JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY 2004, 55, Suppl 2, 5–17
www.jpp.krakow.pl
S.J. KONTUREK*,P. C. KONTUREK**, T. PAWLIK***, Z. SLIWOWSKI*,
W.OCHMAÑSKI***, E. G. HAHN*
DUODENAL MUCOSAL PROTECTION BY BICARBONATE
SECRETION AND ITS MECHANISMS
* Department of Physiology, Jagiellonian University Medical College, Cracow, Poland
** First Department of Medicine, University Erlangen-Nuernberg, Erlangen, Germany
*** Department of Internal Medicine and Gerontology, Jagiellonian Medical College
Proximal
portion
of
duodenum
is
exposed
to
intermittent
pulses
of
gastric
H
+
discharged by the stomach. This review summarizes the mechanisms of duodenal
mucosal integrity, mainly the role of mucus-alkaline secretion and the mucous barrier
protecting surface epithelium against gastric H . The mucous barrier protects the
+
leaky duodenal epithelium against each pulse of gastric H , which penetrates this
+
barrier and diffuses into duodenocytes, but fails to damage them due to; a) an
enhanced
expression
prostaglandins
(PG)
production
of
intestimal
peptide
several
NO,
of
and
cyclooxygenase-1
of
nitric
stimulating
neurotransmitters
also
(VIP),
oxide
duodenal
HCO3
stimulating
pituitary
(COX-1),
(NO)
-
with
synthase
release
(NOS)
of
with,
protective
however,
secretion and b) the release of
HCO3
secretion such as vasoactive
adenylate-cyclase
activating
polypeptide
(PACAP), acetylcholine, melatonin, leptin and ghrelin released by enteric nerves and
mucosal cells. At the apical duodenocyte membrane at least two HCO3 /Cl anion
+
exchangers operate in response to luminal H to provide adequate extrusion of HCO3
into duodenal lumen. In the basolateral portion of duodenocyte membrane, both non+
electrogenic (NBC) and electrogenic (NBCn) Na -HCO3 cotransporters are activated
by the exposure to duodenal acidification, causing inward movement of HCO3 from
extracellular fluid to duodenocytes. There are also at least three Na /H
+
amiloride-sensitive exchangers, eliminating H
+
+
(NHE1-3)
which diffused into these cells. The
Helicobacter pylori (Hp) infection and gastric metaplasia in the duodenum with
bacterium inoculating metaplastic mucosa and inhibiting HCO3
secretion by its
endogenous inhibitor, asymetric dimethyl arginine (ADMA), may result in duodenal
ulcerogenesis.
Key
w o r d s : Duodenal
mucosal
barrier,
duodenal
HCO3 ,
prostaglandins,
CCK, vagal nerves, sodium-bicarbonate cotransport, H /Na
+
/Cl exchanger
-
+
nitric
oxide,
exchanger, HCO3
-
6
INTRODUCTION
The duodenal cluster unit consists of a group of organs, including duodenum
itself,
stomach,
pancreas,
liver
and
biliary
tree.
These
organs
originate
embryologically from the closely related structures, whose functions are regulated,
at least in part, by the duodenum. The lining of the duodenum is equipped with a
variety of receptors sensitive to chemical (pH, osmolarity, and nutrients) and
physical factors (pressure and contractility of duodenum) that activate neurohormonal mechanisms maintaining the integrity of the duodenal mucosa and also
involved in the control of gastric, pancreatic and hepato-biliary functions.
This article is designed to overview the mucoso-protective and anti-ulcer
mechanisms of the duodenum, which is intermittently exposed to various irritants
emptied by the stomach, especially the aggressive factors such as gastric acid (H )
+
and pepsin as well as other irritants present in the ingested food, contaminated by
bacteria and their toxins or originating from the stomach or biliary tree.
Since
its
identification
in
the
stomach
by
Prout
in
1823
of
HCl
(1),
its
secretory mechanisms have been the subject of extensive investigations during
last century leading to discovery of such stimulants as vagal nerves by Pavlov in
1886 (2), gastrin by Edkins in 1906 (3), and histamine by Popielski in 1916 (4).
