No abstract

Proton pump inhibitors (PPIs) have been shown to be effective in preventing gastric and duodenal ulcers in high-risk patients taking nonsteroidal anti-inflammatory drugs (NSAIDs); by contrast, scarce information is available concerning the effects of PPIs on intestinal damage induced by NSAIDs in humans or in experimental animals. We examined the effects of lansoprazole and omeprazole on the intestinal injury induced by indomethacin in the conscious rat. PPIs were administered by the intragastric route at 30, 60 and 90 micromol/kg, 12 h and 30 min before and 6 h after indomethacin treatment. The effects of omeprazole and lansoprazole were evaluated on: (1) macroscopic and histologic damage; (2) mucosal polymorphonuclear cell infiltration; (3) oxidative tissue damage and (4) bacterial translocation from lumen into the intestinal mucosa. Lansoprazole and omeprazole (at 90 micromol/kg) significantly decreased (P<0.01) the macroscopic and histologic damage induced by indomethacin in the rat small intestine. Furthermore, both drugs greatly reduced (P<0.01) the associated increases in myeloperoxidase levels and lipid peroxidation induced by indomethacin, whereas they only moderately affected (P<0.05) the translocation of enterobacteria from lumen into the intestinal mucosa. These data demonstrate that omeprazole and lansoprazole can protect the small intestine from the damage induced by indomethacin in the conscious rat. The intestinal protection, possibly related to antioxidant and anti-inflammatory properties of these drugs, may suggest new therapeutic uses of PPIs in intestinal inflammatory diseases.

The effects of the histamine H(4) receptor antagonist JNJ7777120 were evaluated in a model of acute skin inflammation induced by local application of croton oil. The influence of strain on the effect of JNJ7777120 was investigated in four different mouse strains (CD-1, NMRI, BALB/c and C57BL/6J). In CD-1 mice, JNJ777720 (30-100 mg/kg subcutaneously, s.c.) exerted a dose-dependent inhibition of croton oil-induced ear inflammation and polymorphonuclear leucocyte infiltration, as confirmed by histological evaluation of ear tissues. JNJ7777120 (30-100 mg/kg) did not reduce ear oedema in NMRI, BALB/c or C57BL/6J mice. The positive control, dexamethasone (2 mg/kg s.c.) induced significant anti-inflammatory effects only in CD-1 and NMRI mice. In these strains, also the histamine H(1) -receptor blocker pyrilamine (30 mg/kg s.c.) significantly reduced ear oedema at 2 h after croton oil challenge, being as effective as JNJ7777120 in CD-1 mice. Taken together, these data demonstrate that the H(4) receptor antagonist JNJ7777120 may reduce acute croton oil-induced skin inflammation as effectively as H(1) receptor blockade. However, present experiments evidenced for the first time marked strain-related differences in the JNJ7777120 pharmacological activity, which have to be carefully considered when using this ligand to characterize histamine H(4) receptor functions in murine models and translating preclinical data to clinical human settings.

The assessment of the protective actions of H2-receptor antagonists against gastric mucosal lesions by necrotizing agents relies on the gross observation of the gastric mucosa only. We examined the activity of famotidine against 0.6 N HCl-induced damage and the role of parietal cells by light and transmission electron microscopy. Rats received famotidine 0.3-10 mg/kg intragastrically. Sixty minutes later 0.6 N HCl (1 ml/rat) was given and after an additional 30 min the stomachs were removed. Macroscopically visible lesions were measured. Histologic lesions were scored on the basis of the depth. The ultrastructure of parietal cells in the isthmus-neck region was examined. Pretreatment with famotidine resulted in a slight increase of macroscopically visible gastric lesions in response to HCl. While the extent of total histologic damage was not modified, the antisecretory dose significantly reduced only lesions deep within the mucosa. Famotidine alone determined the dose-dependent occurrence of a distinct parietal cell morphological state, suggestive of inhibition of the secretory system. A causal link between the protective effect on the region where parietal cells are located, the percentage of cells shifting to the inhibited morphological state, and the inhibitory effect on acid secretion is proposed.

The 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced model of experimental colitis was used to investigate the time-course of alterations in enteric neurotransmission and/or smooth muscle function that occur in chronic inflammation. Myenteric plexus morphology (immunocytochemical markers), functional integrity of cholinergic neurons (3H-choline uptake, acetylcholine release and contractile response to electrical field stimulation) and smooth muscle integrity (contractile response to exogenous acetylcholine) were determined 2, 7, 15, and 30 days after TNBS treatment. In TNBS-treated rats extensive ulcerations of the mucosa and/or the submucosa and increase in colonic weights were accompanied by significant reduction in 3H-choline uptake, acetylcholine release and contractile response to stimulation of enteric nerves. These changes were maximal 7 and 15 days after TNBS treatment. Immunocytochemical marker (PGP 9.5, SNAP 25, synaptophysin and S100 protein) expression was absent in necrotic areas of colons removed 7 days post-injury and partially reduced in colons removed 15 days after TNBS treatment. By contrast, the contractile response to exogenous acetylcholine was significantly increased after 7 days in both inflamed and uninflamed regions and returned to control values by day 30. Likewise, an almost complete recovery of neural cholinergic function and of myenteric plexus morphology was observed 30 days after TNBS treatment. These data suggest that TNBS-induced colitis is associated with progressive and selective alterations in myenteric plexus structure and function, with consequent reduction of cholinergic neurotransmission and abnormality in colonic contractility. The reversibility of myenteric plexus disruption is a clear indication of neuronal plasticity within enteric nervous system as an adaptative mechanism against inflammatory challenges.