Sunao Kawano

Impaired oxygen utilization. A new mechanism for the hepatotoxicity of ethanol in sub-human primates.

The role of oxygenation in the pathogenesis of alcoholic liver injury was investigated in six baboons fed alcohol chronically and in six pair-fed controls. All animals fed alcohol developed fatty liver with, in addition, fibrosis in three. No evidence for hypoxia was found, both in the basal state and after ethanol at moderate (30 mM) or high (55 mM) levels, as shown by unchanged or even increased hepatic venous partial pressure of O2 and O2 saturation of hemoglobin in the tissue. In controls, ethanol administration resulted in enhanced O2 consumption (offset by a commitant increase in splanchnic blood flow), whereas in alcohol fed animals, there was no increase. At the moderate ethanol dose, the flow-independent O2 extraction, measured by reflectance spectroscopy on the liver surface, tended to increase in control animals only, whereas a significant decrease was observed after the high ethanol dose in the alcohol-treated baboons. This was associated with a marked shift in the mitochondrial redox level in the alcohol-fed (but not in control) baboons, with striking rises in splanchnic output of glutamic dehydrogenase and acetaldehyde, reflecting mitochondrial injury. Increased acetaldehyde, in turn, may aggravate the mitochondrial damage and exacerbate defective O2 utilization. Thus impaired O2 consumption rather than lack of O2 supply characterizes liver injury produced by high ethanol levels in baboons fed alcohol chronically.

Chronic effect of intragastric ammonia on gastric mucosal structures in rats

The prevalence ofHelicobacter pylori (HP) in the gastric mucosa of patients with chronic atrophic gastritis has been reported to be significantly higher than in normal mucosa. To clarify the role of HP in the etiology of chronic atrophic gastritis, we assessed the effect of ammonia on the gastric mucosal structure in rats, since HP has a strong urease activity and produces abundant amounts of ammonia. Ammonia administered orally at 0.01% and 0.1% as drinking water for two to four weeks decreased the mucosal thickness and the parietal cell number and oxyntic gland number in a dose- and time-dependent manner. The decrease of mucosal thickness was significantly greater in the antral mucosa than in the body mucosa. The border between the antral and body mucosa shifted toward the cardia, reflecting the decrease in oxyntic gland numbers. Furthermore, intracellular mucin was also decreased in a dose- and time-dependent manner, especially in the antral mucosa. Thus, ammonia chronically administered orally in rats led to changes in gastric mucosal structures and functions. The results suggest that the ammonia produced by HP partly plays an etiologic role in chronic atrophic gastritis.

Mucosal blood flow stasis and hypoxemia as the pathogenesis of acute gastric mucosal injury : role of endogenous leukotrienes and prostaglandins

To clarify the roles of endogenous leukotrienes and prostaglandins in the ethanol-induced gastric mucosal injury, the effect of AA-861 (a selective 5-lipoxygenase inhibitor) and ndomethacin (a cyclooxygenase inhibitor) on the ethanol-nduced gastric mucosal lesions was investigated in fasted ats. Furthermore, the effect of these agents on the gastric ucosal microcirculatory disturbance induced by ethanol was also investigated using laser Doppler velocimetry and eflectance spectrophotometry. Forty percent ethanol caused mucosal microcirculatory stasis and mucosal hypxemia, followed by mucosal injury. The pretreatment with AA-861 reduced the mucosal injury and significantly educed the mucosal congestion and hypoxia induced by 40% ethanol. The pretreatment with indomethacin did not educe the gastric mucosal damage or influence the mucosal blood flow stasis and the mucosal hypoxemia induced y ethanol. These results suggested that the increase of endogenous leukotrienes after intragastric administration of thanol is responsible for the mucosal microcirculatory disturbance and mucosal tissue hypoxemia resulting in the mucosal injury, and that the decrease of prostaglandins alone may not play an important role in ethanol-induced mucosal injury.

Age-related change in human gastric mucosal energy metabolism

Many investigators have reported a decrease in mucosal blood flow resulting in impairment of gastric mucosal energy metabolism in animal experiments. Recently, endoscopic studies using reflectance spectrophotometry and laser Doppler flowmetry have indicated that gastric mucosal blood flow in humans decreases with age. However, changes in energy metabolism in human gastric mucosa with age remains obscure. In this study, we measured adenine nucleotides in biopsy samples from human gastric mucosa, using high-performance liquid chromatography, and investigated changes in energy metabolism with age in subjects proven normal endoscopically. Energy charge (EC = (ATP + 1/2 ADP)/ATP + ADP + AMP) in the gastric antral and body mucosa showed decrease with age. When the subjects were divided into two groups, less than and more than 65 years old, the EC level was significantly lower in the latter than the former in both antral and body mucosa (0.65 +/- 0.06 versus 0.74 +/- 0.03 in the antrum, 0.73 +/- 0.04 versus 0.79 +/- 0.04 in the body) and significantly less in the antral mucosa than in body mucosa in both groups. The adenosine triphosphate (ATP) level in the older group showed a significant decrease (6.48 +/- 1.14 versus 9.63 +/- 1.92 in the antrum, 8.59 +/- 1.64 versus 10.60 +/- 2.13 in the body) compared with those less than 65 years old. In the antral mucosa of the older group the adenosine diphosphate (ADP) level was also significantly lower than that in the group less than 65. In conclusion, in the elderly, the energy metabolism in human gastric mucosa is impaired, and this may weaken their defensive mechanism.

Changes in the Intracellular Calcium Ion Concentration in the Gastric Mucosa in a Rat Ischemia-Reperfusion Model

To investigate the role of the intracellular calcium ion in the development of acute gastric mucosal lesions, phosphorylase a activity was measured as an index of the intracellular calcium ion concentration ([Ca2+]i), using Lowrys method, in the rat ischemia-reperfusion model. [Ca2+]i increased significantly at the end of the ischemic state without acute mucosal lesions (AGML). After reinfusion, [Ca2+]i showed a slight increase and AGML developed. Continual intravenous infusion of the calcium channel blocker, diltiazem (1 mg/kg/hr), inhibited the increase in [Ca2+]i in the ischemic state and reduced the development of AGML after reinfusion. These results suggest that the increase in [Ca2+]i in the ischemic state plays an important role in the development of AGML.

Protective effect of PGD2 against ethanol-induced gastric mucosal injury in rats.

The protective effect of prostaglandin D2 (PGD2) in ethanol-, HCl-, or NaCl-induced gastric mucosal injury was investigated. To clarify the mechanism, the gastric mucosal hemodynamics were also investigated using reflectance spectrophotometry and laser Doppler flowmetry in anesthetized rats. PGD2 administered orally significantly reduced the ethanol-induced mucosal injury. Although it did not reach any significance, PGD2 also reduced 0.6 N HCl-induced mucosal damage, and slightly reduced 25% NaCl-induced mucosal damage. Topical application of PGD2 did not affect gastric mucosal hemodynamies at steady state before the administration of necrotizing agent. However, PGD2 significantly improved the gastric mucosal microcirculatory congestion caused by ethanol, and partly improved 0.6 N HCl-induced ischemia. However, it did not improve the 25% NaCl-induced mucosal congestion. The results indicated that PGD2 had a protective effect in the ethanol-induced gastric mucosal injury through the improvement of gastric mucosal microcirculation. However, further investigations are needed to clarify the precise effect of PGD2 in 0.6 N HCl- or 25% NaCl-induced mucosal damage.