With the synthesis of antagonists of H2-receptors discovered by Black (5) and
proton pump inhibitors by Sachs et al. (6), that were found to inhibit all forms of
gastric secretion including that induced by meal, a major break-through occurred
in gastric physiology (Fig. 1).
Gastric acid and pepsin as aggressive factors
Gastric acid (and pepsin), is considered as major aggressive factor against the
gastro-duodenal mucosa as outlined in 1910 by German surgeon, K. Schwarz (7),
who formulated famous dictum "No acid - no ulcer", implying that the presence
of acid is the "condition sine qua non" of ulcer formation (see Fig. 1). It is of
interest that in the same publication, Schwarz considered "the mucosal resistance"
as important factor contributing to the possible ulcerogenesis. Schwarz's dictums
related to pathogenesis of peptic ulcer formation was not challenged until Allen
and Garner (8) and then Flemstrom and Garner (9) provided direct evidence for
the ability of gastro-duodenal mucosa to respond to the action of gastric acid with
an immediate and abundant secretion of HCO3 . Apparently, the secretion of
HCO3
-
was soon found to be an active, metabolism-dependent transport occurring
along the entire gastrointestinal tract.
Duodenal alkaline secretion
As peptic ulcers in humans develop both in the stomach and duodenum,
especially in its upper portion, “duodenal cup”, we used dogs with canulated
pouches prepared from the oxyntic and antral portions of the stomach and with
7
Major discoveries and historical figures in gastrology
* the presence of HCl in the stomach by W. Prout in 1823
* gastric HCl secretion controlled by vagus by I.P. Pavlov in 1895
* gastric HCl secretagogue - gastrin by J.S. Edkins in 1902
* histamine as gastric HCl secretagogue by L. Popielski
in 1916
* H2-receptor antagonists by J. Black in 1972 and proton pump
inhibitors by G. Sachs in 1980 showed that they inhibit
HCl secretion stimulated by various stimuli (histamine,
histamine,
vagal excitation & meal)
meal) and exbibit antianti-ulcer efficacy
* lend support for old K. Schwarz’s (1910) concept
that ulcer formation requires gastric acid to
attenuate mucosal protection and induce ulcer
according to his dictum „NO ACID NO ULCER”
Mucosal
resistance
Parietal
cells
Acid
G
Gastrin
Fig. 1. Historical background of major discoveries in gastrology supporting the initial concept of
Schwarz dated from 1910 that gastric acid is required as an aggressive factor to attenuate mucosal
protection and to induce gastric or duodenal peptic ulceration.
loops fashioned from the proximal and distal duodenum, a direct evidence was
obtained evidence that, indeed, upper GI mucosa possesses the ability to secrete
HCO3 , the most effective in this respect being proximal part of the duodenum,
though
some
less
impressive
alkaline
secretion
was
also
noticed
in
distal
duodenum and in the gastric antrum and corpus (10). Another study on the in situ
perfused proximal duodenum including duodenal bulb kept between two balloons
in conscious dogs, showed higher HCO3
-
secretion than that released by the
isolated (and externally denervated) proximal duodenal loop of similar length,
suggesting an important role of extrinsic autonomic innervation in the maintance
of this secretion (11). Interestingly, such denervation of the proximal duodenum
resulted
also
reflexes
controlling
in
the
elimination
gastric
H
+
of
acid-induced
secretion
(12).
duodeno-gastric
Actually,
the
inhibitory
balance
between
protective and aggressive factors acting on the mucosa plays a decisive role in the
pathogenesis of mucosal lesion or integrity (Fig. 2).
As expected from the concept of Boldyreff's (13), who first recognized at the
end of 19
th
century the cyclic periodicity of motor and secretory gastrointestinal
functions, it was found that also the duodenal alkaline secretion shows periodicity
8
Peptic ulcer
Mucosal integrity
Aggressive Factors
(excessive H+-pepsin,
pepsin,
NSAIDs,
NSAIDs, H. pylori )
Fig.
2.
