Endogenous prostaglandin I2 regulates the neural emergency system through release of calcitonin gene related peptide.

BACKGROUND: We previously reported that endogenous prostaglandin I(2), generated by a mild irritant, sensitised calcitonin gene related peptide (CGRP) containing sensory nerves and facilitated the release of CGRP and gastric mucosal protection against ethanol. Administration of capsaicin also inhibited ethanol induced gastric mucosal injury through immediate release of CGRP from primary sensory neurones, which is termed the neural emergency system. In the present study, we tested whether endogenous prostaglandin I(2) also modulates the cytoprotective action of capsaicin using prostaglandin I receptor knockout mice (IP(-/-)). METHODS: The stomachs of IP(-/-) or their wild-type counterparts (IP(+/+)), anaesthetised with urethane (1.225 g/kg), were doubly cannulated from the oesophageal and duodenal sides, and the gastric mucosa was perfused (1 ml/min) with physiological saline. Perfusate was changed to 50% ethanol alone, or 50% ethanol containing capsaicin (16 approximately 1600 micro M). The injured area was estimated at the end of each perfusion experiment. In some animals, CGRP-(8-37), a CGRP antagonist (0.3 mg/kg), or indomethacin (1 mg/kg) was intravenously injected before perfusion of 50% ethanol containing capsaicin. RESULTS: Capsaicin inhibited the injured area in a dose dependent manner. Fifty per cent ethanol containing capsaicin (480 micro M) immediately increased intragastric levels of CGRP although 50% ethanol alone did not. The protective action of capsaicin (480 micro M) against ethanol was completely abolished by intravenous injection of CGRP-(8-37). Indomethacin also inhibited the protective action of capsaicin, and this was accompanied by reduced levels of intragastric CGRP. Intragastric levels of prostaglandin E(2) were not increased by capsaicin treatment but those of 6-keto-prostaglandin F(1alpha), a metabolite of prostaglandin I(2), were markedly increased. No protective action of capsaicin was observed in IP(-/-) which lacked the ability to increase intragastric CGRP levels in response to ethanol containing capsaicin. The CGRP content of the stomach from untreated IP(-/-) did not differ from those in IP(+/+). Capsaicin (160 micro M) together with intragastric perfusion of beraprost sodium (PGI(2) analogue, 2.5 micro g/ml) showed enhanced protection against ethanol induced injury. This enhanced protection was completely blocked by intravenous injection of CGRP-(8-37). CONCLUSIONS: The present results suggest that endogenous prostaglandin I(2) enhances the protective action of the capsaicin mediated neural emergency system against ethanol induced gastric mucosal injury through enhancement of CGRP release.

Effects of oral administration of Echinacea purpurea (American herb) on incidence of spontaneous leukemia caused by recombinant leukemia viruses in AKR/J mice.

Four-week-old female AKR/J mice were given oral doses of powdered leaves from Echinacea purpurea three times weekly for 8 weeks (7.5 mg/mouse/week): controls received phosphate-buffered saline. Mean survival age of experimental AKR/J mice treated with the E. purpurea preparation was significantly prolonged and enlargement of thymic lymphoma in experimental mice was significantly suppressed compared with controls. In normal 3-week-old female AKR/J mice, mortality from thymic lymphoma was delayed markedly after injection into the thymus of cell-free extract of thymus from the experimental 28-week-old female AKR/J mice that received the oral E. purpurea preparation was injected directly into the thymus. Proliferation of endogenous recombinant murine leukemia viruses (MuLV) in the thymus was markedly inhibited after the first oral administration of the E. purpurea preparation as compared with untreated controls (final age, 28 weeks). Production of endogenous interferon (IFN)-gamma in AKR/J mice was also effectively augmented by the oral treatment with the E. purpurea preparation, however, the production of other cytokines such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-12 was minimal. These results suggest that this suppressive effects on spontaneously occurring leukemia caused by endogenous recombinant MuLV in female AKR/J mice may depend on enhancement of nonspecific immune or cellular immune systems (or of both) by the E. purpurea preparation.

Kaolin-induced writhing response in mice: activation of the plasma kallikrein-kinin system by kaolin.

A mechanism of writhing reaction induced by kaolin, a known activator of factor XII, was studied. Kaolin induced a distinct writhing response, when injected intraperitoneally into mice (2.5 mg/mouse). The response disappeared in 15 min, but it was reproduced by intraperitoneal injection of captopril, 20 micrograms, into mice who had received the injection of kaolin 60 min before. This later response as well as the early one was not produced when mice were pretreated with bromelain (10 mg/kg, intravenously), 30 min before the kaolin administration. Therefore we determined if bromelain, a known depleter of plasma prekallikrein and a high molecular weight (HMW) kininogen, depletes those in mice. Plasma was collected from mice with or without pretreatment of bromelain, and kinin release of these plasma samples was examined by action of kaolin. The bromelain-treated mouse plasma released kinin amount of less than detection limit when activated with kaolin, whereas normal plasma released about 300 ng/ml of kinin of bradykinin equivalent as assessed by rat uterus contraction. Furthermore, activation of prekallikrein by kaolin was observed in mouse plasma as amidase activity to produce fluorescence from the synthetic substrate. It was completely diminished in the presence of soybean trypsin inhibitor. These results suggest that bromelain could deplete the HMW-kininogen in mouse plasma in the same way as in rat plasma. Furthermore, it is assumed that the kinin released from HMW-kininogen by kaolin could be responsible for inducing the writhing response.

