Role of transient receptor potential vanilloid 4 activation in indomethacin-induced intestinal damage.

Gastrointestinal ulcers and bleeding are serious complications of nonsteroidal anti-inflammatory drug (NSAID) use. Although administration of antibiotics and Toll-like receptor 4 knockdown mitigate NSAID-induced enteropathy, the molecular mechanism of these effects is poorly understood. Intestinal hyperpermeability is speculated to trigger the initial damage due to NSAID use. Transient receptor potential vanilloid 4 (TRPV4) is a nonselective cation channel expressed throughout the gastrointestinal tract epithelium that is activated by temperature, extension, and chemicals such as 5,6-epoxyeicosatrienoic acid (5,6-EET). The aim of this study was to investigate the possible role of TRPV4 in NSAID-induced intestinal damage. TRPV4 mRNA and protein expression was confirmed by RT-PCR and immunochemistry, respectively, in mouse and human tissues while TRPV4 channel activity of the intestinal cell line IEC-6 was assessed by Ca(2+)-imaging analysis. TRPV4 activators or the NSAID indomethacin significantly decreased transepithelial resistance (TER) in IEC-6 cells, and indomethacin-induced TER decreases were inhibited by specific TRPV4 inhibitors or small-interfering RNA TRPV4 knockdown, as well as by the epoxygenase inhibitor N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide, which decreased 5,6-EET levels. In TRPV4 knockout mice, indomethacin-induced intestinal damage was significantly reduced compared with WT mice. Taken together, these results show that TRPV4 activation in the intestinal epithelium caused epithelial hyperpermeability in response to NSAID-induced arachidonic acid metabolites and contributed to NSAID-induced intestinal damage. Thus, TRPV4 could be a promising new therapeutic target for the prevention of NSAID-induced intestinal damage.

TRPV2 ion channels expressed in inhibitory motor neurons of gastric myenteric plexus contribute to gastric adaptive relaxation and gastric emptying in mice.

Gastric adaptive relaxation (GAR) is impaired in ~40% of functional dyspepsia (FD) patients, and nitric oxide (NO) released from inhibitory motor neurons plays an important role in this relaxation. Although the underlying molecular mechanism of GAR is poorly understood, transient receptor potential channel vanilloid 2 (TRPV2) mechano- and chemoreceptors are expressed in mouse intestinal inhibitory motor neurons and are involved in intestinal relaxation. The aim of this study was to evaluate the distribution of TRPV2 in inhibitory motor neurons throughout the mouse gastrointestinal tract and the contribution of TRPV2 to GAR. RT-PCR and immunohistochemical analyses were used to detect TRPV2 mRNA and protein, respectively. Intragastric pressure was determined with an isolated mouse stomach. Gastric emptying (GE) in vivo was determined using a test meal. TRPV2 mRNA was detected throughout the mouse gastrointestinal tract, and TRPV2 immunoreactivity was detected in 84.3% of neuronal nitric oxide synthase-expressing myenteric neurons in the stomach. GAR, which was expressed as the rate of decline of intragastric pressure in response to volume stimuli, was significantly enhanced by the TRPV2 activator probenecid, and the enhancement was inhibited by the TRPV2 inhibitor tranilast. GE was significantly accelerated by TRPV2 agonist applications, and the probenecid-induced enhancement was significantly inhibited by tranilast coapplication. Mechanosensitive TRPV2 was expressed in inhibitory motor neurons in the mouse stomach and contributed to GAR and GE. TRPV2 may be a promising target for FD patients with impaired GAR.

Fragmented CagA protein is highly immunoreactive in Japanese patients.

