ICAM-1 and P-selectin expression in a model of NSAID-induced
gastropathy
Z.
Morise1,
S.
Komatsu1,
J. W.
Fuseler1,
D. N.
Granger1,
M.
Perry2,
A. C.
Issekutz3, and
M. B.
Grisham1
1 Department of Molecular and
Cellular Physiology, Louisiana State University Medical Center,
Shreveport, Louisiana 71130;
2 School of Physiology and
Pharmacology, University of New South Wales, Sydney, Australia
2052; and 3 Department of
Pediatrics and Microbiology and Immunology, Dalhousie University,
Halifax, Nova Scotia, Canada B3H 3J5
 |
ABSTRACT |
A growing body of experimental evidence suggests
that neutrophilic polymorphonuclear leukocyte (PMN)-endothelial cell
interactions play a critical role in the pathophysiology of
nonsteroidal anti-inflammatory drug (NSAID)-induced
gastropathy. The objective of this study was to directly
determine whether the expression of endothelial cell adhesion molecules
is enhanced in a model of NSAID-induced gastropathy. Gastropathy was
induced in male Sprague-Dawley rats via oral administration of
indomethacin (Indo, 20 mg/kg). Lesion scores, blood-to-lumen clearance
of 51Cr-EDTA (mucosal
permeability), and histological analysis (epithelial necrosis) were
used as indexes of gastric mucosal injury. Gastric mucosal vascular
expression of intercellular adhesion molecule 1 (ICAM-1) or P-selectin
were determined at 1 and 3 h after Indo administration using the dual
radiolabeled monoclonal antibody (MAb) technique. For some experiments,
a blocking MAb directed at either ICAM-1 (1A29) or P-selectin (RMP-1)
or their isotype-matched controls was injected intravenously 10 min
before Indo administration. We found that P-selectin expression was
significantly increased at 1 h but not 3 h after Indo administration,
whereas ICAM-1 expression was significantly increased at both 1 and 3 h
after Indo treatment. The blocking ICAM-1 and P-selectin MAbs both
inhibited Indo-induced increases in lesion score, mucosal permeability,
and epithelial cell necrosis. However, the Indo-induced gastropathy was
not associated with significant PMN infiltration into the gastric
mucosal interstitium, nor did Indo reduce gastric mucosal blood flow.
We propose that NSAID-induced gastric mucosal injury may be related to
the expression of P-selectin and ICAM-1; however, this mucosal injury
does not appear to be dependent on the extravasation of inflammatory
cells or mucosal ischemia.
neutrophils; endothelial cells; inflammation
 |
INTRODUCTION |
NONSTEROIDAL ANTI-INFLAMMATORY drug (NSAID)-induced
gastric mucosal injury significantly limits the use of these drugs for the treatment of chronic inflammatory disorders such as rheumatoid arthritis. Although it has been proposed that the mechanism by which
NSAIDs induce this gastric mucosal injury is via their ability to
inhibit cyclooxygenase (COX)-mediated production of "protective" prostaglandins, several lines of evidence suggest that the mechanism may be more complex than originally thought. For example, Ligumsky et
al. (14) have shown that inhibition of prostaglandin production by
>95% via rectal administration of certain NSAIDs did not induce gastric ulcers. In addition, recent studies by Langenbach et al. (12)
demonstrate that homologous recombination to disrupt the Ptgs 1 gene encoding for COX-1 in mice
does not result in spontaneous gastric ulcers. In fact, these
COX-1-deficient animals are less sensitive to NSAID-induced gastropathy
than their age-matched wild-type controls.
It is becoming increasingly apparent that neutrophilic
polymorphonuclear leukocytes (PMNs) may play an important role in the pathogenesis of NSAID-induced gastropathy. Wallace and colleagues (27-29) have demonstrated that NSAID-induced gastric ulcerations may be attenuated by rendering animals neutropenic or by infusing blocking antibodies directed against CD18, intercellular adhesion molecule 1 (ICAM-1), P-selectin, and to a lesser extent
E-selectin. The latter findings suggest that NSAIDs may
enhance the expression of cell adhesion molecules on the surface of
endothelial cells. Qualitative data that support this possibility were
provided by immunohistochemical experiments that demonstrate an
increased staining of gastric venules for ICAM-1 30 min after oral
administration of indomethacin (Indo) (2). The mechanisms
by which adhesion of PMNs to postcapillary venules induces gastric
epithelial cell injury are not at all clear. There has been some
suggestion that leukocyte adhesion and/or aggregation occludes
the microvasculature, resulting in ischemic mucosal injury (2,
27-29). The recent development of a method to quantify surface
expression of endothelial cell adhesion molecules in vivo (19) has
prompted us to determine the temporal effects of Indo on gastric
mucosal surface expression of P-selectin and ICAM-1 in vivo in an
established model of NSAID-induced gastropathy. Furthermore, we
compared these Indo-induced changes in adhesion molecule expression to
PMN extravasation and blood flow in the gastric mucosa.
 |
METHODS |
Indo-induced gastropathy.
