We examined the effect of diethyldithiocarbamate (DDC), the superoxide dismutase (SOD) inhibitor, on the development of gastric lesions induced by indomethacin in rats. Indomethacin (25 mg/kg) was given subcutaneously, and gastric acid secretion, motility, lipid peroxidation, vascular permeability, and myeloperoxidase as well as gastric lesions were measured. Indomethacin produced high-amplitude contractions of the stomach and caused hemorrhagic lesions in the corpus mucosa with significant increase in neutrophil-related processes such as myeloperoxidase activity, vascular permeability and lipid peroxidation. These changes caused by indomethacin were all significantly inhibited by prior administration of atropine (3 mg/kg s.c). Pretreatment of the animals with DDC (75-1,000 mg/kg s.c.) prevented these lesions induced by indomethacin in the corpus mucosa in a dose-dependent manner ( > 100 mg/kg), though at high doses ( > 750 mg/kg) some damage was found in both the antrum and duodenum. DDC showed a significant inhibition against the gastric mucosal SOD activity ( > 400 mg/kg), yet potently suppressed the increase of lipid peroxidation, vascular permeability, and myeloperoxidase activity caused by indomethacin. DDC dose-dependently ( > 75 mg/kg) inhibited the enhancement of gastric motility caused by indomethacin and showed a weak antisecretory effect at high doses ( > 750 mg/kg). These results showed that DDC reduced indomethacin-induced gastric lesions by suppressing gastric motility, despite inhibiting SOD activity. This study also indicates the prime importance of gastric hypercontraction in the pathogenesis of this lesion model and suggests that other events including the neutrophil-related processes may be secondary to gastric hypercontraction caused by indomethacin.

The role of nitric oxide (NO) in the gastric mucosal blood flow response and the healing of HCl-induced gastric lesions was investigated in rats. After 18 h fasting rats were given 0.6 N HCl p.o. for the induction of gastric lesions, and 1 h later they were fed normally. After induction of gastric lesions, they were repeatedly administered the NO synthase inhibitors N^G-nitro-L-arginine methyl ester (L-NAME 5-20 mg/kg p.o. twice daily) or aminoguanidine (20 mg/kg s.c. once daily) for 7 days. Gastric lesions caused by HCl healed almost completely within 5 days with granulation and to an extent with re-epithelialization. Repeated administration of L-NAME but not aminoguanidine significantly delayed the healing of gastric lesions in a dose-dependent manner. The damaged mucosa secreted less acid, but showed a marked rise in H⁺ permeability, resulting in luminal acid loss accompanied by an increase of mucosal blood flow. Aminoguanidine did not significantly affect any of these functional changes observed in the stomach after damage by HCl, whereas L-NAME treatment slightly reversed the decreased acid response, increased the luminal H⁺ loss, and totally inhibited the mucosal hyperemic response associated with luminal acid loss in the damaged mucosa. In addition, the deleterious influences of L-NAME on the mucosal blood flow response and the healing of gastric lesions were significantly antagonized by co-administration of L-arginine but not of D-arginine (500 mg/kg × 2, i.p.). Luminal output ofNO^-₂/NO^-₃ was significantly increased in pylorus-ligated stomachs in control rats on days 3 and 5 after damage, and such increases in gastric NO output were completely attenuated by L-NAME treatment. These results suggest that endogenous NO may contribute to the healing of acute gastric injury by mediating the mucosal hyperemic responses associated with acid back-diffusion and by facilitating acid disposal in the damaged mucosa. NO mediating such responses and participating in the healing aspect of gastric lesions may be produced by the constitutive type of NO synthase.

