirin took a standard dose of omeprazole (20 mg) every other day. Two months later, gastroscopy was performed to examine the healing of the ulcers.ResultsBoth the omeprazole qd and omeprazole qod administrations effectively prevented aspirin-induced gastric peptic ulcers, with no significant difference between the two groups in the inhibition of parietal cell secretion of gastric acid and cell apoptosis. However, omeprazole 1/d3 failed to completely prevent aspirin-induced gastric mucosal injury. Notably, the gastrin levels, cell proliferation ability and cholecystokinin B receptor expression of the omeprazole qd group were significantly higher than those of the omeprazole qod group. In clinical work, patients with peptic ulcers caused by aspirin were given a standard dose of omeprazole every other day, and their ulcers healed after 2 months, as observed by gastroscopy.ConclusionsOmeprazole administration once every other day can effectively prevent aspirin-induced peptic ulcers and reduce hypergastrinemia, which may reduce the long-term adverse effects of PPI treatment.

Association of 72-kDa heat shock protein expression with adaptation to aspirin in rat gastric mucosa.

It is well documented that gastric mucosa can increase its resistance to mucosal damage caused by aspirin during repeated long-term administration of aspirin. However, the underlying mechanism of this adaptation is not well established. In the present study, we investigated the effect of long-term (chronic) administration of aspirin on expression of heat shock proteins (HSPs), which are known as endogenous cytoprotectants, in rat gastric mucosa. Rats were administered aspirin (100 mg/kg) daily for up to 20 days. After various periods of aspirin administration, a high dose of aspirin (250 mg/kg) was administered, and the mucosal damage was assessed. Expression of heat shock proteins (HSPs) in gastric mucosa was evaluated by Western blot. Intracellular localization of each HSP was studied immunohistochemically. Prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) levels were also investigated. Long-term aspirin administration resulted in development of resistance to aspirin-induced mucosal damage, and the increase of HSP72 expression correlated with mucosal resistance to aspirin. No significant increase was observed in HSP60 and HSP90 levels. Immunohistochemical study showed an increase of HSP72 in the cytoplasm of mucosal surface cells. The PGE2 level was suppressed and no change in the level of LTB4 was observed. It is possible that HSP72 could play important roles in gastric mucosal adaptation when the PGE2 level is suppressed by NSAIDs.

Studies on the effect of intragastric capsaicin on gastric ulcer and on the prostacyclin-induced cytoprotection in rats

The effect of intragastric (i.g.) capsaicin on experimental gastric ulcer was studied in the 1 h pylorus-ligated rats. Capsaicin applied in 40 ng ml-1 concentration (0.1 microgram kg-1) protected against gastric mucosal injury evoked by i.g. application of acidified aspirin, 96% ethanol or 0.6 M HCl. After a capsaicin concentration of 400 micrograms ml-1 (1 mg kg-1) protection occurred initially, while several hours later mucosal damage evoked by acidified aspirin was enhanced. Capsaicin in 2 and 6 ml kg-1 (10 and 30 mg kg-1) invariably aggravated the aspirin and ethanol-induced gastric mucosal damage. Capsaicin in 0.1 microgram kg-1 did not modify the mucosal protective action of prostacyclin (5 micrograms kg-1) on gastric mucosal injury produced by i.g. application of acidified aspirin, 96% ethanol or 0.6 M HCl. Local capsaicin desensitization induced by application of capsaicin in 2 mg ml-1 (10 mg kg-1) did not interfere with the mucosal cytoprotective effects of prostacyclin against ethanol and aspirin-induced mucosal damage. It is concluded that i.g. capsaicin exerts a dual dose-dependent effect on development of experimental gastric ulcer. Neither i.g. capsaicin in small doses nor local capsaicin desensitization modify the mucosal cytoprotective effects of prostacyclin.

Close arterial infusion of calcitonin gene-related peptide into the rat stomach inhibits aspirin- and ethanol-induced hemorrhagic damage

Afferent neuron-mediated gastric mucosal protection has been suggested to result from the local release of vasodilator peptides such as calcitonin gene-related peptide (CGRP) from afferent nerve endings within the stomach. The present study, therefore, examined whether rat α-CGRP, administered via different routes, is able to protect against mucosal injury induced by gastric perfusion with 25% ethanol or acidified aspirin (25 mM, pH 1.5) in urethane-anesthetized rats. Close arterial infusion of CGRP (15 pmol/min) to the stomach, via a catheter placed in the abdominal aorta proximal to the celiac artery, significantly reduced gross mucosal damage caused by ethanol and aspirin whereas mean arterial blood pressure (BP) was not altered. Intravenous infusion of CGRP (50 pmol/min) did not affect aspirin-induced mucosal injury but significantly enhanced ethanol-induced lesion formation. Intravenous CGRP (50 pmol/min) also lowered BP and increased the gastric clearance of [ 14C]aminopyrine, an indirect measure of gastric mucosal blood flow while basal gastric output of acid and bicarbonate was not altered. Intragastric administration of CGRP (260 nM) significantly inhibited aspirin-induced mucosal damage but did not influence damage in response to ethanol. BP, gastric clearance of [ 14C]aminopyrine, and gastric output of acid and bicarbonate remained unaltered by intragastric CGRP. These data indicate that only close arterial administration of CGRP to the rat stomach, at doses devoid fo a systemic hypotensive effect, is able to protect against both ethanol- and aspirin-induced mucosal damage. As this route of administration closely resembles local release of the peptide in the stomach, CGRP may be considered as a candidate mediator of afferent nerve-induced gastric mucosal protection.