Male Sprague-Dawley rats weighing 225-275 g were obtained from
Harlan Laboratories (Frederick, MD) and were administered Indo (20 mg/kg, dissolved in 5% sodium bicarbonate at the concentration of 10 mg/ml) orally after the deprivation of food, but not water, for
18-22 h. All procedures involving the use of animals were approved
by and in accordance with the guidelines of the Louisiana State
University Medical Center Animal Care and Use Resources Committee.
Measurements of mucosal permeability.
Before and at 1, 2, and 4 h after Indo administration, rats were
anesthetized with an intraperitoneal injection of 120 mg/kg sodium
5-ethyl-1-(1'-methyl-propyl)-2-thiobarbituric acid (Inactin; Byk-Gulden, Konstanz, Germany). Body temperature was maintained at
37°C, with a thermistor-controlled water pad (Aquamatic K-Modules K-20; Baxter, Valencia, CA). The animals underwent tracheostomy, and
the right femoral artery was cannulated for arterial pressure recording
and blood sampling. The right femoral vein was also cannulated for
injection of the isotope marker. A laparotomy was performed using a
midline abdominal incision. Both renal vessels were ligated to prevent
rapid excretion of the radioisotope marker into the urine. The stomach
was cannulated orally using Silastic tubing (Dow Corning, Arlington,
TN; ID 0.025 mm) for infusion of saline (pH 3.5). The stomach was also
cannulated from the proximal portion of the duodenum into the proximal
region of the gastric pylorus, using Silastic tubing (ID 0.25 mm) to
collect the solution. The perfused stomach was returned to the
abdominal cavity, and the abdominal wall was closed to minimize
dehydration of the organs during the experiment. The luminal contents
of the stomach were removed by preperfusion with warm (37°C) saline
(pH 3.5) for 30 min.
Mucosal permeability was determined using the blood-to-lumen clearance
of 51Cr-labeled EDTA as described
previously (32). One hundred microcuries of
51Cr-EDTA (DuPont de Nemours,
Birmington, DE) were injected via the femoral vein catheter. After a
15-min equilibration period, the perfusate was collected every 10 min
for 40 min for the appearance of
51Cr-EDTA. Plasma samples were
obtained at 40 min for use as reference counts. Radioactivity in each
sample was determined using a multichannel gamma counter (Wallace 1282 Compugamma). Blood-to-lumen clearance of
51Cr-EDTA was calculated using the
equation
where
Cper and
Cpl are counts per minute per
milliliter of 51Cr-EDTA in the
lumen perfusate and plasma, respectively, Q is the luminal perfusion
rate (400 µl/min), and W is the weight of the stomach.
Mucosal permeability was determined from the mean of the four clearance
values.
Lesion scoring, tissue preparation, and biochemical analysis.
After measurement of mucosal permeability, the animals were killed with
an overdose of pentobarbital sodium (Butler, Columbus, OH), and the
perfused stomach was excised. The stomach was opened along the greater
curvature and examined. Because Indo produced linear ulcers, the lesion
score of each animal was expressed as the sum of the length of lesions
(mm) (29).
After being weighed, each stomach was sectioned for histology and
myeloperoxidase (MPO) determination. MPO activity was determined as
described previously (32). MPO activity was expressed as units per gram
wet weight of the stomach.
For histological analysis, a tissue sample was obtained from each
animal, fixed, dehydrated, and embedded in JB-4 (Polysciences, Warrington, PA). Sections (2.5 µm) were cut with glass knives and
stained with hematoxylin and eosin.
Measurement of blood flow.
Blood flow was quantified using the radiolabeled microsphere-reference
organ technique (24). Immediately before, 5 min after, and 1, 2, and 4 h after Indo administration, rats were anesthetized via an
intraperitoneal injection of 120 mg/kg Inactin. Body temperature was
maintained at 37°C with a previously described themistor-controlled water pad. The animals underwent tracheostomy to
facilitate breathing. Cannulas placed in the right femoral artery and
the right carotid artery both connected to the pressure transducers.
