JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY 2011, 62, 5, 527-534
www.jpp.krakow.pl
I. PETROVIC1, I. DOBRIC1, D. DRMIC1, M. SEVER1, R. KLICEK1, B. RADIC1, L. BRCIC2, D. KOLENC2, M. ZLATAR1,
K. KUNJKO1, D. JURCIC3, M. MARTINAC3, Z. RASIC1, A. BOBAN BLAGAIC1, Z. ROMIC1, S. SEIWERTH2, P. SIKIRIC1
BPC 157 THERAPY TO DETRIMENT SPHINCTERS FAILURE-ESOPHAGITIS-PANCREATITIS
IN RAT AND ACUTE PANCREATITIS PATIENTS LOW SPHINCTERS PRESSURE
1
Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb, Croatia; 2Department of Pathology, Medical Faculty,
University of Zagreb, Zagreb, Croatia; 3Department of Internal Medicine, Medical Faculty, University of Zagreb, Zagreb, Croatia
Possibly, acute esophagitis and pancreatitis cause each other, and we focused on sphincteric failure as the common
causative key able to induce either esophagitis and acute pancreatitis or both of them, and thereby investigate the
presence of a common therapy nominator. This may be an anti-ulcer pentadecapeptide BPC 157 (tested for inflammatory
bowel disease, wound treatment) affecting esophagitis, lower esophageal and pyloric sphincters failure and acute
pancreatitis (10 µg/kg, 10 ng/kg intraperitoneally or in drinking water). The esophagitis-sphincter failure procedure (i.e.,
insertion of the tubes into the sphincters, lower esophageal and pyloric) and acute pancreatitis procedure (i.e., bile duct
ligation) were combined in rats. Esophageal manometry was done in acute pancreatitis patients. In rats acute pancreatitis
procedure produced also esophagitis and both sphincter failure, decreased pressure 24 h post-surgery. Furthermore, bile
duct ligation alone immediately declines the pressure in both sphincters. Vice versa, the esophagitis-sphincter failure
procedure alone produced acute pancreatitis. What's more, these lesions (esophagitis, sphincter failure, acute pancreatitis
when combined) aggravate each other (tubes into sphincters and ligated bile duct). Counteraction occurred by BPC 157
therapies. In acute pancreatitis patients lower pressure at rest was in both esophageal sphincters in acute pancreatitis
patients. We conclude that BPC 157 could cure esophagitis/sphincter/acute pancreatitis healing failure.
K e y w o r d s : acute pancreatitis, esophagitis, pancreatitis, pentadecapeptide BPC 157, sphincters failure
INTRODUCTION
We suggested that acute esophagitis and pancreatitis may
cause each other, and we focused on whether sphincteric failure
may be the common causative key able to induce either
esophagitis and acute pancreatitis or both of them, and thereby
investigate, the presence of a common therapy nominator.
Finally, we suggested that this may have a reflection in patients
with acute pancreatitis and lower pressure in both the lower and
upper esophageal sphincter.
Therefore, to solve this, we focused on rat acute pancreatitis
induced by bile duct ligation (1) (i.e., pancreatic
hyperstimulation and bile-pancreatic duct obstruction as main
factors for acute biliary pancreatitis (2)), esophagitis and
sphincter failure in rats (tubes in lower esophageal and the
pyloric sphincter (3, 4)), their mutual relationships, both
commonly known (i.e., the role of biliary and pancreatic reflux
in esophagitis induced by duodenogastric reflux were long ago
postulated (5, 6)) and those that may arise from the newly
supposed sphincteric failure as the common causative key (i.e.,
the acinar hyperstimulation the role of uncontrolled delivery due
to the sphincters dysfunction was not particularly considered
(2)), and thereby, mutual aggravation. The other focus was on
possible therapy with the use of stable gastric pentadecapeptide
BPC 157 (GEPPPGKPADDAGLV, M.W. 1419, PL 14736) (7)
and its role in esophagitis, lower esophageal and pyloric
sphincters failure and acute pancreatitis (1, 3, 4).
Likely, as an anti-ulcer peptide BPC 157 (tested for
inflammatory bowel disease, wound treatment, LD1 not
achieved, effective alone without carrier) (7), may affect both
esophagitis and acute pancreatitis and consequently, rescue of
esophagitis sphincters failure (1, 3, 4).
Also, to oversee a practical implication, we investigate this
novel link presentation in patients: whether acute pancreatitis
patients have lower pressure in esophageal sphincters.
Of note, the exact relationship between acute pancreatitis
and esophagitis copresented, was not particularly investigated,
nor sphincteric failure (and its possible causative role)
appreciated particular attention to, whilst different therapies (8)
may induce either acute pancreatitis or esophagitis. Therefore,
the recently reported BPC 157 effect on sphincteric function and
consequent esophagitis development (3, 4), and its previous
effect on acute pancreatitis (1), along with possible novel
findings in esophagitis/pancreatitis rats, may be a combination
of considerable therapeutic interest.
