Kikuko Amagase

Pharmacological control of gastric acid secretion for the treatment of acid-related peptic disease: past, present, and future

Pharmacological agents, such as histamine H(2) receptor antagonists and acid pump inhibitors, are now the most frequently used treatment for such acid-related diseases as gastroduodenal ulcers and reflux esophagitis. Based on increased understanding of the precise mechanisms of gastric acid secretion at the level of receptors, enzymes, and cytoplasmic signal transduction systems, further possibilities exist for the development of effective antisecretory pharmacotherapy. Gastrin CCK(2) receptor antagonists and locally active agents appear to represent promising therapies for the future. Development of gene targeting techniques has allowed production of genetically engineered transgenic and knockout mice. Such genetic technology has increased the investigative power for pharmacotherapy for not only antisecretory agents, but also treatment of mucosal diseases, such as atrophy, hyperplasia, and cancer. Elucidation of the origin of gastric parietal cells also represents an interesting investigative target that should allow a better understanding of not only acid-related diseases, but also the evolution of the stomach as an acid-secreting organ.

Roles of COX inhibition in pathogenesis of NSAID-induced small intestinal damage

Nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin decrease mucosal PGE(2) content by inhibiting cyclooxygenase (COX) activity and produce damage in the small intestine. The development of intestinal lesions induced by indomethacin was accompanied by increases in intestinal motility, enterobacterial invasion, and myeloperoxidase (MPO) as well as inducible nitric oxide synthase (iNOS) activity, together with the up-regulation of COX-2 and iNOS mRNA expression. Neither SC-560, a selective COX-1 inhibitor, nor rofecoxib, a selective COX-2 inhibitor, alone caused intestinal damage, but their combined administration provoked lesions in the small intestine. SC-560, but not rofecoxib, caused intestinal hypermotility, bacterial invasion and the expression of COX-2 as well as iNOS mRNA, yet the iNOS and MPO activity was increased only when rofecoxib was administered together with SC-560. Although SC-560 inhibited PG production, the level of PGE(2) recovered in a rofecoxib-dependent manner. The intestinal hypermotility in response to indomethacin was prevented by both 16,16-dimethyl PGE(2) and atropine but not by ampicillin, yet all these agents inhibited not only the bacterial invasion but also the expression of COX-2 as well as the iNOS activity in the intestinal mucosa following indomethacin treatment, thereby preventing the intestinal damage. These results suggest that inhibition of COX-1, despite causing intestinal hypermotility, bacterial invasion and iNOS expression, up-regulates the expression of COX-2, and the PGE(2) derived from COX-2 counteracts the deleterious events caused by COX-1 inhibition and maintains mucosal integrity. These sequences of events explain why intestinal damage occurs when both COX-1 and COX-2 are inhibited.

Prevention of NSAID-Induced Small Intestinal Mucosal Injury: Prophylactic Potential of Lansoprazole

Non-steroidal anti-inflammatory drugs (NSAIDs), which are used for the treatment of several inflammatory disorders including rheumatoid arthritis, are well known to cause gastroduodenal mucosal lesions as an adverse effect. Recently, the serious problem of NSAID-induced small intestinal damage has become a topic of great interest to gastroenterologists, since capsule endoscopy and double-balloon enteroscopy are available for the detection of small intestinal lesions. Such lesions have been of great concern in clinical settings, and their treatment and prevention must be devised as soon as possible. Proton pump inhibitors (PPI), such as lansoprazole and omeprazole, show a potent anti-secretory effect. PPIs also have a gastroprotective effect, independent of their anti-secretory actions, which is probably mediated by inhibition of neutrophil functions as well as antioxidant actions. Administration of lansoprazole reduced the severity of the intestinal lesions in a dose-dependent manner, but omeprazole had no effect. The amount of heme oxygenase-1 (HO-1) protein in the intestinal mucosa was significantly increased by lansoprazole, but not by omeprazole. These results suggest that lansoprazole, but not omeprazole, ameliorates indomethacin-induced small intestinal ulceration through upregulation of HO-1/carbon monoxide. Therefore, lansoprazole may be useful for preventing the adverse effects of NSAIDs not only in the stomach but also in the small intestine.