The carotid artery cannula was advanced into the left ventricle; the
position of the cannula tip was confirmed by a ventricular pressure
tracing.
Microspheres (15.5 ± 0.1 µm) labeled with
85Sr (DuPont de Nemours) were
suspended in 0.9% NaCl containing 10 µl of 0.05% Tween 80. The
microspheres were dispersed using an ultrasonic bath and then
vigorously vortexed for 2 min before injection. A 0.3-ml suspension
containing ~200,000 microspheres was injected in the left ventricle
over a 15-s period, during which time a reference sample was withdrawn
from the right femoral artery into a heparin-containing glass syringe
at a known rate (0.68 ml/min). After the microsphere injection, the
carotid cannula was attached to a syringe and flushed with 5% Ficoll
solution at a rate equal to the reference withdrawal rate using a
bidirectional infusion pump. The withdrawal period lasted 90 s from the
time of microsphere injection.
Rats were killed by injection of saturated potassium chloride into the
left ventricle. The stomach was harvested according to the method
described previously (12) and separated into mucosa-submucosa and
serosa-muscularis layers. Only the mucosa-submucosa layer with or
without lesions was counted. Radioactivity in each sample was
determined using a multichannel gamma counter (Wallace 1282 Compugamma). Blood flow was calculated using the equation
where
CT and
CR are counts per minute in the
tissue and the reference blood sample, respectively, and RWR is the
reference sample withdrawal rate (0.68 ml/min).
Effects of pretreatment with anti-ICAM-1 and P-selectin antibody.
Ten minutes before Indo administration, a nonbinding (vehicle) murine
immunoglobulin (Ig)G1 directed
against human P-selectin (P23) (16) and a blocking mouse
IgG1 directed against rat ICAM-1 (1A29) (25) were injected via the penile vein. Three hours after Indo
administration (a time when the severity of mucosal injury reached its
peak) lesion score and mucosal permeability were quantified as
previously described for each group. A group pretreated with a mouse
IgG1 directed against rat
P-selectin (RMP-1) (30) was also compared with the nonbinding
monoclonal antibody (MAb)-treated (P23) group.
Quantification of ICAM-1 and P-selectin expression.
Preliminary studies revealed that Indo-induced gastric mucosal injury
was initially observed at 1 h after Indo administration and reached a
maximum at 3 h. Therefore, ICAM-1 and P-selectin expression were
quantified at 1 and 3 h after Indo administration.
The binding MAbs directed against either ICAM-1 (1A29) or P-selectin
(RMP-1) were labeled with 125I (Du
Pont-NEN, Boston, MA), whereas the nonbinding, isotype-matched MAb
(P23) was labeled with 131I.
Radioiodination of the MAbs was performed by the iodogen method (7).
Briefly, 250 µg of protein were incubated with 250 µCi of Na
125I and 125 µg of iodogen at
4°C for 12 min. After the radioiodination procedure, the
radiolabeled MAbs were separated from free
125I by gel filtration on a
Sephadex PD-10 column (Pharmacia, Uppsala, Sweden). The column was
equilibrated with phosphate buffer containing 1% bovine serum albumin
and was eluted with the same buffer. Two fractions of 2.5 ml each were
collected, the second of which contained the labeled antibody. Absence
of free 125I or
131I was ensured by extensive
dialysis of the protein-containing fraction. Less than 1% of the
activity of the protein fraction was recovered from the dialysis fluid.
Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis
showed normal heavy and light chain moieties of expected molecular
weight. Labeled MAbs were stored in 500-µl aliquots at 4°C and
used within 3 wk after the labeling procedure. The specific activity of
labeled MAbs was 0.5 µCi/µg.

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Fig. 1.
Histological appearance of gastric mucosa.
A-D
and
E-H:
normal, indomethacin (Indo)-treated, Indo-treated plus intercellular
adhesion molecule 1 (ICAM-1) antibody, and Indo-treated plus P-selectin
antibody at ×100 and ×40, respectively. Note large areas of
denuded epithelium and ulceration in Indo-treated stomachs
(B and
F).
