Gregory A. Cook

INDOMETHACIN DAMAGE TO RAT GASTRIC MUCOSA IS MARKEDLY DEPENDENT ON LUMINAL pH

1. There is good evidence that acid is a prerequisite for aspirin induced gastric mucosal damage; however, there is inconsistent information available for non‐salicylate NSAID. The present study examines the effect of gastric luminal pH on indomethacin‐induced gastric mucosal damage.

Oral human spasmolytic polypeptide protects against aspirininduced gastric injury in rats

Spasmolytic polypeptide (SP) is a member of the trefoil peptide family; gut peptides that participate in the protection and repair of the gastric mucosa. Previous studies have failed to agree on the mode of action of human SP (hSP). We investigated the effect of orally administered human SP on the protection and repair of rat gastric mucosa in an established in vivo model of damage induced by the non‐steroidal anti‐inflammatory drug aspirin (ASA). The integrity of the gastric mucosa was quantified in four ways: the temporal change in transmucosal potential difference (PD), area of macroscopic damage by planimetry, relative area of microscopic damage by histological morphometry, and the number of deep erosions per centimetre of mucosa sectioned. Human SP (200 μmol/L) administered orally before, or in combination with ASA significantly reduced the fall in PD, the area of microscopic damage, and the number of deep erosions (P < 0.05). The area of macroscopic damage was significantly reduced only in rats where hSP (200 μmol/L) was given in conjunction with ASA (P < 0.05). Human spasmolytic polypeptide (70 or 200 μmol/L) administered after ASA failed to hasten the re‐establishment of PD or stimulate the repair of the gastric mucosa in the 90 min following injury (P>0.05, compared with ASA alone). We conclude that hSP prevents gastric mucosal damage by its topical actions, probably by a rapid interaction with luminal mucins or epithelial cells, but fails to stimulate early restitution in the injured gastric mucosa.

Spatio-temporal expression of trefoil peptide following severe gastric ulceration in the rat implicates it in late-stage repair processes.

Background: The trefoil peptide (TFF1) is a member of a family of mucin‐associated regulatory peptides that are widely distributed in gastrointestinal tissues and have been implicated in the maintenance of the gastric mucosa. The role of TFF1 in gastric mucosal repair was examined by analysis of the spatio‐temporal expression of TFF1 following gastric ulceration in the rat.

Gastric mucosal adaptation to diclofenac injury

Adaptation occurs to the gastric injury produced by nonsteroidal antiinflammatory drugs during continued dosing. The aim of this study was to identify characteristics of this phenomenon that might help in the search for underlying mechanisms. The time frame for onset and offset of adaptation of diclofenac (damage assessed planimetrically) was examined in rats. Adaptation to oral diclofenac took three to five days to develop, and persisted for up to five days after the last dose. It was also demonstrable after subcutaneous dosing or when injury was measured by a change in mucosal potential difference. Diclofenac-adapted rats were protected against injury induced by subsequent exposure to ethanol, indomethacin, aspirin, or piroxicam, indicating that adaptation is not specific to injury by the adapting agent. This cross-adaptation was dose-dependent and characterized histologically by a reduction in deep damage. In conclusion, gastric adaptation to diclofenac is mediated by mechanisms that take several days to develop and be lost. The route of administration appears to be unimportant, but the development of both adaptation and cross-adaptation is influenced by dosage size.

Repair of Rat Gastric Mucosa (Effect of 16,16-Dimethyl Prostaglandin E2)

Prostaglandins protect the gastric mucosaagainst a variety of injurious agents and may acceleratethe recovery of the gastric mucosa following damage. Inprevious studies prostaglandins were given prior to the injurious agent, so it was not possibleto distinguish their potential effects on acceleratingrepair or reducing initial damage. We have investigatedthe effect of 16,16-dimethyl prostaglandin E2 (dmPGE2) on the repair of thegastric muscosa after injury induced by severalinjurious agents. dmPGE2 was given orally 15min prior to aspirin or sodium salicylate, or 30 minafter aspirin, sodium salicylate, or ethanol. dmPGE2 delivered priorto injury reduced the aspirin-induced fall in mucosalpotential difference (PD), but had no effect on thatinduced by sodium salicylate. dmPGE2administered after ASA injury significantly increased recovery of PD (P <0.05), but did not alter the rate of recovery of PD withother damaging agents. Histological damage was decreasedin rats treated with dmPGE2 after aspirincompared to aspirin-only-treated rats (P < 0.02).Exogenous dmPGE2 protects and restoresgastric mucosal integrity after aspirin damage but hasno effect on the repair of sodium salicylate and ethanolinjured mucosa, suggesting that repair of the gastric mucosaafter aspirin damage is enhanced by dmPGE2due to its ability to prevent ongoing damage, ratherthan directly enhancing repair processes.

Correlation between transmucosal potential difference and morphological damage during aspirin injury of gastric mucosa in rats

The potential difference (PD) that is maintained across healthy gastric mucosa is thought to be due to asymmetric ion pumping combined with resistance to back‐diffusion of the separated charge. However, the structures that are responsible for this have not been clearly defined. This study examined the temporal changes in PD in rat stomach after injury by a single dose of aspirin. Multiple linear regression was used to compare this with the time course of several parameters of histological damage: (i) the per cent mucosal length showing superficial (confined to surface and gastric pits), deep (involving the isthmus or deeper in oxyntic glands) and total damage; (ii) the number of discrete erosions; and (iii) the total area of erosions per cm sectioned. Mucosal PD fell during the first 30–60 min after aspirin. Superficial damage appeared early and was already recovering by this time. The time course of deep damage more closely matched the alterations in PD and stepwise regression analysis showed that this could be predicted by the amount of deep damage alone (P < 0.001). Changes in transmucosal PD after acute aspirin injury probably reflect damage to structures in the oxyntic glands and not just the breaking of the surface and pit cell ‘barrier’.