Exacerbation of Nonsteroidal Anti-Inflammatory Drug-Induced Small Intestinal Lesions by Antisecretory Drugs in Rats: The Role of Intestinal Motility

Antisecretory drugs such as histamine H2-receptor antagonists (H2-RAs) and proton pump inhibitors (PPIs) are commonly used for the treatment of gastric and duodenal ulcers induced by nonsteroidal anti-inflammatory drugs (NSAIDs). However, the effects of these drugs on NSAID-induced small intestinal ulcers are not fully understood. The effects of H2-RAs and PPIs on NSAID-induced gastrointestinal lesions and small intestinal motility were examined in rats. Male Wistar rats (180–220 g) were used. Indomethacin (10 mg/kg) was administered orally in fasted or fed rats, and gastrointestinal lesions were examined 24 h after indomethacin administration. Intestinal motility was measured by using a balloon method under urethane anesthesia. Indomethacin produced multiple lesions in the gastric corpus in fasted rats and in the small intestine in fed rats: 1) H2-RAs (cimetidine, ranitidine, and famotidine) and PPIs (omeprazole, lansoprazole, and rabeprazole) markedly inhibited the formation of gastric lesions. 2) The drugs, except for lansoprazole, increased intestinal lesions. 3) H2-RAs augmented the increase in intestinal motility caused by indomethacin, and the effects of H2-RAs on motility and intestinal lesions were markedly inhibited by atropine. 4) Lansoprazole inhibited the formation of intestinal lesions, and the effect was prevented by both pharmacological ablation of capsaicin-sensitive sensory neurons and pretreatment with N-nitro-l-arginine methyl ester, a selective inhibitor of nitric-oxide synthesis. The results suggest that: 1) inhibition of acid secretion by antisecretory drugs may exacerbate NSAID-induced intestinal lesions, 2) H2-RAs further aggravate lesions by increasing intestinal motility via the activation of cholinergic pathways, and 3) lansoprazole protects the intestinal mucosa against NSAID-related ulcerative stimuli.

Dual Action of Nitric Oxide in the Pathogenesis of Ischemia/Reperfusion-Induced Mucosal Injury in Mouse Stomach

Aim: We investigated the roles of NO/NOS isoforms in the pathogenesis of ischemia/reperfusion (I/R)-induced gastric injury in mouse stomachs. Methods: Under urethane anesthesia, the celiac artery was clamped, and then reperfusion was established 30 min later by removal of the clamp. After a 60-min reperfusion, the stomach was examined for macroscopic lesions. Results: Following I/R, hemorrhagic lesions were generated in the mucosa, although ischemia alone caused no visible damage. Prior administration of L-NAME (a nonselective NOS inhibitor) significantly aggravated these lesions, in a L-arginine-inhibitable manner. By contrast, the selective iNOS inhibitor 1400W significantly prevented the occurrence of I/R-induced gastric lesions. The mucosal MPO activity was increased after I/R, and this response was enhanced and attenuated by prior administration of L-NAME and 1400W, respectively. Interestingly, the later treatment with L-NAME, given 10 min before reperfusion, significantly reduced the severity of the I/R-induced gastric damage, in a L-arginine-dependent manner. The expression of iNOS mRNA was up-regulated in the stomach following I/R, with an increase of mucosal NO content, and the NO production was significantly inhibited by both L-NAME and 1400W. Conclusion: Endogenous NO plays a dual role in the pathogenesis of IR-induced gastric damage; NO/cNOS is protective while NO/iNOS is proulcerogenic during I/R.

Effect of (S)-4-(1-(5-Chloro-2-(4-fluorophenyoxy)benzamido)ethyl) Benzoic Acid (CJ-42794), a Selective Antagonist of Prostaglandin E Receptor Subtype 4, on Ulcerogenic and Healing Responses in Rat Gastrointestinal Mucosa