The
imbalance
between
various
Protective Factors
(mucus-HCO
mucus-HCO3secretion
mucosal barrier,
barrier,
mirocirculation,
mirocirculation,
mucosa restitution )
aggressive
and
protective
factors
contribute
to
ulcerogenesis.
in phase with migrating motor complex (MMC), reaching peaks at phases II and
III and nadir at phase I of this MMC (10). Feeding interrupts this periodicity and
induces more uniform alkaline secretion. The rise in HCO3
-
at the phase II and III
has been attributed to the alkaline stimulation by increments in plasma motilin
and ghrelin and activation of cholinergic neurons of enteric nervous system
(ENS) as this alkaline secretion can be suppressed by atropine (11). Since at phase
II/III, there is also an increase in gastric acid secretion and enhanced gastric
emptying with progressive motor activity, it is possible that gastric H
+
into the duodenum acts on luminal duodenal HCO3
-
partial pressure, pCO2, stimulating additionally HCO3
-
discharged
to release CO2, raising its
secretion (11).
Vagal excitation, such as achieved with sham-feeding in dogs, was found to
result in a dramatic stimulation of proximal duodenal alkaline secretion that could
be
partly
attenuated
using
atropine
(11),
suggesting
that
vagal-cholinergic
innervation plays an important role in the regulation of sham-feeding-induced
secretion, that was
duodenal HCO3 . Unlike vagally-induced duodenal HCO3
relatively little affected by suppression of prostaglandin (PG) biosynthesis with
indomethacin (11), basal and HCl- or arachidonic acid-induced duodenal alkaline
secretion was found to be PG-dependent. These acidic stimulants applied on the
9
duodenal mucosa caused concentration-dependent increase in the HCO3
-
as well
as in mucus glycoprotein secretion (14). The increase in duodenal HCO 3 brought
about by arachidonic acid were prevented by the pre-treatment with indomethacin
similarly as those induced by HCl. As mucus layer covering the epithelial surface
of
the
duodeum
is
the
first
line
of
mucosal
defense
against
chemical,
predominantly acidic irritant, as well as the mechanical, bacterial or enzymatic
insults, the components responsible for these protective functions appear to be
highly glycosylated mucus glycoproteins. Following arachidonate application,
mucus
glycoproteins
were
significantly
enriched
in
phospholipids
and
this
certainly enhanced the protective qualities of the mucus gel.
Using similar to our technique of duodenal perfusion technique in humans,
Isenberg and his colleagues (15) found that in normal subjects, the proximal
duodenal HCO 3 secretion reached higher values than that in distal duodenum and
that
it
was
greatly
enhanced
by
mucosal
acidification
or
administration
of
exogenous PGE2. In contrast, duodenal ulcer (DU) patients show reduced HCO3
-
response to luminal acid, despite of higher endogenous PGE2 release by proximal
duodenum
due
to
overexpression
of
COX-2
and
this
deficiency
of
alkaline
secretion has been attributed to mucosal infection with Hp, inflammation and
scarring (16). The eradication of Hp was found to increase duodenal alkaline
secretion and this could be attributed to the recovery of duodenal mucosa from
the inflammation induced by Hp infecting the gastric metaplastic areas in the
duodenum (16). These and other studies seem to confirm that both in humans and
animals, PGE2 is a potent stimulant of duodenal HCO3
-
secretion and appears to
be responsible, at least in part, for basal and acid-induced alkaline secretion (12,
13, 16, 17). The mucus-alkaline secretion occurs in the mucosa of the entire
gastrointestinal tract, the most extensive being that of duodenum, where mucous
cells exhibit high activity of carbonic anhydrase and active exchanger HCO3
extruding HCO3
-
-
/Cl
-
into the duodenal lumen (Fig. 3).
Neuro-hormonal mechanisms of alkaline secretion
In addition to PG, numerous other substances both naturally occurring or used
therapeutically, have been reported to contribute to the stimulation of duodenal
alkaline
secretion.
We
reported
that
sucralfate
and
colloidal
bismuth
citrate
(DeNol), administered in humans in peptic ulcer therapy, increased significantly
duodenal
HCO3
-
secretion
and
this
has
been
attributed
to
PG-dependent
stimulation, but as bismuth is known to suppress H. pylori (Hp) activity, this
effect could be also explained by the eradication or, at least, suppression of this
bacterium infection in these subjects though testing for Hp was not available at
this time (20).
