GASTROENTEROLOGY

CLINICAL

TRENDS

AND

Cytoprotection
ANDRE

ROBERT

Department

of Experimental

TOPICS

77:761-767,1979

.-

by Prostaglandins
Biology,

The Upjohn

Prostaglandins
(PG) are a group of ZO-carbon
oxygenated fatty acids that are present in most mammalian cells and tissues.
Approximately
20 of these
chemicals
have been identified
in tissues and body
fluids, whereas
hundreds
have been synthesized
as
analogs
or derivatives
of the natural
PG. Although
their highest concentration
is found in seminal fluid,
the gastrointestinal
mucosa contains
relatively
large
amounts.
Prostacyclin
(PGI,), recently
discovered,
is
the most abundant
PG formed
by the gastric mucosa. It was suggested
that PGI, and PGE,, also present in the mucosa,
may affect the regulation
of gastric
mucosal
blood
flow
and
acid
secretion.,
Prostaglandins
affect almost every biologic system
and sometimes
in different
directions.
For instance,
PG of the E and F,,, type stimulate
smooth
muscle
contraction
including
the uterus, whereas
PG of the
A and I type do not; PG of the A, E, and I type are
potent vasodilators,
whereas
PG of the F,, type are
vasoconstrictors;
PG of the E type are bronchodilators, whereas
PG of the B and F type are bronchoconstrictors.
PG also affect gastrointestinal
functions.
PGE,,
PGE,, and PGA, as well as certain methyl analogs of
PGE, inhibit
gastric
secretion
in animals
and humans?
prevent
ulcer formation
in animals,, and
reportedly
accelerate
ulcer healing in humans.7.H The
antiulcer
effect is presumed
to be due to the antisecretory
activity of these compounds.
Recently,
a new property
of PG was discovered,
called cytoprotection,!
which designates
the property of many PG to protect the mucosa of the stomach and the intestine
from becoming
inflamed
and
necrotic,
when this mucosa
is exposed
to noxious
agents. This property
is separate,
and unrelated
to,
inhibition
of gastric secretion.
We shall summarize
here the observations
that led to the concept of cytoprotection
and discuss
its mechanism
and the possible implications
of these findings. A review on the
subject has recently appeared.
Rcccivcd February
1, 1979. Accepted
April 10, 1979.
Address
requests
for reprints
to: Andre Robert, M.D., Ph.D.,
Dcpartmcnt
of Expcrimcntal
Biology,
The Upjohn
Company,
Kalamazoo,
Michigan 49001.
0 1979 by the American
Gastroenterological
Association
0016.5085/79/100761-07$02.00

Company,

Kalamazoo,

Gastric
Gastric

Michigan

Cytoprotection
Injury

Produced

by NOSAC

Most NOSAC (nonsteroidal

antiinflammatory
compounds),
such as aspirin, indomethacin,
phenylbutazone,
naproxen,
and ibuprofen,
can produce
gastric damage in animals
and humans,
characterized
by bleeding,
focal necrosis,
and sometimes
frank ulcers.
Many examples
of massive
bleeding
and sometimes
perforation
attributed
to treatment
with NOSAC have been reported
in humans.
Aspirin is the most frequent
cause either because
it is
particularly
noxious
for the stomach
or because,
as
an over-the-counter
drug, it is much more used than
other NOSAC.
Experimental
models,
especially
in
the rat, have been developed
to study these NOSACinduced
gastric
lesions.
It was found that the incidence and severity of these lesions are dose-dependent, that they develop after either oral or parenteral
(intraperitoneal,
subcutaneous)
administration
of
NOSAC,
and that they can be prevented
by prior
treatment
with antacids
and antisecretory
drugs,,
including
PG.
Subsequent
findings,
however,
suggested
a different interpretation
since certain
PG which are not
antisecretory
in rats still prevented
NOSAC-induced
lesions,
and since even in the case of antisecretory
PG, the dose inhibiting
NOSAC-induced
lesions was
much smaller than the threshold
antisecretory
dose.
This was the first indication
that PC could protect
the gastric
mucosa
against
damaging
agents
by a
mechanism
other than inhibition
of acid secretion.
Further
studies
demonstrated
that two PG analogs, 15(R) and 15(S)-15-methyl
PGE, methyl
ester,
prevented
gastric lesions produced
in rats by aspirin
plus the hourly
addition
of 160 mM HCl, or by
acidified taurocholate.
Cimetidine,
given at an antisecretory
dose, was ineffective.
Another
study,
however,
showed
that cimetidine
and probanthine,
even when given at nonantisecretory
doses, reduced
gastric lesions produced
by acidified aspirin. However, PG arc in a class by themselves
as regards
cytoprotection,
for the following
reasons: (a) Cimetidine and probanthine
reduced
gastric lesions
only