A "drop-stamp method" has been developed for the design and fabrication of molecular interfaces. The amphiphilic protein HFBII, isolated from filamentous fungi, was employed as a genetically taggable molecular carrier for the formation of a structrally ordered layer of functional protein molecules on a solid surface. In this study, the interfacial behavior of maltose-binding protein tagged with HFBII (MBP-HFBII fusion protein) at both the air/water and water/solid interfaces was investigated. A rigid molecular layer of MBP-HFBII fusion protein was successfully formed through the drop-stamp procedure by employing an intermixed system, in which HFBII molecules are intermingled as nanospacers to prevent the intermolecular steric hindrance of the fusion protein. The results show that the drop-stamp method can be utilized in the high-throughput fabrication of structurally ordered molecular interfaces.

We investigated the effects of pituitary adenylate cyclase-activating polypeptides (PACAPs) on gastroduodenal HCO(3)- secretion in anesthetized rats and characterized their effects by comparison with the effects of vasoactive intestinal polypeptide (VIP). Under urethan anesthesia, a rat proximal duodenal loop or a rat stomach mounted in an ex vivo chamber (in the absence of acid secretion) was perfused with saline, and HCO(3)- secretion was measured at pH 7.0 using a pH-stat method and by addition of 10 mM HCl. Intravenous injection of PACAP-27 stimulated HCO(3)- secretion in a dose-dependent manner in the duodenum, but not in the stomach, although this peptide had no effect on duodenal HCO(3)- secretion after intracisternal administration. The duodenal HCO(3)- stimulatory action was similarly observed after intravenous administration of PACAP-38 and VIP, and the potency of action was in the following order: PACAP-27 > PACAP-38 = VIP. The duodenal HCO(3)- stimulatory action of PACAP-27 was potentiated by pretreatment with 3-isobutyl-1-methylxanthine, similar to that of prostaglandin E2, and was significantly attenuated by PACAP-(6--27) (PACAP antagonist) or Ac-Tyr1,D-Phe2-VIP (VIP antagonist) but was not affected by bilateral vagotomy or prior administration of atropine, verapamil, and indomethacin. Forskolin, the stimulator of adenylate cyclase, also increased HCO(3)- secretion in the duodenum, but not in the stomach. These results suggest that 1) PACAP is a potent stimulator of HCO(3)- secretion in the duodenum, but not in the stomach, and may be involved in the peripheral regulation of duodenal HCO(3)- secretion, 2) this action is mediated by adenosine 3',5'-cyclic monophosphate, probably through PACAP and VIP receptors, and 3) adenosine 3',5'-cyclic monophosphate is a mediator in duodenal, but not in gastric, HCO(3)- secretion.

Background: Several severity scoring systems for predicting mortality are established in community-acquired pneumonia (CAP). Objectives: The predictability of the aggravation such as requirement for mechanical ventilation in addition to mortality was examined in CAP patients with acute respiratory failure by using the age, dehydration, respiratory failure, orientation disturbance and blood pressure (A-DROP) scoring system which was proposed by the Japanese Respiratory Society. Methods: This study was a prospective, multicenter, observational cohort study. The severity of pneumonia was examined using A-DROP and Pneumonia Severity Index (PSI) which originated from the Infectious Disease Society of America. Requirement for mechanical ventilation and mortality were evaluated for 28 days. Results: 482 CAP patients with acute respiratory failure were enrolled in the study. The 28-day mortality and mechanical ventilation rates were 12.3 and 14.4%, respectively. There were no significant differences in the areas under the receiver-operator characteristic curves for prediction of mortality between A-DROP and PSI (χ² test; p = 0.3613). In the subgroup analyses by severity, the A-DROP scoring system showed a severity-dependent increase of mortality (moderate 5.6%, severe 16.1%, extremely severe 27.1%, Cochran-Armitage trend test; p < 0.0001). Similar results were obtained for mechanical ventilation rate (moderate 9.8%, severe 16.7%, extremely severe 25.4%, Cochran-Armitage trend test; p = 0.0006). The compliance with scoring the A-DROP was higher than that with scoring the PSI (96.9 vs. 71.6%). Conclusions: The results of this study suggest that the A-DROP scoring system could be a simple CAP risk scoring system which could predict not only mortality, but also the requirement for mechanical ventilation.