H. Paimela

Current Features of Peptic Ulcer Disease in Finland: Incidence of Surgery, Hospital Admissions and Mortality for the Disease During the Past Twenty-five Years

Background: Medical therapy of peptic ulcer disease (PUD) has improved dramatically during the past 20 years with the introduction of modern antisecretory drugs as well as eradication therapy of Helicobacter pylori. During the 1990s, there has been a 3-fold increase in the consumption of histamine2-receptor antagonists and proton-pump inhibitors, but also an 8-fold increase in the consumption of nonsteroidal anti-inflammatory drugs (NSAIDs) in Finland. Methods: The incidence of surgery, hospital admissions and mortality for PUD was analysed between 1972 and 1999; the data were collected from the National Research and Development Centre for Welfare and Health and from the National Centre for Statistics. In the analysis, the codes of the International Statistical Classification of Diseases 8-10 were used. Results: In 1987, 11.9 elective operations (per 10 5 inhabitants) were performed (mean of 2 consecutive years), but only 1.3 in 1997, a reduction of 89%. In 1987, 5.2 emergency operations for ulcer perforation or bleeding were performed, whereas there were 7.5 in 1997, an increase of 44%. The annual hospital admission rate increased from 38.3 admissions (per 10 5 inhabitants) in 1972 (mean ± s (standard deviation) of 5 consecutive years) to 68.7 in 1992. This 79% increase was mainly due to bleeding from gastric ulcer in elderly women. The overall annual mortality rate increased between 1972 and 1992 from 6.4 to 8.4 deaths (per 10 5 inhabitants), i.e. by 31%. The mortality rate from ulcer perforation and haemorrhage increased from 4.2 deaths in 1972 to 7.3 deaths in 1992, i.e. by 74%. Conclusions: The increasing incidence rates of emergency surgery, hospital admissions and mortality for PUD in the 1980s and 1990s have started to decrease in the most recent years in Finland. This epidemiologic change probably reflects both the demographic change and an increased consumption of NSAIDs, among the elderly people, in particular. The most recent epidemiologic change may reflect an increased consciousness about the harmful effects of conventional NSAIDs. Regardless of the constantly occurring emergency surgery, elective surgery for PUD is hardly ever required today.

Intracellular pH in isolated Necturus duodenal mucosa exposed to luminal acid

Regulation of intracellular pH in gastric epithelial surface cells exposed to luminal acid was investigated in isolated Necturus antral mucosa using microelectrode technique. Exposure of the mucosa to luminal pH 2 acidified intracellular pH from 7.21 +/- 0.01 to 6.95 +/- 0.04 (N = 50). Removal of Na+ from the perfusates or addition of amiloride (1 mM) to serosal perfusate (containing HCO3-) had no influence on intracellular pH during exposure to pH 2 (N = 6), but removal of HCO3-/CO2 from or addition of 4, acetamido-4-isothiocyanatostilbene-2,2-disulfonic acid (0.5 mM) to the serosal perfusate (containing Na+) acidified intracellular pH from 7.02 +/- 0.03 to 6.45 +/- 0.15 (p less than 0.01, N = 10) and from 6.97 +/- 0.06 to 6.58 +/- 0.26 (p less than 0.01, N = 6), respectively, in 15 min. In tissues exposed to mucosal pH 6, epithelial surface pH was about 1.3 pH units higher than pH of the mucosal bulk solution. Removal of Cl-/HCO3- from the serosal perfusate acidified epithelial surface pH by about 0.5 pH units (p less than 0.01, N = 6), suggesting that serosal HCO3- sustains intracellular pH, at least in part, by generating an alkaline buffer layer at the epithelial surface. In the absence of HCO3-/CO2, a stable intracellular pH was obtained when the tissue was exposed to mucosal pH 2.7, but in this situation intracellular pH was sensitive to Na+ removal or amiloride addition, intracellular pH decreasing from 7.00 +/- 0.07 to 6.48 +/- 0.10 (p less than 0.01, N = 6) and from 6.86 +/- 0.06 to 6.32 +/- 0.01 (p less than 0.01, N = 7), respectively, in 15 min. The data suggest that in gastric epithelium exposed to luminal acid, physiological intracellular pH is primarily maintained by the buffer action of serosal HCO3- transported to the epithelial surface to impede the entry of luminal H+ into mucosal tissue. Removal of the sheltering HCO3- unmasks a second line, Na(+)-dependent and amiloride-sensitive intracellular pH regulatory mechanism, presumably a Na+/H+ antiport.