762

ROBERT

GASTROENTEROLOGY

when

aspirin
was given with HCl at a normality
of
less. When aspirin
was given with stronger
acid (0.35 N), neither
cimetidine
nor probanthine
prevented
the gastric injury,
whereas
a PG (16,16dimethyl
PGE,) was still totally cytoprotective,
even
at a nonantisecretory
dose.lY (b) Cimetidine
and probanthine
at doses inhibiting
gastric acid secretion
by
more than 90% did not prevent
gastric damage produced by either aspirin
+ 0.35 N HCl, or absolute
ethanol (see next section Gastric
Injury Produced
by Necrotizing
Agents).
16,16-Dimethyl
PGE, and
other PG, even when given at very low doses, were
totally
protective
against
these
two damaging
agents.1B,20
These findings were recently
extended
to humans.
Occult bleeding
produced
in healthy
volunteers
by
administration
of high doses of aspirin (600 mg four
times a day) was prevented
by concurrent
treatment
with PGE, (1 mg orally four times a day). Similarly,
PGE, (0.33 mg three times
a day) and 15(R)-15methyl PGE, (40 pg three times a day) prevented
occult bleeding
produced
in arthritic
patients
by indomethacin
(50 mg three times a day). Administration
of the PG did not reduce the antiarthritic
effect of indomethacin.
Since PGE, was previously
shown not
to be antisecretory
when given orally to humans,
even at higher doses,L3 and since the source of aspirin-induced
bleeding
is primarily
the stomach,
these
results
represent
the first clinical
demonstration
of
gastric cytoprotection.
0.15

or

Gastric
Agents

Injury

Produced

by Necrotizing

Since antisecretory
agents and antacids
can
prevent
NOSAC-induced
gastric lesions under certain conditions,
one had to conclude
that the presence of acid played an important
role in their development.
Whether
PG could prevent such lesions by
a pure cytoprotective
mechanism,
independent
of
inhibition
of acid secretion,
required
an animal
model of gastric injury
that would not respond
to
antisecretory
agents nor to antacids.
Only with such
a model would it be possible
to determine
whether
nonantisecretory
PG would be truly cytoprotective.
Such a model was developed
in which gastric mucosal necrosis
was produced
in rats by oral administration of necrotizing
agents. The procedure
was as
follows.
The animals
were fasted for 24 hr, after
which one milliliter
of one of the following
agents
was given orally: absolute
ethanol, a strong acid, or a
strong base (0.6 N HCl or 0.2 N NaOH), a hypertonic
solution
(25% NaCl), and boiling water. The animals
were killed 1 hr later, and their stomachs
were examined
for the presence
of lesions. The latter consisted of elongated
necrotic
bands l-10 mm long by
1-3 mm wide, usually parallel to the long axis of the