Intragastric capsaicin protects against aspirin-induced lesion formation and bleeding in the rat gastric mucosa

Previous work has indicated that capsaicin-sensitive afferent neurons are involved in gastric mucosal defense mechanisms. The present study investigated whether stimulation of these neurons by intragastric administration of capsaicin would protect against aspirin-induced mucosal damage in the luminally perfused rat stomach. Capsaicin (25–640 μM), administered together with acidified (pH 1.5) aspirin (25 mM), inhibited macroscopically visible lesion formation and gastric bleeding in a concentration-dependent fashion. Capsaicin (160 μM) also attenuated the aspirin-induced fall in the gastric potential difference. An inhibitory effect of capsaicin (160 μM) on aspirin-induced gastric injury was also seen by light and scanning electron microscopy. Aspirin alone caused a vast ablation of the gastric surface epithelium, resulting in exposure of the lamina propria. In the presence of capsaicin, the depth of mucosal injury, the area totally deprived of surface epithelial cells, and the severity of surface desquamation were diminished. As capsaicin is a selective stimulant of thin afferent neurons, it would appear that these neurons participate in mechanisms of gastric defense against aspirin injury. Prevention of hemorrhagic damage seems to be the primary effect of afferent nerve-mediated gastroprotection, although injury to the surface epithelium is also reduced to some degree.

Damage and protection of the human gastric mucosa: A multiparameter assessment

Studies in animals and humans have indicated that endogenous prostaglandins as well as synthetic prostaglandin analogues can prevent gastric mucosal damage induced by various agents. Methods were developed to assess induced damage and the effects of potentially protective agents (synthetic prostaglandin analogues and the histamine [H 2]-receptor antagonist cimetidine) on the human gastric mucosa by measuring ion fluxes and transmucosal potential difference, as well as by observations with gastrointestinal endoscopy. Commonly ingested agents, such as aspirin, 1,300 mg, and 20 percent ethanol increased hydrogen ion and sodium ion fluxes, decreased potential difference, and caused gross mucosal damage, as observed by endoscopy. Conversely, acetaminophen, 2,600 mg, and 10 percent ethanol did not have any significant effects. Hyperosmolar solutions (1,800 and 3,600 mOsm/kg) also produced acute damage. Sodium taurocholate (10 mmol/liter) when instilled into the stomach, either at pH 1.1 or 7.0, produced both functional and structural damage. When given as a single dose, neither 15(R)15-methyl PGE 2 nor the synthetic PGE, analogue, misoprostol, prevented mucosal damage induced by aspirin and taurocholate (pH 1.1), respectively. Cimetidine, 400 mg orally, however, did reduce aspirin-induced mucosal damage, and this effect was independent of gastric acid inhibition.

Effect of geranylgeranylacetone on aspirin-induced changes in gastric glycoproteins.

The effects of aspirin and treatment with geranylgeranylacetone (GGA), an antiulcer drug, on the content of gastric glycoproteins were investigated in pylorus-ligated rats. In normal rats, the amount of gastric glycoproteins in the mucous layer was about 1.5 times higher than that in the gastric mucosa, indicating that the glycoproteins were distributed in the mucous layer as a highly concentrated state. Aspirin (100 mg/kg, p.o.) decreased the content of gastric glycoproteins both in the mucous layer and in the gastric mucosa. The amount of the macromolecular fraction in the gastric juice, which corresponded to the gastric glycoproteins on the basis of molecular size, was not affected by aspirin. GGA (300 mg/kg, i.d.) could prevent the decreases of the total amount of gastric glycoproteins in the mucous layer plus gastric mucosa. These results indicated that the glycoproteins coating the surface of the gastric mucosa may play a role as a defensive mechanism and that GGA exerted an antiulcer effect on aspirin-induced mucosal damage through preventing the decreases in gastric glycoproteins.