To support these expectations, the reported BPC 157
beneficial effects (i.e., throughout 20 months) may both
effectively recover long-term esophagitis and sphincteric failure
528
that may closely mimic human condition (temporary tube
insertion into the lower esophageal and pyloric sphincter in rats
with otherwise intact and not mutilated gastrointestinal tract;
whilst the effect on acute pancreatitis, and vice versa, was not
investigated) (3, 4). Also, BPC 157 was known to inhibit
esophagitis development in rats with esophago-jejunal
anastomosis (9), where the ulcerogenic effect of free alkaline
reflux, trypsin and deconjugated bile salts should be viewed (5).
Previously, focusing on acute pancreatitis, a consistent
improvement of bile duct-ligated acute pancreatitis was regularly
noted following BPC 157 pentadecapeptide medication using
peroral or parenteral routes, and was further supported by the
measurement of decrease of serum amylase levels in both
prophylactic and therapeutic regimens (1). Thereby, considering
that bile duct ligation would actually prevent bile reflux and
consequent ulcerogenic effect, it may be interesting to investigate
whether the bile duct ligation may attenuate esophagitis and
sphincter failure or contrary, aggravate.
Thus, the effect of bile duct ligation and acute pancreatitis on
esophagitis and sphincter failure, with or without tube insertion
into the lower esophageal and pyloric sphincter, was investigated
along with BPC 157 application. Likewise, the added effect of
tube insertion into the lower esophageal and pyloric sphincter on
sphincter failure, esophagitis and acute pancreatitis was also
studied in conjunction with BPC 157 therapy. In addition, to
observe whether this may be present in patients with acute
pancreatitis, we investigate whether the patients admitted
because of acute pancreatitis may have a lower pressure in
esophageal sphincters.
MATERIAL AND METHODS
Animals
Wistar Albino male rats (200 g b.w.) were randomly
assigned to the experiments (10 animals at least per each
experimental group), all of which were approved by the Local
Ethic Committee. Furthermore, all experiments were carried out
under blind protocol, and the effect was assessed by examiners
who were completely unaware of the given protocol.
Drugs
Pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, M.W.
1419), (Diagen, Ljubljana, Slovenia) dissolved in saline, was
used in all experiments. The peptide BPC 157 is part of the
sequence of human gastric juice protein BPC, and is freely
soluble in water at pH 7.0 and saline. It was prepared as
described previously (1, 3, 4) with 99% high pressure liquid
chromatography (HPLC) purity, expressing 1-des-Gly peptide as
an impurity.
Medication to counteract development of esophagitis-sphincter
failure and/or acute pancreatitis
In principle, the given regimens follow those previously
used in esophagitis and acute pancreatitis studies (1, 3, 4, 7).
After initial surgery, at 30 mins, rats received (i)
intraperitoneally, one bolus application of saline (5.0 ml/kg) or
pentadecapeptide BPC 157 (10 µg/kg, 10 ng/kg) (ii) per-orally,
since the 30 mins throughout the next 24 hours, drinking water
only (control) or pentadecapeptide BPC 157 in drinking water
(10 µg/kg, 0.16 µg/ml, 12 ml/day) until they randomly
underwent a second operation under deep anesthesia to directly
assess lower esophageal sphincter and pyloric sphincter pressure
before sacrifice.
Surgical procedures
The previously described protocols were used (1, 3, 4, 7).
Initially, all of the rats were anesthetized and subjected to the
procedure originally used to solely induce esophagitis-sphincters
failure (one tube was placed and sutured into the pylorus, and
another tube was placed into the lower esophageal sphincter) or
to solely provoke acute pancreatitis (ligation of the bile duct at its
point of entry into the duodenum), as described before (1, 3, 4, 7).
When procedures (bile duct ligation and tube insertion) were
combined, the bile duct and tube insertion were simultaneously
carried out. After 24 h, all of them were again anesthetized to
implant a Foley catheter into the stomach, through the esophageal
(lower esophageal sphincter pressure assessment) or the duodenal
incision (pyloric sphincter pressure assessment) for manometrical
evaluation of the pressute into the sphincters as described before.
Exception includes those subjected to immediate sphincter
pressure assessment after bile duct ligation.
Lower esophageal sphincter pressure assessment and pyloric
sphincter pressure assessment
As described before (1, 3, 4, 7), in all rats manometrical
evaluation (cmH2O) was performed with a water manometer
connected to the drainage port of the Foley catheter as described
(the values of 68-76 cmH2O for lower esophageal sphincter and
68-74 cmH2O for pyloric sphincter were considered to be
normal as determined before). The proximal side of the
esophageal or distal side of the duodenal incision was ligated to
prevent regurgitation.
Alternatively, in addition to the protocols to investigate the
effect at 24 hours, to assess the immediate effect of bile duct
ligation on sphincter function (i) saline (5.0 ml/kg) or
pentadecapeptide BPC 157 10 µg/kg or 10 ng/kg i.p. application
was immediately given after bile duct ligation and 5 min
thereafter, a manometrical evaluation was performed as before.