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|
Rats were anesthetized with an intraperitoneal injection of 120 mg/kg
Inactin. Body temperature was maintained at 37°C with a
thermistor-controlled water pad. The animals underwent tracheostomy to
facilitate breathing, and the right carotid artery and left jugular
vein were cannulated. To measure ICAM-1 expression, a mixture of 5 µg
of 125I-ICAM-1 MAb (1A29), 5 µg
of 131I-labeled nonbinding MAb
(P23), and 100 µg of unlabeled ICAM-1 MAb was administered through
the jugular vein catheter. To measure P-selectin expression, a mixture
of 5 µg of 125I-P-selectin MAb
(RMP-1) and 5 µg of
131I-nonbinding MAb (P23) was
administered through the jugular vein catheter. These doses of MAbs
were determined in our previous report for ICAM-1 (19) and in
preliminary experiments for P-selectin. Thereafter, the animals were
heparinized (1 mg/kg sodium heparin) and rapidly exsanguinated by
vascular perfusion with sodium bicarbonate buffer via the jugular vein
and simultaneous blood withdrawal via the carotid artery. The inferior
vena cava was then severed at the thoracic level, and the carotid
artery was perfused with sodium bicarbonate buffer. After completion of
the exchange transfusion, organs were harvested and weighed.
The activities of 125I (binding
MAb) and 131I (nonbinding MAb) in
harvested gastric mucosa and in 100-µl aliquots of cell-free plasma were counted in a 14800 Wizard 3 gamma-counter (Wallace, Turku, Finland), with automatic correction for background activity and spillover. The injected activity in each experiment was calculated by
counting a 5-µl sample of the mixture containing the radiolabeled MAbs. The radioactivities remaining in the tube used to mix the MAbs,
the syringe used to inject the mixture, and the jugular vein catheter
were subtracted from the total calculated injected activity. The
accumulated activity of each MAb in the stomach was expressed as the
percent of the injected dose (%ID) per gram of tissue. The equation
used to calculate ICAM-1 and P-selectin expression was as follows
This
equation was modified from the original method (10) to correct the
tissue accumulation of nonbinding MAb for the relative plasma levels of
both binding and nonbinding MAbs (10). This value, expressed as %ID,
was converted to µg MAb/g tissue by multiplying the above value by
the total injected binding MAb (µg), divided by 100.
Statistics.
All values are presented as means ± SE. The data were analyzed
using one-way analysis of variance followed by Student-Newman-Keuls multiple comparisons test. Statistical significance was set at P < 0.05.
 |
RESULTS |
Intragastric administration of Indo induced linear hemorrhagic lesions
primarily in the corpus of the stomach that were first observed
macroscopically at 1 h after administration. These hemorrhagic erosions
continued to develop over the next 2-3 h and were characterized histologically by mucosal injury (edema, necrosis, and exfoliation of
the mucosal epithelial cells into the gastric lumen), hemorrhage, and
formation of a "mucoid cap" (a layer of mucus, fibrin, and necrotic tissue) (Fig. 1). Histological inspection of
the tissue indicated that active Indo-induced gastric mucosal injury
peaked between 3 and 4 h. At 4 h after Indo administration, repair of the mucosal barrier was evident, and thus gastric mucosal lesions and
51Cr-EDTA clearance were performed
at 3 h after Indo administration. Interestingly, we found no
histological evidence of neutrophil infiltration, nor did we observe
any increase in tissue MPO activity (23.4 ± 14.2 vs. 29.7 ± 12.5 U/g tissue for control vs. 3 h after Indo). Furthermore, we found
that Indo did not decrease total organ or mucosal blood flow in the
stomach. In fact, we observed a significant hyperemia in the lesioned
areas of the mucosa before (i.e., 1 h) and at the time of frank
ulceration (Fig. 2).

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Fig. 2.
Gastric mucosal blood flow measured at different times after Indo
administration. 1hr-L, 2hr-L, and 4hr-L: blood flow in areas destined
to lesion (1 h) or in actual lesion areas (2 and 4 h); 1hr, 2hr, and
4hr: blood flow in normal-appearing mucosa at various times after Indo
treatment. Values are means ± SE;
n = 5-6/group.
* P < 0.01 vs. control.
** P < 0.05 vs. control.
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We found that ICAM-1 surface expression in the gastric mucosa increased
significantly (43%) at both 1 and 3 h after Indo administration, corresponding to the time of earliest mucosal lesion and peak mucosal
injury, respectively (Fig. 3). P-selectin
expression in the gastric mucosa increased by ~55% only at 1 h after
Indo administration (Fig. 4).

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Fig. 3.