Since
administration
of
L-nitro-arginine
derivatives,
such
as
L-NNA,
was
reported to inhibit gastric and duodenal alkaline secretion and these effects were
reversed by the addition of L-arginine to L-NNA, endogenous nitric oxide (NO)
10
Duodenum
(HCO3- secretion)
Lumen
3Na+
Saliva
1500 ml/day
ATP
2K+
ClHCO3+
Gastric H+
Na+
HCO3-
H+
CA
Ingest
2000 ml H2O/day
H2O +CO2
H2CO3
H2O + CO2
2.25 nM/30 min
2.20 nM/30 min
1500
ml/day
HCO3-
Duodenal
HCO3-
Gastric
H+
Gastric
juice
2000 ml/day
Bile
500 ml/day
Fig. 3. The mucosa of the duodenum is capable of producing and secreting into the lumen of HCO3
through various mechanisms, out of which the most efficient mechanisms operate in the duodenum.
The volume of ingested fluids and secreted juices from various GI organs are also shown.
has been also implicated in the regulation of duodenal HCO3 secretion (21). This
is in keeping with the observation that exogenous donors of NO, such as glycerine
trinitrate, or stimulants of sensory nerves releasing CGRP such as capsacin (at
lower doses) were also effective stimulants of gastro-duodenal alkaline secretion
(21). This has been confirmed recently by Takeuchi et al. (22), who documented
that NO, like PG, is involved in acid-induced duodenal HCO3 secretion and could
be attributed to the upregulation of constitutive NO synthase (cNOS) (Fig. 4).
Yao et al. (23) identified in in vitro preparation of rabbit duodenal mucosa
the HCO 3
-
secretory pathways related to vasoactive intestinal peptide (VIP)
and cyclic AMP. Glad et al. (24) confirmed in anesthetized pigs that VIP and
its
chemical
(PACAP),
Sjoblom
analog,
stimulate
and
pituitary
duodenal
Flemstrom
adenylate
as
(25)
well
as
reported
cyclase-activating
hepatobiliary
recently
polypeptide
HCO 3
that
-
secretion.
melatonin,
a
neurotransmitter released by neurons of the enteric nervous system of the gut,
is also an effective stimulant of duodenal alkaline secretion in anesthetized rats
and suggested that this indole is involved in H -induced alkaline secretion
+
acting
via
MT 2
receptors.
Furthermore,
sensory
nerves
in
the
duodenal
11
mucosa,
activated
by
acid
or
small
doses
of
topical
capsaicin,
have
been
proposed to be involved in the stimulation of alkaline secretion ether by axonreflex
with
the
release
of
sensory
neuropeptides
such
CGRP
that
in
turn
activates the release and action of NO (21). The overall mechanisms operating
in the duodenum in response to topical application of H
NOS-NO
and
sensory
nerves-CGRP-NO
systems.
+
involve COX-PG,
Furthermore,
novel
hormones such as PYY, ghrelin, melatonin VIP, orexins or CCK have been
proposed to contribute to duodenal HCO 3
Quantitatively, the amounts of HCO3
-
-
secretin (Fig. 4).
secreted by canine proximal duodenum
are only a small portion of the amounts of maximally stimulated gastric H
+
secreted in the stomach (11). Jarbur et al. (26) who quatitated gastric acid and
duodenal alkaline secretion in fasting humans reported that the amounts of HCO3
-
produced in the duodenum under basal conditions were similar to duodenal loads
of gastric H
+
and this production may be mediated, at least in part, by increased
pCO2 generated in the duodenal lumen from the HCO3
-
hydrolysis by gastric H
+
during phase III of MMC (see Fig. 4).
Mucus-alkaline secretion and formation of protective mucosal barrier in the
stomach differ from those in the duodenum. In the stomach, gastric mucosa is
covered by tight epithelial cells with continuous surface mucus layer to which
HCO3
-
is secreted by goblet cells, creating the pH gradient across mucus layer
that neutralizes any H
diffusing from the gastric lumen towards the surface
+
epithelial cells and thus preventing their acidification and damage (Fig. 5). The
total amount of HCO3
-
secreted by the gastric mucosa is relatively small when
pCO2, COX-1 -PG &
cNOS-NO
cNOS-NO system
Luminal H+1
Neurohumorals:
Melatonin, VIP,
PACAP, CGRP,
Motilin, PYY,
OX-A & -B
GHRELIN, CCK
HCO3transport
Cholinergic
pathway (Ach)
Fig. 4. Involvement of various factors activated by duodenal acid in the mechanisms of HCO3
secretion in duodenal mucosa.