Vol. 77, No. 4. Part 1

stomach.
Usually,
15-20 such lesions were found per
stomach.
They were located in the corpus (the portion of the stomach
secreting
acid and pepsin);
the
antrum
was less affected. Substances
tested for possible cytoprotection
were administered
before the
necrotizing
agents, either orally, subcutaneously,
or
intraperitoneally.
Many PG of A, B, E, F, and I types prevented
formation
of these necrotic
lesions, the degree of protection
was dose-dependent,
and the protective
doses were very 10w.~.~~In the case of PG with antisecretory
activity,
as little as l/lOOth
of the antisecretory
dose was cytoprotective.
Certain
PG devoid of gastric antisecretory
activity
at any dose in
rats [e.g., 15(R)-15-methyl
PGF,,;
16,16-dimethyl
PGA,]
were still cytoprotective.,
These
results
showed
that certain
PG were cytoprotective
although they had no effect on gastric secretion.
We
concluded
that the two properties,
antisecretory
and
cytoprotective,
were independent
of each other.
If indeed
PG inhibited
formation
of gastric
necrotic lesions by a mechanism
other than inhibition
of gastric
secretion,
it would
follow
that antisecretory
agents as well as antacids
should not be
cytoprotective.
To this end, we investigated
the effects of an anticholinergic
agent (methscopolamine
bromide),
a histamine
H, receptor
antagonist
(ci(0.15 M sodium
bicarbonate
metidine),
and antacids
and a pH 7 buffer). Methscopolamine
bromide
(10
mg/kg subcutaneously)
and cimetidine
(50 mg/kg intraperitoneally)
were given 30 min before oral administration
of one milliliter
of either absolute
ethanol or 0.6 N HCl. These doses had been found, in
other studies, to inhibit acid output in rats by more
than 90%. Each of the antacids
was given orally, in
separate
experiments,
in a volume of 2 ml, 1 min before absolute
ethanol.
In all cases, the animals
were
killed in 1 hr after the necrotizing
agents. None of
these compounds
was cytoprotective:
The incidence
of animals
with necrotic
lesions,
the number
of lesions, and their severity
were not significantly
different from the values obtained
in control animals.
This meant that even in the presence
of high doses
of antisecretory
agents
(doses that almost
abolish
acid secretion),
or by alkalinization
of the gastric
contents
(by administration
of large amounts
of antacids), necrotizing
agents such as absolute
ethanol
could still produce
gastric mucosal
damage.
These
findings
reinforced
the conclusion
that the cytoprotection
produced
by PG was unique,
and in no
way related to an effect on gastric secretion.
Cytoprotection
by PG was also demonstrated
in
dogs. 15(S)-15-methyl
PGE, methyl
ester, given locally, prevented
the breaking
of the gastric mucosal
barrier by ethanol,
as shown by ion fluxes (H, Na,
K+) to and from Heidenhain
pouches.s
Similar
results were obtained
with 16,16-dimethyl
PGE,, given

Octohtzr

CYTOPROTECTION

1979

intravenously,
and the effect was dose dependent.
Similar protection,
including
prevention
of changes
in the transmucosal
electrical
potential
difference,
was obtained
after intravenous
infusion
of prostacyclin (PGIJ.

Intestinal

Cytoprotection

Cytoprotection
by PG was also demonstrated
for the intestine.
Most NOSAC
(indomethacin,
flufenamic
acid, ibuprofen,
and
phenylbutazone,
naproxen),
when given at high doses to rats, can produce an intestinal
syndrome
characterized
by multiple ulcerations
of the small intestine,
from the upper jejunum
to the terminal
ileum, with eventual
perforations,
peritonitis,
and death
within
3-4
These
lesions
were
prevented
by
condays.,
comitant
administration
of a variety of PG.-: This
was called intestinal
cytoprotection.
Neither
histamine HZ receptor
antagonists,13 anticholinergics,
nor
antacids
affected this syndrome
(unpublished);
this
is not surprising
since the contents
of the small intestine are already
neutral or alkaline.
Gastric acidity indeed cannot play a role in the pathogenesis
of
these intestinal
lesions,
since acid secreted
by the
stomach
is either reabsorbed
by the duodenum
or
neutralized
in the duodenal
lumen by bile and pancreatic juice.
More recently,
another
type of lesion was produced in the rat terminal
ileum by repeated
administration of high doses of prednisolone.
These lesions
appeared
after approximately
5 days of treatment,
and their incidence
increased
up to the 8th day, at
which time many animals
were dying. The lesions
usually
involved
the terminal
ileum only, although
in some animals
they extended
upward
and reached
the jejunum.
They consist of multiple necrotic ulcers
originating
from the mucosal side. Many of these ulcers perforate
and produce
adhesions
of intestinal
loops.
This syndrome
resembles
regional
ileitis.
These prednisolone-induced
intestinal
lesions were
prevented
by 16,16-dimethyl
PGE,, and the degree of
protection
was
dose-dependent.
Prednisolonetreated
animals
who also received
the PG survived
the 8-day treatment.:
Therefore,
intestinal
cytoprotection
by PC is not limited to lesions produced
by NOSAC but includes
also damage produced
by a
steroid. Whether
intestinal
injury produced
by other
agents would also be prevented
by a PG remains
to
be seen.

Nonspecificity

of Cytoprotective

PG

One interesting
aspect of cytoprotection,
gastric and intestinal,
is that PG of practically
every
type (A, B, C, D, E, F,,,, FzR, I) share this property.
The only difference
between
them is their potency:

BY PROSTAGLANDINS

763

Some are extremely

active (e.g., 16,16-dimethyl
PGE,
has an ED,, for gastric cytoprotection
of 50 ng/kg intragastrically)
whereas others are much weaker [e.g.,
15(R)-15-methyl
PGF,,, with an ED,,, of 100 pg/kg intragastrically].
The fact that PG are not equally
active is not surprising;
what is surprising
is that so
many of them, though not all, exhibit this property.
In fact, certain
PG are known to have opposite
effects on other systems,
yet are cytoprotective.
For
example,
PGE, is vasodilating,
bronchodilating,
and
an inhibitor
of platelet aggregation,
whereas
PGF,,, is
vasoconstricting,
bronchoconstricting,
and inactive
on platelet aggregation;
yet, both are cytoprotective.
In fact, certain
PG have no appreciable
biologic
property,
either in vivo or in vitro, other than being
cytoprotective.