ICAM-1 expression in gastric mucosa at 1 and 3 h after oral Indo
administration. MAb, monoclonal antibodies. Values are means ± SE; n = 5-6/group.
* P < 0.001 vs. control.
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Fig. 4.
P-selectin expression in gastric mucosa at 1 and 3 h after oral Indo
administration. Values are means ± SE;
n = 5-6/group.
* P < 0.001 vs. control.
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The pathophysiological role of ICAM-1 and P-selectin in this model of
gastropathy was assessed using monoclonal blocking antibodies directed
against either ICAM-1 or P-selectin. We found that administration of
anti-ICAM-1 antibody (1A29) significantly attenuated the increases in
both lesion score and mucosal permeability caused by Indo, compared
with the nonbinding control MAb (Fig. 5).
Administration of anti-P-selectin antibody (RMP-1) also significantly
attenuated the increases in both lesion score and mucosal permeability
caused by Indo, compared with the nonbinding control MAb (Fig.
6).

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Fig. 5.
Effect of pretreatment with anti-ICAM-1 antibody (1A29) (2 mg/kg iv) on
Indo-induced increases in lesion score
(A) and mucosal permeability
(B). Type-matched nonbinding
antibody (P23) was used for sham group. Values are means ± SE;
n = 5-6/group.
* P < 0.001 vs. control.
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Fig. 6.
Effect of pretreatment with anti-P-selectin antibody (RMP-1; 0.5 mg/kg
iv) on Indo-induced increases in lesion score
(A) and mucosal permeability
(B). Type-matched nonfunctioning
antibody (P23) was used for sham group. Values are means ± SE;
n = 5-6/group.
* P < 0.05 vs. control.
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|
 |
DISCUSSION |
There is a growing body of experimental evidence to suggest that
neutrophil-endothelial cell interactions play a critical role in the
pathophysiology of NSAID-induced gastropathy (2, 27-29). Evidence
supporting this concept comes from studies demonstrating a reduction in
NSAID-induced gastric damage in neutropenic rats (28), as well as
studies demonstrating a protective effect with pretreatment with
monoclonal antibodies that block certain adhesion molecules such as
CD18, ICAM-1, P-selectin, and to a lesser extent E-selectin (27, 29).
Furthermore, intravital microscopic studies have shown that Indo and
aspirin promote leukocyte adherence in postcapillary venules of the
mesentery (3, 4). Although one report suggests that certain NSAIDs may
enhance gastric ICAM-1 expression using immunohistochemical
localization methods, there has been no direct quantification of
adhesion molecule expression in animals receiving NSAIDs. The dual
radiolabeled antibody technique (19) allows for measurements of ICAM-1
and P-selectin expression with a resolution that is not possible with
immunostaining techniques. Using this method, we found that endothelial
surface expression of P-selectin and ICAM-1 is significantly increased
by intragastric Indo administration. The increased adhesion molecule
expression preceded the extensive mucosal injury induced by Indo. These
data suggest that the enhanced surface expression of the two
endothelial cell adhesion molecules may represent a cause of the
mucosal injury rather than a consequence of Indo-induced
gastropathy. The increase in P-selectin and ICAM-1
expression in the stomach at 1 h after Indo administration was in some
respects unexpected. In vitro studies using human umbilical vein
endothelial cells have demonstrated that P-selectin expression induced
by histamine is very rapid because of its translocation from
Weibel-Palade bodies to the endothelial cell surface. In
vivo studies have shown that P-selectin expression is enhanced from 10 to 60 min after intravenous histamine injection in mice (6). These data
are in fact consistent with our observations and intravital
observations demonstrating increased and persistent rolling of
leukocytes in venules exposed to histamine (11). On the other hand,
transcriptional upregulation of P-selectin expression induced by
lipopolysaccharide (LPS) is not apparent until at least 2 h after
challenge (6), suggesting that the increase of P-selectin expression we
observed in our model of NSAID-induced gastropathy is due primarily to
its translocation from Weibel-Palade bodies to the surface of the
endothelial cell. It has also recently been reported that
leukotrienes C4 and
D4 induce the P-selectin
translocation from Weibel-Palade bodies, suggesting a mechanism whereby
Indo enhances P-selectin expression (8, 20). An
interesting point to note is that a 55% increase in P-selectin
expression represents an increase in ~200 molecules of P-selectin per
endothelial cell, assuming a surface area of ~125
cm2 of the vascular bed in 1 g
stomach tissue, and there are 50,000 endothelial
cells/cm2 of vascular bed.