Exogenous Surface-Active Phospholipid Protects Necturus Gastric Mucosa Against Luminal Acid and Barrier-Breaking Agents

The nature of the protective action of exogenous surface-active phospholipid on gastric mucosa was studied in isolated Necturus antral mucosa by measuring intracellular pH and intraepithelial potentials and resistances with a microelectrode technique. Exposure of the antral mucosa to luminal pH 2 acidified intracellular pH in surface epithelial cells by 0.6-0.3 pH units. A 20-minute pretreatment with exogenous (pulmonary) surfactanlike phospholipid completely abolished this effect. Obviously, phospholipid protected the mucosa against intracellular acidosis by decreasing the apical cell membrane conductance to H+ (and other ions), because it increased apical cell membrane resistance by +108% and total transcellular resistance by +86% but had no significant effects on paracellular or total transepithelial resistances. In mucosas exposed to three barrier-breaking agents, 10 mmol/L acetylsalicylic acid, 20% (vol/vol) ethanol, and 10 mmol/L taurocholate, at acid luminal perfusate (pH 2.0-2.5), a profound intracellular acidification of 0.9-1.3 pH units/15 min occurred. Pretreatment of the tissue with phospholipid significantly opposed intracellular acidification, but the modulatory influences on the changes in intraepithelial potentials or resistances were less conspicuous and mostly insignificant.

Role of Na+-H+-antiport in restitution of isolated guinea pig gastric epithelium after superficial injury

In addition to its pHi regulatory function Na+-H+-antiport is also involved in volume regulation of epithelial cells, particularly in neutral conditions. It is also known that the antiport is activated after ligand binding following growth factor receptor activation. The aim of the present study was to evaluate the role of the antiport in restitution of gastric mucosa and whether its activity is dependent on the type of superficial injury. Therefore the fundic epithelium of guinea pig stomach was perfused in an Ussing chamber in neutral conditions. Na+-H+- and Cl−-HCO3−-antiports were inhibited with 1.0 mM amiloride, 1.0 mM SITS, or with HCO3− removal and Na+-K+-2Cl2−-cotransporter with 0.3 M furosemide during 4 hr of restitution after superficial injury induced either by 1.25 M NaCl or by 1.0% Triton. Luminal exposure of the epithelium to amiloride had no effect on restitution but serosal application abolished the process completely. The inhibitory effect of amiloride was similar after both NaCl and Triton injury. The inhibition of Cl−-HCO3−-antiport with SITS interfered with the process as well, while HCO3− removal had no significant inhibitory effect, nor did the inhibition of Na+-K+-2Cl−-cotransporter. The morphologic findings were in accordance with the electrophysiologic measurements in each pair of tissues. It is concluded that the Na+-H+-antiport is essential for the epithelial cells during restitution even in neutral conditions, but a functional Cl−-HCO3−-antiport is also required. The activity of Na+-H+-antiport is sensitive to basolateral amiloride and is necessary regardless of the type of chemical injury.

Present Views on Restitution of Gastrointestinal Epithelium

reviewed by Silen (15) and Lacy (16). A brief luminal exposure to hypertonic saline was used to induce superficial injury to oxyntic mucosa. Morphologically evident reepithelialization occurred concurrently with the return of mucosal electrophysiological parameters and the tissues ability to secrete acid. Restitution was found to take place in frog gastric mucosa over a 4-hr period (7) and somewhat more rapidly in the