EFFECT OF GERANYLGERANYLACETONE ON ASPIRIN-INDUCED CHANGES IN GASTRIC GLYCOPROTEINS

The effects of aspirin and treatment with geranylgeranylacetone (GGA), an antiulcer drug, on the content of gastric glycoproteins were investigated in pylorus-ligated rats. In normal rats, the amount of gastric glycoproteins in the mucous layer was about 1.5 times higher than that in the gastric mucosa, indicating that the glycoproteins were distributed in the mucous layer as a highly concentrated state. Aspirin (100 mg/kg, p.o.) decreased the content of gastric glycoproteins both in the mucous layer and in the gastric mucosa. The amount of the macromolecular fraction in the gastric juice, which corresponded to the gastric glycoproteins on the basis of molecular size, was not affected by aspirin. GGA (300 mg/kg, i.d.) could prevent the decreases of the total amount of gastric glycoproteins in the mucous layer plus gastric mucosa. These results indicated that the glycoproteins coating the surface of the gastric mucosa may play a role as a defensive mechanism and that GGA exerted an antiulcer effect on aspirin-induced mucosal damage through preventing the decreases in gastric glycoproteins.

Relationship between lesion formation and permeability of rat gastric mucosa to H+ and other cations.

The relationship between lesion formation and ionic permeability has been investigated in rat gastric mucosa in vivo. Changes in these parameters were measured in the mucosa treated topically with prostaglandins E2 and A2 and/or aspirin. Particular attention was paid to the net flux of H+ ions across the gastric mucosa. The effect of aspirin concentrations of 5 mM, 20 mM and '40 mM' (the latter, a suspension in a saturated solution) was investigated. Aspirin concentrations of 20 mM and '40 mM' produced a marked increase in lesion formation and increased the net mucosal to serosal flux of H+ ions. Aspirin 5 mM produced a significant increase in lesion formation but did not cause a significant change in net H+ ion flux. This result suggests that aspirin can have a direct irritant effect on the gastric mucosa and that the back diffusion of H+ ions is not a pre-requisite for the development of overt mucosal ulceration. The effect of topically applied prostaglandin E2 (PGE2) on aspirin-induced gastric mucosal damage was investigated. Concentrations of PGE2 of 10(-5) M and 10(-4) M ameliorated aspirin-induced damage, but these changes were not necessarily accompanied by a significant reduction in net H+ ion flux. Again, this result is not consistent with a direct relationship between lesion formation and mucosal permeability to H+ ions. Since PGA2 did not ameliorate aspirin-induced mucosal damage, the protective effect of PGE2 could not be attributed to its conversion to PGA2 in the acidic environment of the gastric lumen. 5 Changes in gastric mucosal potential difference (p.d.) and net fluxes of Na+ and K+ ions may occur without a concomitant change in the permeability of the gastric mucosa to acid back-diffusion. Thus, the assumption cannot be made that a change in the permeability of the gastric mucosa to one particular ion reflects a general increase in ionic permeability.

Assessment of gastric mucosal damage: Comparative effects of aspirin and fenclofenac on the gastric mucosa of the guinea pig

Gastric mucosal damage in the guinea pig was assessed by measuring the concentrations of blood and deoxyribonucleic acid (DNA) in gastric washings and by morphological examination of the mucosa. Exposure of the mucosa to aspirin in suspension at pH 2.0 for 10 min caused an increase in the rate of accumulation of DNA in the washings together with gastric bleeding and the formation of macroscopically visible erosions. Under similar conditions of administration, fenclofenac (2-(2,4-dichlorophenoxy)phenylacetic acid) had little effect. In solution at pH 7.4, aspirin-induced mucosal damage was minimal, whereas fenclofenac produced a large increase in the rate of accumulation of DNA in the gastric washings but only slight blood loss and visibly detectable damage. Microscopical examination of the mucosa after aspirin at pH 2.0 revealed the presence of deep focal erosions but, at pH 7.4, only a few shallow erosions were observed. The appearance of the mucosa after fenclofenac at pH 2.0 was similar to that of control animals. At pH 7.4, the drug caused widespread exfoliation of surface mucosal cells but no penetrating erosions of the type seen after aspirin. Estimation of the DNA concentration in gastric washings was found to be a sensitive index of mucosal damage, detecting superficial as well as focal cell loss. Damage was detected macroscopically only when the erosions were deep or accompanied by bleeding.

Effects of blood glucose levels on aspirin-induced gastric mucosal damage

In female rats aspirin-induced gastrin mucosal damage was increased and glycoprotein synthesis decreased by fasting and by insulin administration. Glucose added to the drinking water during the fasting period reduced mucosal damage and increased glycoprotein synthesis to control levels. Alloxan diabetes did not affect mucosal damage or glycoprotein synthesis. Alloxan diabetes plus insulin restored blood glucose levels to normal, and susceptibility to aspirin damage and glycoprotein synthesis were also normal. Alloxan diabetes plus fasting restored blood glucose levels to normal but increased aspirin-induced mucosal damage and reduced glycoprotein synthesis. In vitro incubation of gastric mucosal homogenates showed that diburyryl cyclic AMP and theophylline inhibited glycoprotein synthesis but dibutyryl cyclic GMP had no significant effects. The importance of an adequate supply of glucose to the gastric mucosa and the effects of cyclic nucleotides on glycoprotein synthesis are discussed.