Cytoprotection

by Aspirin

Unexpectedly,
aspirin
was found to be cytoprotective
in rats. A single oral or subcutaneous
administration
prevented
the development
of indomethacin-induced
intestinal
lesions.
Since
both
aspirin
and
indomethacin
inhibit
PG cyclooxygenase
activity,
this antagonism
was surprising and is still unexplained.
It may be that aspirin, a
weak inhibitor
of the enzyme,
occupies the receptor
sites of the enzyme without blocking significantly
its
activity.
Indomethacin,
a potent inhibitor
of the enzyme, could not exert its effect because the receptor
sites are being occupied
by aspirin.
The respective
doses needed
for each compound
favor such competitive inhibition:
Indomethacin
produces
intestinal
lesions at 7.5 mg/kg (417 nmol) whereas
125 mg/kg
of aspirin
(3494 nmol or 8.4 times more) is required
to block this effect of indomethacin.

Mechanism

of Cytoprotection

The mechanism
of cytoprotection,
intestinal,
is not known.
The following
are considered.

PG Needed

to Replace

gastric and
possibilities

a PG Deficiency

Gastric
and intestinal
lesions
produced
by
NOSAC may have a common
etiology.
Prostaglandins are formed in the body by the transformation
of
a substrate,
arachidonic
acid, into PG endoperoxides
by an enzyme
called cyclooxygenase.
These endoperoxides
in turn are transformed
into the various
PC (PGE,,
PGF,,,,
prostacyclin,
or PGI,)
and
thromboxanes.
NOSAC,
such as aspirin
and indomethacin,
inactivate
the cyclooxygenase,
so that PG
are no longer
generated
from arachidonic
acid.
This results in a PG deficiency.
The PG deficiency
thus produced
by the NOSAC. rather than a direct

764

ROBERT

GASTROENTEROLOGYVol. 77.No.4,Partl

effect of the NOSAC themselves, is responsible for

the damage produced to the gastric and intestinal
mucosa. This conclusion is based on the following
observations:
(a) Various NOSAC, chemically unrelated, produce identical gastric and intestinal lesions
and inhibit the cyclooxygenase;
(b) replacement
therapy
with PG prevents
the development
of
NOSAC-induced
lesions, gastric and intestinal; and
(c) although intestinal lesions are discernible only at
24-48 hr after treatment
with a NOSAC, complete
protection is obtained if a PG is administered
only
once, at the time the NOSAC is given; this is the
time when the PG depletion by the NOSAC occurs.
In the case of prednisolone-induced
intestinal le
sions, one can invoke a similar mechanism of PG
deficiency.
Prednisolone
prevents
the release of
arachidonic
acid from phospholipids
by inhibiting
the enzyme, phosppolipase
A, necessary for this reaction.7 Again, replacement
therapy with the end
product, i.e., a PG, protects by keeping the tissue levels of PG at or above normal, thereby preventing the
development of a PG deficiency.
The presence of PG in cells appears to be necessary for gastrointestinal
epithelial cells to maintain
their integrity. If PG content is reduced by pretreatment with a NOSAC or a corticosteroid,
these
cells become vulnerable; they can no longer resist
the damaging effect of their immediate environment
(acid, pepsin, ingested substances, in the case of gastric cells, and noxious substances such as bile acids,
food by-products, and bacterial toxins in the case of
intestinal cells). Replacement therapy with a PG restores cellular resistance
to potentially
damaging
substances present in gastric and intestinal contents.
PG Needed in Amounts