TOLERANCE OF RAT DUODENUM TO LUMINAL ACID

The tolerance of the duodenal mucosa to luminal acid was investigated by measuring with a liquid sensor pH microelectrode technique the epithelial surface pH (pHs) and subepithelial tissue pH (pHt) in rat proximal (duodenal bulb, Brunner gland area) and distal duodenum exposed to luminal acid. Under basal conditions, pHs was roughly equal in both parts of the duodenum; proximal duodenum, 7.40 ± 0.14 (mean ± sem) at the villus tip and 7.54 ± 0.16 at the depth of crypt; distal duodenum, 7.46 ± 0.19 and 7.55 ± 0.09, respectively. Yet, exposure of the mucosa to luminal acid (10 mM HCl) provoked a significantly lesser decrease of pHs (0.25 ± 0.13 vs 0.42 ± 0.12 pH units) in the proximal duodenum, suggesting that the response of epithelial HCO3 secretion to luminal acid is stronger in that part of the duodenum. Further, the initial acidification of pHs was followed in the proximal duodenum by a secondary alkalinization of pHs, leading to normalization of pHs, which may suggest activation of compensatory protective mechanisms. pHt at the villus tip was likewise roughly equal in both parts of duodenum (7.29 ± 0.05 vs 7.17 ± 0.04), but, again, acidification of the luminal perfusate progressively from 10 to 100 mM HCl induced a much earlier and significantly more profound acidification in the distal than in the proximal duodenum. The possible contribution of Brunner glands to the greater mucosal tolerance to acid in the proximal duodenum was assessed by investigating whether stimulation or inhibition of Brunner gland secretion modulates the response of the duodenal mucosa to acid. It appeared that even though stimulation of Brunner gland secretion by secretin increased slightly but significantly pHs (0.10 ± 0.03 pH units), it did not alleviate intramucosal acidosis during exposure to luminal acid. In contrast, inhibition of Brunner gland secretion by somatostatin had no influence on pHs but markedly enhanced the susceptibility of the mucosa to tissue acidosis during acid exposure. This suggests that Brunner glands may, indeed, have a role in the mucosal defense against acid but that this protective action is mediated by some other mechanisms than stimulation of alkaline secretion. The data indicate that the proximal duodenum has a greater tolerance against luminal acid than distal duodenum, presumably due to a stronger stimulatory response of HCO3 secretion to luminal acid. In addition, the action of the Brunner glands may contribute to the enhanced capacity of the proximal duodenum to withstand luminal acid.

Calcium Signaling Is Involved in EthanolInduced Volume Decrease and Gap Junction Closure in Cultured Rat Gastric Mucosal Cells

Ethanol is a well-established “barrier breaker” in gastric mucosa, but its detailed effects at the cellular level remain unclear. We have previously shown that the intracellular free calcium concentration is increased, gap junctions are closed, and cell volume is decreased after exposure to 5% (v/v) ethanol in primarily cultured rabbit gastric epithelial cells. Rat gastric mucosal (RGM) cells were grown to confluence on a coverslip or on a filter membrane. Gap junctional diffusion was measured in 5-carboxyfluorescein-loaded cells by bleaching a small area with a laser and measuring the recovery with confocal microscope. Intracellular calcium was measured spectrofluorometrically in fura-2-loaded cells. For cell volume measurements the cell monolayer was loaded with calcein and imaged along the Z-axis with a confocal microscope. The changes in fluorescence intensity were intercepted as a measure of cell volume change. TMB-8 was used to inhibit intracellular calcium release and lanthanum to block plasma membrane calcium selective ion channels, while BABTA served as an intracellular calcium chelating agent. Results showed that ethanol (7.5%, v/v) exposure increased intracellular calcium from 69± 7 to 142± 11 nM (N = 5; P < 0.05), decreased cell volume by −23± 5% (N = 8; P < 0.05), and induced gap junction closure (fluorescence recovery from 37± 9 to 15± 3%; N = 6; P < 0.05). A serosal potassium channel blocker, quinine, almost completely prevented the ethanol-induced cell volume decrease (from −23± 5 to −3± 3%), suggesting that opening of basolateral potassium channels underlies cell shrinkage. BABTA inhibited completely (from 35± 3 to 39± 4 nM; N = 6; P < 0.05), and TMB-8 + lanthanum partially (from 60± 6 to 92± 12 nM; N = 6; P < 0.05), the ethanol-induced intracellular calcium increase. BABTA also abolished the ethanol-induced volume decrease (from −23± 5 to 1± 4%; N = 6; P < 0.05), while TMB-8 + lanthanum had a lesser effect on it (from −23± 5 to −11± 3%; N = 9; P < 0.05). They also abolished the closure of gap junctions induced by ethanol (fluorescence recovery, 38± 5% for BABTA and 30± 4% for TMB-8 + lanthanum). We conclude that luminal ethanol opens basolateral calcium-dependent potassium selective channels with resultant shrinkage of the cells and blocks the intercellular gap junctions. These actions are mediated by intracellular calcium signaling.