Experimental approach to a role of the increased T-kininogen level in carrageenin-induced pleurisy of rats.

In order to elucidate the biological role of T-kininogen, it's levels in plasma, exudate, and liver were measured by radioimmunoassay in rats following the induction of carrageenin pleurisy. T-kininogen level in the liver microsomes was increased markedly at 8-24 hr after the carrageenin injection, and its plasma level increased at 24-48 hr with a delay. Pretreatment with dexamethasone suppressed the pleural exudate accumulation almost completely, but inhibited the T-kininogen level in plasma or liver only partially. When rats were pretreated with carrageenin injection into a paw 2 days prior to intrapleural injection of carrageenin, the pretreatment did not affect the pleurisy development, even though the plasma level of T-kininogen was greatly increased. Increased level of T-kininogen correlated well with the thiol protease inhibitor activity found in the plasma and exudate. These results indicate that an increase in the T-kininogen level does not influence the exudation, but might act as an inhibitor of thiol proteases that could be released at the inflammatory site.

[Isolation perfusion chemotherapy using cisplatin in malignant tumors of the extremities].

Since 1960 isolation perfusion chemotherapy has been performed as a preoperative procedure combined with surgery in 226 patients with malignant tumor of the extremities in our department. In this report we presented the result of isolation perfusion chemotherapy using cisplatin (CDDP) for 27 patients since 1983. The histologic classification of the malignant tumor was osteosarcoma in 17 patients, malignant fibrous histiocytoma (MFH) of bone in 8, and other tumor in 2. The extremity was perfused with CDDP (100 micrograms/ml) for 60 minutes. Of 27 patients, 11 were treated with hyperthermic isolation perfusion. The two-year survival rate of the 15 patients with osteosarcoma was 80%, and that of the 7 patients with MFH of bone 71%. The tumor was microscopically analyzed, and the ratio of necrotic to viable tumor cells was calculated. The degree of tumor necrosis was classified as excellent (greater than or equal to 95%), good (80-94%), fair (50-79%), and poor (less than 50%). Of 16 patients, 7 were excellent, 5 good, 3 fair and 1 poor. We concluded that isolation perfusion chemotherapy using CDDP is an effective procedure combined with surgery for malignant tumor of the extremities.

Prolonged activated partial thromboplastin time and deficiency of high molecular weight kininogen in brown Norway rat mutant (Katholiek strain).

Activated partial thromboplastin time (APTT) was examined in Brown Norway (B/N) Katholiek rat, which was previously reported as high molecular weight kininogen deficient. APTT of B/N Katholiek was prolonged to 35 sec in comparison with B/N Kitasato and SD rat, showing APTT of 22-24 sec. The mixture of B/N Katholiek plasma and B/N Kitasato plasma (1:1) showed normal APTT value. B/N Katholiek plasma corrected the abnormally prolonged human coagulation factor deficient plasmas, such as XI, XII and prekallikrein deficient plasmas, while it did not correct the APTT of HMW kininogen deficient, Fitzgerald plasma. Intravenous injection of bromelain, which was previously reported to produce prolonged hypotension through the activation of factor XII to release bradykinin, induced slight effect in Katholiek rat, while in Kitasato rat it showed prolonged hypotension in similar degree as SD rat. Contents of coagulation factors in B/N Katholiek thus measured as well as the values of prekallikrein and HMW kininogen previously reported were summarized and suggested that B/N Katholiek rat could be similar deficiency as Fitzgerald trait.

[Case of lipohyperplasia of the ileocecal valve with adenocarcinoma of the ascending colon].

A rare case of lipohyperplasia of the ileocecal valve contiguous with adenocarcinoma of the ascending colon is reported. The patient was a 67-year-old female with a chief complaint of muco-bloody stool. Barium enema X-ray study revealed a filling defect in the proximal portion of the ascending colon, suggestive of Borrmann II-type carcinoma and enlargement of the ileocecal valve. Ileocecotomy and right colectomy were performed. Histological examination disclosed that the tumor of the ascending colon consisted of well differentiated adenocarcinoma; the proliferation of fat tissue in the submucosa of the ileocecal valve was diagnosed as lipohyperplasia of the ileocecal valve. The histogenesis of this lipohyperplasia seems to be secondary development induced by the adenocarcinoma of the ascending colon.