12
Gastric lumen
Mucosal defence mechanism
H+
pH 1.5
Pepsin
MucusBicarbonate
Barrier
Mucosal defence mechanism
H+
Mucus Pepsinogen
HCO3H+
Mucus
H+
H2O + CO2
Neutralization
Epithelial
Tigh
Junctions
HCO3-
pH 2.0
HCO3- +
pH 7.0
HCO3-
HCO3 H+
Fig.
5.
In
the
stomach
luminal
gastric
H
+
does
not
reach
the
mucosal
cells
because
of
its
neutralization by HCO3 secreted continuously by surface epithelial cells. Pepsin molecules infuse
-
only into the upper portion of the mucus layer, causing its degradation but do not reach the surface
of gastric epithelium.
compared to maximal gastric H
+
secretion, but due to the fact that HCO3
secreted into the thin layer of adherent mucus gel, this HCO3
-
-
is
secretion is highly
effective in neutralizing the penetrating luminal H . By contrast the duodenum is
+
covered, however, by a leaky epithelium and has thicker mucus gel with more
abundant
secretion
mechanism
against
of
HCO3 ,
gastric
H
+
which
is
thought
discharged
to
to
the
duodenum is supplied with large amounts of HCO3
-
be
the
primary
duodenum.
defence
Although,
the
originating from the pancreas
and biliary tree and secreted in response to duodenal acidification due to release
of
secretin,
the
major
"chemical
battlefield"
with
gastric
H
+
entering
the
duodenum is the duodenal bulb. The bulb is located just distal to gastric antrum
and proximal to the pancreatico-biliary ducts and uniquely exposed to a highly
variable pH environment due to peristaltically conveyed pulses of concentrated
gastric H
discharged by the stomach to duodenum. Since the duodenum does not
have
inherent
+
the
acid
protective
structural
properties
of
the
stomach
with
intercellular tight junctions, it evolved very efficient means for defence against
gastric H . The proximal duodenum could be compared to the titration chamber
+
with gastric H
+
neutralized mostly by the HCO3
-
originating from the bulbar
13
mucosa and secreted due to local action on duodenocytes of numerous mediators
including already mentioned PG, NO, Ach, melatonin, VIP, PACAP and probably
also motilin-like peptide, ghrelin PYY leptin, as well as CCK, all secreted by
intestinal mucosal cells and released into the duodenal lumen (see Fig. 4).
Duodenocyte membrane transport systems
It should be emphasized that HCO3 does not increase immediately upon the
start of acid perfusion of duodenal bulb but rather somewhat later after acid
challenge
when
H
ions
+
already
diffused
into
duodenocytes
and
reduce
their
intracellular pH (pHi). To understand the sequence of events following duodenal
acid
challenge,
it
is
necessary
to
identify
the
apical
and
basolateral
transport
mechanisms in duodenocytes. It has been proposed (26, 27), the apical duodenocyte
membrane is equipped with active exchangers HCO3 /Cl , extruding HCO3
to
duodenal lumen in exchange for Cl (AE - anion exchanger) and several types of
Na /H
+
+
exchangers (NHE1-3) eliminating the H
+
from the duodenocytes back to
duodenal lumen (Fig. 6). The AE has been related to cystic fibrosis transmembrane
conductance regulator (CFTR) protein and found to be expressed predominantly in
a pical membrane of duodenocytes in duodenal crypts (28, 29). At the baso-lateral
+
duodenocyte membrane both electroneutral Na -HCO3
cotransport (NBC1) and
electrogenic cotransport NBC (NBCn1) as well as N /H
+
NHE1
pNBC1
Fig.
6.
Duodenocytes
membrane.
are
equipped
?
HCO3H+
CO2
(HCO3-)n
Apical
SLC26Ax
Cl-
exchanger (NHE) are
HCO3-
ClCFTR
+
Na+
with
numerous
AE2
Cltransporters
at
Basolateral
the
apical
and
basolateral
14
Fig.