BACKGROUND: High-molecular-weight cell-associated proteins (HM-CAP) assay is the most popular serological immunoassay worldwide and has been developed from US isolates as the antigens. The accuracy is reduced when the sera are from adults and children in East Asia including Japan. To overcome the reduced accuracy, an enzyme immunoassay using Japanese strain-derived HM-CAP (JHM-CAP) was developed, in which the antigens were prepared by exactly the same procedure as HM-CAP. The performance of JHM-CAP was better than that of HM-CAP in Japanese adults as well as in children. The higher sensitivity was because of the presence of 100-kDa protein that was absent in the preparation of HM-CAP antigen. MATERIALS AND METHODS: Immunoblot analysis and peptide mass fingerprinting methods were used to identify the distinctive 100-kDa protein present in JHM-CAP antigens. The peptide sequence and identification were analyzed by Mascot Search on the database of Helicobacter pylori. The identified protein was confirmed by immunoblot with a specific antibody and inhibition assay by the sera. RESULTS: The distinctive 100-kDa protein was a fragment of CagA derived from Japanese clinical isolates, and the sera of Japanese patients had strongly reacted to the protein, probably to the exposed epitope on the fragmented CagA. The fragmentation of CagA had occurred in the process of antigen preparation in Japanese isolates, not in US isolates even under the same preparation. CONCLUSION: The distinctive 100-kDa protein was a fragment of CagA protein of H. pylori derived from Japanese clinical isolates, and Japanese patients including children are likely to react strongly to the exposed epitopes on fragmented CagA.

[A case of pancreatic acinar cell carcinoma with a giant liver metastasis successfully treated with combination of gemcitabine and peroral S-1].

Pancreatic acinar cell carcinoma is rare, and its incidence is less than 1% of all the malignant pancreatic tumors. Little is reported on effectiveness of chemotherapy. We report a 64-year-old male patient with pancreatic acinar cell carcinoma and a giant metastatic liver tumor, which responded to combination chemotherapy with gemcitabine(GEM)and peroral S-1 administration. The patient had upper abdominal pain and hypervascular tumors in liver(15 cm in diameter)and pancreas tail (3 cm in diameter), which were detected by an enhanced abdominal computed tomography(CT)scan, and was admitted for further examination. Abdominal angiography, FDG-positron emission tomography(PET), and liver tumor biopsy led to a diagnosis of pancreatic acinar cell carcinoma in the pancreas tail with liver metastasis. The patient was then treated with combination chemotherapy, which consisted of intravenous infusion of GEM and peroral administration of S-1, and the metastatic liver tumor was markedly reduced(partial response in RECIST). Although the prognosis of patients with unresectable pancreatic acinar cell cancers is generally unfavorable, it is suggested that the GEM/S- 1 combination chemotherapy is effective for these patients' treatment.

[Infliximab-induced lupus erythematosus in a case of ulcerative colitis].

Infliximab is widely used in the treatment of inflammatory bowel disease, but despite its good clinical efficacy and tolerance, drug-induced autoimmune disorders have been reported as adverse reactions and are a matter of concern. Here we report a patient with ulcerative colitis who developed drug-induced lupus erythematosus after infliximab treatment. While this is a rare complication of infliximab, early diagnosis and successful management are essential.

[Mucoprotective drugs and aspirin-induced gastric injury].

Low-dose aspirin is widely used for anti-thrombotic strategy in the elderly. Despite the excellent benefits, GI bleeding due to gastric/duodenal ulcers or injury is a major complication in aspirin users. In animal model, low-dose aspirin induced gastric injury is prevented by the administration of proton-pump inhibitor(PPI), exogenous PGE2 and atropine. In clinical trials, PPI and famotidine (40 mg/d) are proven to have the preventive effect to gastric ulceration induced by low-dose aspirin use. Although gastric mucoprotective drugs including PG are speculated to show the preventive effect, the supportive clinical evidences are limited. Large-scaled, randomized clinical trials are required to confirm the clinical benefits of gastric mucoprotective drugs to low-dose aspirin induced gastric injury.

Esophageal small-cell carcinoma with syndrome of inappropriate secretion of antidiuretic hormone.

Small-cell carcinoma (SCC) of the esophagus is rare, and its clinical characteristics remain poorly understood. A 54-year-old man was given a diagnosis of esophageal SCC and underwent esophagectomy. Four months after surgery, he was admitted to our hospital because of rapidly developing hyponatremia. Syndrome of Inappropriate Secretion of Antidiuretic Hormone (SIADH) due to extensive recurrence of SCC was diagnosed. Combined chemotherapy with irinotecan and cisplatin has dramatically reduced metastatic tumors, and it was concomitantly effective for SIADH. This case demonstrates that esophageal SCC could induce SIADH as a paraneoplastic syndrome and that the above combined chemotherapy was feasible and effective.