Recent research showed the involvement of prostaglandin E receptor subtype 4 (EP4) in hypersensitivity to inflammatory pain and suggested that the EP4 receptor is a potential target for the pharmacological treatment of inflammatory pain. We examined the effects of (S)-4-(1-(5-chloro-2-(4-fluorophenyoxy) benzamido)ethyl) benzoic acid (CJ-42794), a selective EP4 antagonist, on gastrointestinal ulcerogenic and healing responses in rats, in comparison with those of various cyclooxygenase (COX) inhibitors. CJ-42794 alone, given p.o., did not produce any damage in the gastrointestinal mucosa, similar to 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole (SC-560) (COX-1 inhibitor) or rofecoxib (COX-2 inhibitor), whereas indomethacin (nonselective COX inhibitor) caused gross lesions. Rofecoxib but not CJ-42794, however, damaged these tissues when coadministered with SC-560 and aggravated gastric lesions produced by aspirin. Indomethacin and SC-560 worsened the gastric ulcerogenic response to cold-restraint stress, yet neither CJ-42794 nor rofecoxib had any effect. Furthermore, indomethacin and SC-560 at lower doses damaged the stomach and small intestine of adjuvant arthritic rats. In arthritic rats, rofecoxib but not CJ-42794 provoked gastric ulceration, whereas CJ-42794 produced little damage in the small intestine. The repeated administration of CJ-42794 and rofecoxib as well as indomethacin impaired the healing of chronic gastric ulcers with a down-regulation of vascular endothelial growth factor expression in the ulcerated mucosa. These results suggest that CJ-42794 does not cause any damage in the normal rat gastrointestinal mucosa and in the arthritic rat stomach and does not worsen the gastric ulcerogenic response to stress or aspirin in normal rats, although this agent slightly damages the small intestine of arthritic rats and impairs the healing of gastric ulcers.

Endogenous prostaglandin E2 accelerates healing of indomethacin‐induced small intestinal lesions through upregulation of vascular endothelial growth factor expression by activation of EP4 receptors

Background and Aims:  The effects of an EP4 agonist/antagonist on the healing of lesions produced by indomethacin in the small intestine were examined in rats, especially in relation to the expression of vascular endothelial growth factor (VEGF) and angiogenesis.

Potential role of the NADPH oxidase NOX1 in the pathogenesis of 5-fluorouracil-induced intestinal mucositis in mice.

Although NADPH oxidase 1 (NOX1) has been shown to be highly expressed in the gastrointestinal tract, the physiological and pathophysiological roles of this enzyme are not yet fully understood. In the present study, we investigated the role of NOX1 in the pathogenesis of intestinal mucositis induced by the cancer chemotherapeutic agent 5-fluorouracil (5-FU) in mice. Intestinal mucositis was induced in Nox1 knockout (Nox1KO) and littermate wild-type (WT) mice via single, daily administration of 5-FU for 5 days. In WT mice, 5-FU caused severe intestinal mucositis characterized by a shortening of villus height, a disruption of crypts, a loss of body weight, and diarrhea. In Nox1KO mice, however, the severity of mucositis was significantly reduced, particularly with respect to crypt disruption. The numbers of apoptotic caspase-3- and caspase-8-activated cells in the intestinal crypt increased 24 h after the first 5-FU administration but were overall significantly lower in Nox1KO than in WT mice. Furthermore, the 5-FU-mediated upregulation of TNF-α, IL-1β, and NOX1 and the production of reactive oxygen species were significantly attenuated in Nox1KO mice compared with that in WT mice. These findings suggest that NOX1 plays an important role in the pathogenesis of 5-FU-induced intestinal mucositis. NOX1-derived ROS production following administration of 5-FU may promote the apoptotic response through upregulation of inflammatory cytokines.

5-HT3 receptor antagonists ameliorate 5-fluorouracil-induced intestinal mucositis by suppression of apoptosis in murine intestinal crypt cells

Chemotherapeutic agents, including 5‐fluorouracil (5‐FU), frequently cause intestinal mucositis resulting in severe diarrhoea and morphological mucosal damage. 5‐HT3 receptor antagonists are clinically effective in the treatment of nausea and emesis during cancer chemotherapy. Therefore we here have examined the effects of 5‐HT3 receptor antagonists on 5‐FU‐induced intestinal mucositis in mice.

Protective effect of lafutidine, a histamine H2 receptor antagonist, against loxoprofen‐induced small intestinal lesions in rats

Background and Aims:  We examined the effect of lafutidine, a histamine H2 receptor antagonist with a mucosal protective action mediated by capsaicin‐sensitive sensory neurons (CSN), on intestinal lesions produced by loxoprofen administration in rats.