7.
Hipothetical
events
leading
to
duodenal
ulcerogenesis
related
to
H.
infection,
pylori
increased acid load, duodenitis and ADMA production.
present
(30).
Kaunitz
and
Akiba
(31)
summarizing
the
protective
duodenal
response to gastric acid challenge in humans pointed out that luminal H
diffusing
+
into the duodenocytes, lowers pHi and initially decreases the buffer power of these
cells but subsequently decrease HCO3
secretion due to the decrease of CFTR
conductance. Lowering pHi immediately increases, however, the activity of baso-
lateral NBC1 and promotes an inward movement of HCO3 from extracellular fluid
to increase the cellular content of HCO3
and its secretion to duodenal lumen
through CFTR-related HCO3 /Cl exchanger. Furthermore, acidic intracellular pHi
increases the activity of basolateral NHE and enhances an extrusion of H
+
submucosal
space
with
increase
of
cellular
alkali
load.
Luminal
H
+
into the
in
the
duodenum also increases the mucus secretion from goblet cells, resulting in the
increase
of
the
thickness
of
mucus
gel.
This
increase
in
mucus
secretion
is
accompanied by an enhancement of mucosal blood flow mediated by the H
+
stimulation of the sensory nerves releasing CGRP and NO causing vasodilation in
the mucosa. H
+
in duodenum may also release ghrelin and leptin into duodenal
lumen from the surface epithelial cells and these peptides, similarly to CCK already
reported to stimulate duodenal HCO3
should also be considered as candidate
stimulatants of duodenal alkaline secretion of physiological importance.
15
Duodenal ulcer patients may not only exhibit excessive gastric H
secretion
+
and accelerated gastric emptying of H , thus enhancing duodenal acidification
+
and
mucosa
damage,
but
also
produce
a
potent
endogenous
asymetric
dimethylated arginine derivative (ADMA) that reduces duodenal HCO3
to
gastric
H
and
+
thus
favours
the
damage
of
duodenal
mucosa
-
response
and
ulcer
formation in these patients (32) (Fig. 7).
CONCLUDING REMARKS
This overview provides an insight into how duodenal mucosa defends itself
against the damage by pulses of concentrated gastric H
+
entering the duodenum.
Unlike in the stomach, where mucosal barrier with tight epithelial cells and
covering mucus layer actually prevent luminal H
+
from entering and damaging
the surface epithelium, in the duodenum the epithelial cells are leaky permitting
luminal
H
+
to
diffuse
into
the
duodenocytes
and
acidify
subsequent activation of the baso-lateral Na -HCO3
+
alkali load in these cells and excessive HCO3
apical
membrane
activates
-
HCO3 /Cl
basolateral
duodenocytes
and
-
Na /H
+
exchangers.
+
of
their
interior
with
cotransporter, leading to
secretion due to activation of
Acidic
exchangers
acidification
-
-
pHi
causing
submucosal
of
duodenocytes
extrusion
tissue
with
of
H
+
also
from
stimulation
of
capsaicin receptors on afferent nerves leading to increased mucosal blood flow
and
increased
thickness
of
mucus-gel
layer
enhancing
duodenal
protective
activity. In certain conditions such as Hp infection, the inflammatory changes in
the mucosa result in decrease in mucus-alkaline secretion, partly due to ADMA
effect and mucosal resistance to acid injury leading to the formation of peptic
ulcerations.
Eradication
produce HCO3
-
of
Hp
restores
the
ability
of
duodenal
mucosa
to
due to reduction in ADMA formation and the restoration of the
integrity of duodenal mucosa.
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Pavlov IP. The Work of the Digestive Glands. Charles Griffin and Co, Ltd, London 1902.
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Popielski L.
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R e c e i v e d : 27 March 2004
A c c e p t e d : 28 May 2004
Author's address: Prof. Stanislaw J. Konturek, M.D., Department of Physiology Jagiellonian
University Medical College 16, Grzegorzecka St., 31-531 Krakow, Poland tel. (+48-12) 4211006
fax (+48-12) 4211578
E-mail: mpkontur@cyf-kr.edu.pl