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The pathogenetic role of fibronectin-related substance （FNRS）, which was immunohistologically identified mainly in the lower portion of the gastric fundic mucosa, was studied using an ethanol （EtOH）-induced gastric ulcer model of the rat. Macroscopic and microscopic changes occurred in the gastric mucosa immediately （usually within 5 minutes） and developed time-dependently after the ingestion of 100% EtOH. The FNRS in the fundic mucosa decreased similarly and time-dependently and could be hardly detected 60 minutes after the ingestion of 100% EtOH. The ulcer index（UI） increased and inversely the FNRS score decreased time-dependently, showing a mirror-image manner. 20% EtOH did not cause visible mucosal alterations, but the FNRS decreased with time. The latter changes, however, were observed to a lesser degree than those in both 50% and 100% EtOH groups. These gastric mucosal lesions, which were adjudged from macroscopic and histological changes, developed in a concentration-dependent manner for EtOH. The changes in UI and FNRS score appeared to show a mirror image. Pretreatment with either cimetidine （30 and 50 mg/kg, i. v.）, 11（R）, 16, 16-trimethyl prostaglandin E2 （tmPGE2; 10 and 50 μg/kg, p. o.） or sulfhydryl cysteamine （50 and 200 mg/kg, s. c. i.） significantly prevented macroscopic and microscopic changes in the gastric mucosa which were induced 60 minutes after the ingestion of 50% EtOH. These drugs significantly decreased the UI but increased the FNRS score, dose-dependently. These results indicate that the FNRS located in the lower portion of the fundic mucosa, in which acid and pepsin are actively secreted, plays a protective role in the pathogenesis of the EtOH-induced gastric ulcer of the rat. It is also suggested that the FNRS may be mediated by H2 receptor and/or endogenous PG.

To clarify the pathogenesis of duodenal ulcer and the mucosal protection mechanism of the duodenum, which is continuously exposed to excessive H+ in the gastric juice, the morphological alterations in Brunner's glands were observed using cysteamine-induced duodenal ulcer in rats. The results were as follows; 1） Periodic acid Schiff （PAS）-positivity and glycoprotein M2 distribution in the Brunner's glands were markedly reduced after cysteamine administration. The dilatation and flatness of the Brunner's gland cells were also induced by cysteamine administration. These morphological alterations in the Brunner's glands were remarkably inhibited by pretreatment with secretin or cetraxate. 2） Electron microscopically, the apical cytoplasm of the Brunner's gland cells was filled with numerous secretory granules （SG） and the cells showed a characteristic convex appearance toward the lumen in the control group, whereas these SG remarkably decreased in number and subsequently the cells showed a concave appearance toward the lumen after cysteamine administration. Marked flatness of the Brunner's gland cells with microvilli was also demonstrated after cysteamine administration. However, no significant morphological alterations were found in the nucleus, rough-surfaced endoplasmic reticulum （RER）, Golgi's apparatus, mitochondria and other organelles. 3） Pretreatment with either secretin, somatostatin, atropine or cetraxate, but not with cimetidine, clearly prevented the above electron microscopic changes in the Brunner's gland cells caused by cysteamine administration. Interestingly, the SG appeared to increase in the group pretreated with somatostatin. 4） These electron microscopic findings were supported by morphometric analysis using a computerized image analyzer. Namely, %SG （ratio of the area occupied by SG to Brunner's gland cells） slightly decreased 1 hour after and significantly decreased 12 hours after cysteamine administration compared with that in the untreated group. ?5） No significant changes in the %SG were found in the group pretreated with secretin, atropine, cimetidine 1 hour after cysteamine administration, whereas a significant increase in the %SG was found in the group pretreated with somatostatin or cetraxate. In addition, the reduction of the %SG seen 12 hours after cysteamine administration was significantly prevented by pretreatment with secretin, somatostatin, atropine or cetraxate, but was not inhibited by cimetidine. These results strongly suggested that the morphological changes in the duodenal Brunner's glands, which were confirmed by histological, immunohistological and electron microscopic observations, were associated with the pathogenesis and development of the duodenal ulcer and it was surmised that the Brunner's glands played an important role in the duodenal mucosal protection mechanism.

In attempt to clarify the pathogenesis of cysteamine-induced duodenal ulcer in rats, duodenal mucosal blood flow （DMBF） and duodenal mucosal vascular architecture were examined using hydrogen gas clearance method and intra-arterial infusion technique with India ink as a tracer. The effect of pretreatment with secretin, somatostatin, atropine, cimetidine, cetraxate and proglumide on the impaired duodenal microcirculation induced by cysteamine administration was also investigated. The results were as follows; 1） A significant decrease of the DMBF occurred as early as 5 min after cysteamine administration and lasted up to 60 min later, whereas no significant changes in the DMBF were found in the control group treated with saline alone. The dramatical reduction of the DMBF seemed to be in paralell with the degree of the duodenal mucosal alteration with an initial edema caused by cysteamine administration. On the other hand, cysteamine did not exert any influence on the gastric mucosal blood flow （GMBF）. 2） Pretreatment with either secretin, somatostatin, atropine, cimetidine or cetraxate significantly inhibited the reduction of the DMBF induced by cysteamine administration. In any event, these agents appeared to have beneficial effects to prevent the weakness and/or breakdown of the duodenal mucosal protection mechanism, but no similar effect was found in the group pretreated with proglumide, an antigastrin agent. 3） Intraduodenal instillation of 0.1 N HCl did not produce an effect on the DMBF compared with that in the control group with saline administered into the duodenum. 4） Using India ink as a tracer, it was demonstrated that cysteamine induced morphological and functional changes in the duodenal mucosal microcirculation system as an early effect and that these mucosal changes were prevented by pretreatment with secretin or cetraxate. These results strongly suggested that the morphological and functional alterations in the duodenal? mucosal microcirculation system, which is an important mechanism of duodenal mucosal protection, might greatly be associated with the pathogenesis and development in the cysteamine-induced duodenal ulcer.