Greater

than Normal

Replacement
therapy in situations in which
the body stores of PG, at least in the gastrointestinal
tract, have been depleted may explain certain forms
of cytoprotection.
However, in the case of gastric necrosis produced by agents such as absolute ethanol,
a strong acid or base, or boiling water, the mechanism is obviously different. These agents do not induce a PC deficiency, they kill cells by contact. The
fact that PG prevent such acute cellular necrosis is
still unexplained. When these necrotizing agents are
placed in the stomach, the amount of PG present in
gastric cells appears to be insufficient to provide
adequate protection. Extra amounts are needed to
increase the cellular resistance above normal, so that
these cells can withstand
the contact with these
highly damaging agents.
An analogy can be made with corticosteroids.
A
corticosteroid
deficiency leads to a well-characterized syndrome,
Addisons
disease. Aeplacement

therapy with corticosteroids

restores the blood levels of these hormones to normal, and as a result the
signs and symptoms of the disease disappear. This is
analogous to gastric and intestinal lesions resulting
from a PG deficiency, such as brought about by administration of NOSAC. Exogenous treatment with
PG replenishes the tissues with the deficient compounds and no lesions develop. On the other hand,
in rheumatoid arthritis the blood level of corticosteroids is normal. Extra amounts of corticosteroids,
in
the form of exogenous treatment, are needed to control the disease. This is analogous to gastric lesions
produced by necrotizing agents such as absolute ethanol. In this case, exogenous treatment with PG does
not correct a deficiency, but rather increases cellular
resistance to the point that gastric damage will not
take place. In both situations (replacement
therapy
and extra amounts), PG are cytoprotective
either by
making the cells stronger or by keeping the injurious
agent away from the cells.

Endogenous

Formation

of Cytoprotective

PC

The following studies suggest that PG can be

formed by the stomach to protect the mucosa. Oral
administration
to rats of mild irritants, 15 min before giving necrotizing agents, was found to be cytoprotective. For example, one milliliter of either 20%
ethanol, 0.35 N HCl or 0.075 N NaOH completely
protected the stomach from mucosal necrosis produced by absolute ethanol, 0.6 N HCl or 0.2 N NaOH.
Moreover, there was cross protection: each of the
mild irritants protected against any of the necrotizing agents listed above as well as against gastric necrosis produced by taurocholate.39 Furthermore,
either mild irritants
or PG, when given before
necrotizing
agents, maintained
gastric secretory
function (e.g., acid secretion) which was otherwise
abolished
when necrotizing
agents were given
a1one.4o
Gastric cytoprotection,
both morphologic
and
functional, seems to be mediated by endogenous formation of cytoprotective
PG, since such protection
was blocked by prior treatment with indomethacin,
a compound
inhibiting PG cyclooxygenase
activity.- Therefore,
PG are cytoprotective
not only
pharmacologically,
i.e., after exogenous administration, but also physiologically,
since they can be
formed in response to the presence of irritants in the
gastric lumen. It is likely that cytoprotective
PG are
continuously
generated by the stomach and the intestine: their formation may be a defense mechanism for the gastrointestinal
tract. Figure 1 illustrates the concept of cytoprotection
by endogenous
and exogenous PG.

Octohcr 1979

CYTOPROTECTION

BY PROSTAGLANDINS

765

How Do PG Work
The mechanism
by which PG exert their cytoprotective
effect is unknown.
The following
hypotheses are considered.
(1) PG may stimulate
mucus secretion.
Some
evidence
exists that certain
PG stimulate
synthesis
and release
of gastric
mucus.+
Newly
formed
mucus could provide
a physical
shield against
irritants normally
found in the gastric lumen. However,
such mucus would have to be released within 1 min
after treatment,
since PG are cytoprotective
when
given orally as early as 1 min before administration
of absolute
ethano1.2 In the case of intestinal
cytoprotection,
no data exist on the effect of PG on
mucus formation.
(2) PG may affect the sodium pump. Sodium
is normally
transported
from the mucosal
side of
gastrointestinal
mucosal
cells to the serosal
side.
This process is enhanced
in vivo by 16,16-dimethyl
PGE,. lndomethacin,
applied
to the canine gastric
mucosa in vitro inhibited
active transport
of sodium
from the mucosal
side to the serosal
side. This
would lead to intracellular
accumulation
of sodium
which, in turn, would induce retention
of anions and
water.
Osmotic
swelling
would
damage
the cells
and, in the presence
of luminal
acid, lead to mucosal
lesions. Addition
of 16,16-dimethyl
PGE, to the indomethacin-treated
mucosa
restored
the mucosa-toserosa movements
of sodium. This property
of PG of
stimulating
the sodium
pump was proposed
as a
possible mechanism
for cytoprotection.
(3) PG may activate
adenylyl
cyclase.
Several
PG stimulate
adenylyl
cyclase activity in the gastric
mucosa of several species.4-47 However,
newer techniques
utilizing
isolated
gastric mucosal
cells have
helped
clarify
this effect. It was found that PGE,
stimulates
formation
of cyclic AMP almost
exclusively
in nonparietal
cells.4H Many of these nonparietal
cells originate
from the surface epithelium,
where
cytoprotection
seems to take place. Cyclic
AMP, stimulated
by PG, may be the mediator
for
cytoprotection.
(4) PG may act on the gastric mucosal circulation Several
PG affect gastric mucosal
blood flow.
Antisecretory
PG (PGE,, PGE,) decrease,blood
flow
secondarily
to their inhibitory
effect on parietal
cells.! Prostacyclin
(PGI,), however,
although
an inhibitor
of gastric secretion,
increases
gastric mucosal blood flow in rats51 and dogs,27 and is also cytoprotective
in the same species.27, It was suggested
that the increase
in mucosal blood flow may explain
the cytoprotective
effect of PGI,.
It is doubtful,
however,
that a change
in gastric
mucosal
blood
flow plays a major role in cytoprotection
because PG
known
to have opposite
effects in other vascular