Recent trends in mortality from peptic ulcer disease in Finland

The enormous change of medical therapy of peptic ulcer disease in the 1970s has resulted in a significant decrease of elective ulcer surgery. It has been speculated whether this might be reflected in the mortality of the disease. Therefore, in the present study, the mortality rate of the disease was evaluated in Finland during the past 17 years covering the dramatic change in the medical therapy: the introduction of H2-receptor antagonists. This was done with a population-based epidemiological study by analyzing 1262 death certificates of people dying from peptic ulcer disease in Finland between 1972 and 1989. The study showed that there has been almost twofold increase in the mortality of the disease between 1972 and 1989 in Finland. This was mainly due to the significantly increased number of fatal ulcer hemorrhages in older people but also mortality from ulcer perforations increased. This unfavorable epidemiological progress was most striking among elderly women and became manifest during the 1980s. We conclude that mortality from peptic ulcer disease has significantly increased in Finland due to fatal ulcer hemorrhages and perforations. This epidemiological change became manifest in the 1980s, concurrently with the dramatic change in the medical therapy of peptic ulcer disease.

Gastric mucosal acid-base balance

Abstract. Acute gastric ulceration induced by haemorrhagic shock is associated with profound intramucosal acidification due to diffusion of luminal H+ into the mucosa. High‐HCO3−metabolic alkalosis protects the mucosa against this ulceration, whereas low‐HCO3−respiratory alkalosis does not, suggesting that lack of systemic and intramucosal HCO3−. rather than tissue acidosis per se, renders the mucosa susceptible to ulceration. In normal mucosa, disruption of the mucosal barrier by taurocholate, ethanol or acetylsalicylic acid leads to efflux of alkali (HCO3−) from the mucosa, with generation of an alkaline buffer layer at the epithelial surface to protect the mucosa from further damage. In ischaemic mucosa no such protective alkaline layer is formed, and exposure to luminal acid leads to severe acidification of and damage to the mucosa. The efflux of alkali may be driven by capillary hydrostatic pressure, since no such protective alkaline efflux occurs in vitro, but rather exposure to luminal acid and barrier‐breaking agents results in intracellular acidification. The potential pathogenetic role of a disrupted intramucosal acid‐base balance, as well as the protective effect of systemic and intramucosal HCO3− in acute gastric stress ulceration is further substantiated by the in vitro findings that perfusion conditions simulating in vivo ulcerogenic conditions provoke intracellular acidosis, and serosal HCO3− significantly contributes to the maintenance of normal intracellular pH in surface epithelial cells exposed to luminal acid.

Reperfusion but Not Acute Ischemia in Pig Small Intestine Induces Transcriptionally Mediated Heat Shock Response in situ

Background: Although there is data on the cytoprotective role of heat shock proteins in intestinal ischemia-reperfusion, the effects of ischemia and reperfusion per se on the small intestinal heat shock response have been poorly characterized. Methods: Four female pigs were subjected to 60-min ischemia by superior mesenteric artery occlusion followed by 360-min reperfusion. Systemic and local hemodynamics were monitored. Samples from the jejunal mucosa and muscularis were obtained for histology and for time series molecular biologic analyses of heat shock transcription factor 1 (HSF1), hsp70 mRNA and Hsp70 protein. Results: A 30-min reperfusion of jejunum after a preceding 1-hour ischemia results in a significantly increased DNA-binding activity of HSF1, in a 10-fold increase of hsp70 mRNA in the mucosal and in a 7-fold increase in the muscular layers. Translational activation and accumulation of Hsp70 protein occurs after 60 min of reperfusion in the intestine. Nevertheless, a 60-min ischemia inducing mucosal detachment does not induce the heat shock response at any level analyzed. Conclusions: Ischemia alone is insufficient to induce the heat shock response, whereas subsequent reperfusion induces the response via transcriptionally mediated induction of Hsp70 synthesis both in the mucosal and muscular layers.