The rapid and significant increase in ICAM-1 expression on the surface
of endothelial cells was more surprising. However, work by Lo et al.
(15), as well as Asako et al. (4), has shown that oxidant- or
NSAID-induced increases in ICAM-1 expression or leukocyte adhesion may
occur as early as 30 min to 1 h in vitro or in vivo. Stimulation of
those endothelial cells with LPS, cytokines, or
H2O2
led to increased expression of ICAM-1 (18), which was accompanied by
increased binding of neutrophils to endothelial cells (1). This
increase of ICAM-1 expression was observed at ~3 h and was maintained
over 24 h. We observed significant increases in ICAM-1 expression at 1 and 3 h in vivo. Mast cells have been considered possible effector
cells in NSAID gastropathy by virtue of their ability to synthesize and
release certain cytokines. Indeed, tumor necrosis factor (TNF)-
has
been demonstrated to be elevated in NSAID-induced gastropathy, and this
cytokine is well known to increase surface expression of ICAM-1 in
vitro and in vivo (22). However, Rioux and Wallace (21) recently
reported that mast cells may not play a significant role in NSAID
gastropathy in that serum mast cell protease II and mast cell
degranulation were not elevated after Indo administration. Furthermore,
mast cell-deficient mice exhibited the same degree of gastric injury as
did their wild-type controls (21). Making the same assumptions as
above, an increase in ICAM-1 expression of 43% represents an increase
of ~11,500 molecules of ICAM-1 per endothelial cell.
Although we have focused on endothelial cell adhesion molecules, it
should be noted that adhesion molecules on the neutrophil cell surface
are also important determinants for Indo-induced gastropathy. Wallace
and colleagues (27, 29) have demonstrated that MAbs directed against
CD18 adhesion molecules attenuated the development of NSAID-induced
gastropathy. There is evidence to suggest that CD11/CD18 is expressed
on leukocytes in both functional and nonfunctional conformations, and
activation of leukocytes leads to a change in the conformation of
CD11/CD18, thereby promoting adhesion (23, 31). This proadhesive
alteration in CD11/CD18 conformation may be elicited by leukotriene
B4 (26) as well as
platelet-activating factor and TNF-
(23).
The enhanced expression of P-selectin and ICAM-1 induced by Indo
appears to be an important step in the development of gastric mucosal
injury. We, as well as others, have demonstrated that immunoneutralizing antibodies to P-selectin or ICAM-1 inhibit the
development of gastric lesions as assessed by macroscopic, histological, and physiological determinations (Figs. 5 and 6). The
mechanisms by which Indo-induced PMN-endothelial interaction promotes
gastric mucosal injury are not at all clear. Previous studies have
suggested that Indo-induced leuko-aggregation or ischemia may
promote mucosal injury (9). However, we, as well as others, have been
unable to observe an ischemic event in response to NSAIDs with the use
of the microsphere-reference organ technique (5, 13, 17). Indeed, when
we quantify mucosal blood flow in the actual lesion area, we see a
modest but significant hyperemia and not an ischemia beginning
in the very early stages of ulcer development (Fig. 2). Thus the role
of blood flow in NSAID-induced gastropathy remains controversial. It is
conceivable that leukocyte plugging in a small percentage of
capillaries within the gastric mucosa does occur; however, this would
not be detected by the method employed in this study. Another
interesting yet perplexing observation is the lack of any significant
PMN infiltration into mucosal interstitium (Fig. 1). Exactly how
adhesion of PMNs to the postcapillary venules induces epithelial cell
necrosis in the absence of an inflammatory infiltrate or ischemic event
remains speculative. One possible mechanism could involve
receptor/ligand interaction in the form of CD18/ICAM-1 binding, which
could activate specific signaling pathways within the endothelial
cells, resulting in the production of certain cytokines capable of
promoting epithelial cell apoptosis and/or necrosis. The
precise mechanisms for epithelial cell injury remain the subject of
active investigations.
 |
ACKNOWLEDGEMENTS |
This work was supported in part by the National Institute of
Diabetes and Digestive and Kidney Diseases Grant DK-47663.
 |
FOOTNOTES |
Address for reprint requests: M. B. Grisham, LSU Medical Center, Dept.
of Molecular and Cellular Physiology, 1501 Kings Highway, Shreveport,
LA 71130.
Received 8 September 1997; accepted in final form 29 October 1997.
 |
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