Mucosal necrosis by noxious agents can be due to direct

damage to cells (e.g., ethanol, toxins) or to a local prostaglandin
deficiency
(JPG) (e.g., administration
of aspirin or indomethacin).
PG given either exogenously
or
formed
endogenously
by administration
of mild irritants prevent
(W)such
necrosis.
This prevention
of
mucosal necrosis is called cytoprotrction.

beds (e.g., PGE, is vasodilator,

PGF,,, is vasoconstrictor) are both cytoprotective.
(5) PG may protect
the gastric mucosal
barrier. Several PG of the E type as well as PGI, were
shown to protect the gastric mucosal
barrier.
They
prevented
gastric alterations
(increased
fluxes of H,
Na, K, decreased
transmucosal
electrical
potential
difference,
and increased
pepsin secretion)
produced
by intragastric
administration
of either aspirin, indomethacin,
taurocholate
or ethanol
in dogs and
rats.7.L~7. Cytoprotection
may therefore
result
from a tightening
of the gastric mucosal
barrier.
If
so, the mechanism
of such effect still remains
to be
explained,
and may involve
the possibilities
mentioned in hypotheses
1-4 discussed
above.

Implications

of Cytoprotection

by PG

The observation
that PG arc cytoprotective
has physiologic
interest.
It identifies
a class of natural compounds
whose presence
seems to be necessary for maintaining
cellular integrity
of the gastrointestinal
mucosa.
Cytoprotective
PG may be of
special
importance
for epithelia
that are normally
exposed to a hostile environment
such as the gastrointestinal
mucosa. Whether
cytoprotection
by PG is
of equal significance
for other mucosae
such as that
of the respiratory
and genitourinary
tracts remains
to be seen. Similarly,
there are no data on whether
PG are cytoprotective
for other epithelia
(e.g., skin,
liver) or for non-epithelial
cells. The cytoprotective
property
of PG may have practical
applications
in
the treatment
of various forms of inflammatory
diseases of the gastrointestinal
tract. Whenever
cells
are damaged
by extracellular
(gastric and intestinal
contents,
microorganisms)
or intracellular
(ischemia,

GASTROENTEROLOGY

viruses)
agents, one can envisage
the possibility
of
administering
a PG for the purpose of enhancing
the
resistance
of these cells. Although
at the moment the
experimental
models have shown that PG are cytoprotective
when
given
before
administration
of
noxious
agents but not after (these models do not allow quant:itation
of the rate of healing),
reversal
of
damaged
tissue to normal structure
is a likely possibility. Prostaglandins
may interrupt
the deleterious
effect of irritants
and allow recovery
of the injured
tissue.
Whether
cytoprotective
PG will have clinical
applications
remains
to be seen. On the basis of the experimental
observations
reviewed
here, such compounds
may be useful in the treatment
of gastritis
such as caused
by irritants
(alcohol,
aspirin,
and
other NOSAC) and biliary reflux, gastritis associated
with gastric
ulcer, gastric
infections
such as gastroenteritis
of infants,
and virus gastritis,
and perhaps reflux esophagitis.
In the case of NOSAC-induced gastric lesions,
so common
after aspirin,
the
rationale
would be not only to increase
the resistance of cells above normal, but to counteract
the PG
deficiency
brought
about by the NOSAC treatment.
Presumably,
cytoprotective
PG might also be useful
in the treatment
of inflammatory
bowel
disease,
since they prevented
two forms of intestinal
necrotic
lesions
produced
in animals,
namely
those caused
by NOSAC and by prednisolone.

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