Esophagitis and acute pancreatitis assessment 24 hours after
surgery
In all rats, esophagitis macroscopical assessment was
completed accordingly with scores of 0-4 using direct esophagus
scanning (ScanMaker i900; Microtek, Willich, Germany) as
described previously (3, 4): normal glistening mucosa(score 0),
edematous mucosa with focal hemorrhagic spots (score 1),
multiple erosions with hematins attached (score 2), tiny
esophagus with hemorrhagic and linear yellowish lesions (score
3), tiny esophagus with coalesced hemorrhagic and yellowish
lesions (score 4). Subsequently, the oesophagus samples were
placed in 10% formalin and used for histopathological
examination. Likewise, in all rats, pancreas damage was
assessed using the same macroscopic system as previously
described (1) (score 0: pancreas without necrosis; score 1:
pancreas with edema only; score 2: separate hemorrhagic zones
and/or foci of necrosis, largest diameters <1mm; score 3:
separate hemorrhagic zones and/or foci of necrosis, largest
diameters > 3mm; score 4: confluent hemorrhagic zones and/or
foci of necrosis, largest diameters >6mm; scope 5: diffuse
hemorrhagic zones and/or necrosis in whole pancreas) and after
the pancreas tissue was routinely processed for histological
investigation as described (1) a modified microscopical analysis
(1) included necrosis (score 0 -3: 0- none; 1- foci of necrosis less
than 5 acini; 2- foci of necrosis between 5 and 10 acini; 3 - foci
of necrosis more than 10 acini). Blood samples were taken from
the aorta abdominalis as described before, and the serum
amylase and lipase values were determined using Pliva Zagreb
Reagent, according to the previously described method (1).
529
Values between 21-67 (lipase) and 23-91 (amylase) U/L were
again calculated as normally present in rats without pancreas
pathology (1).
Assessment in patients
All 10 patients with acute pancreatitis (6 women and 4 men,
mean age 54.5±8.2 years) (Ranson criteria), underwent
endoscopy and esophageal manometry according to standard
protocol, approved by Hospital Ethic Committee, as described
before (10, 11), and esophageal manometry was performed
immediately after admission to the department. In 8 patients the
cause of pancreatitis was biliary, whereas, in the other 2 patients
the cause was etilic genesis. The majority of patients (7 cases)
had mild pancreatitis while 3 presented with severe pancreatitis,
but their recovery proceeded without any major complications.
The results were compared with values of control healthy
subjects (our gastrointestinal motility lab) (16 female, 14 male,
mean age 48.5±10.7) with normal esophageal manometry values
and normal esophagogastroduodenoscopy findings (LA score).
Table 1. Procedures, therapy regimens, lesions assessment. After initial surgery, at 30 min, rats received (i) intraperitoneally, one bolus
application of saline (5.0 ml/kg) or pentadecapeptide BPC 157 (10 µg/kg, 10 ng/kg) (ii) per-orally, since the 30 min throughout the
next 24 hours, drinking water only (control) or pentadecapeptide BPC 157 in drinking water (10 µg/kg, 0.16 µg/ml, 12 ml/day) until
they randomly underwent a second operation under deep anesthesia to directly assess lower esophageal sphincter and pyloric sphincter
pressure before sacrifice. *P<0.05, at least vs. control.
Procedures, therapy regimens, lesions assessment
Lesions assessment
Procedures
used
24 hours
Esophagitis
procedure:
tube into
LES+tube
into PS
24 hours
pancreatitis
procedure:
bile duct
ligation
Combined
procedure
24 hours
esophagitis
procedure
(tube into
LES+tube
into PS)
+
24 hours
pancreatitis
procedure
(bile duct
ligation)
Therapy
regimens
Saline
5 ml/kg
i.p.
BPC 157
10 µg/kg
i.p.
BPC 157
10 ng/kg
i.p
Drinking
water
12 ml/day
p.o.
BPC 157
10 µg/kg
p.o.
Saline
5 ml/kg
i.p.
BPC 157
10 µg/kg
i.p.
BPC 157
10 ng/kg
i.p.
Drinking
water
12 ml/day
p.o.
BPC 157
10 µg/kg
p.o
Saline
5 ml/kg
i.p.
BPC 157
10 µg/kg
i.p.
BPC 157
10 ng/kg
i.p.
Drinking
water
12 ml/day
p.o.
BPC 157
10 µg/kg
p.o.
Esophagitis
score (0-4)
Min/Med/Max
2/3/4
Serum enzymes values
Pancreatitis
units/litre, means±S.D.
Macroscopical
Microscop Amylase
Lipase
score (0-5)
ical score
Min/Med/Max
(0-3)
Min/Med/
Max
2/3/4
1/2/3
2120±247
101±7
0/1/2*
0/1/2*
1/1/2*
1050±124*
86±9*
1/1/2*
1/1/2*
1/1/2*
1120±138*
88±7*
2/3/4
2/3/4
2/2/3
2231±237
112±11
0/1/2*
1/1/2*
1/1/2*
1247±105*
85±9*
2/3/4
3/3/4
2/3/3*
5050±475
415±67
0/1/2*
1/1/2*
1/1/2*
3153±375*
212±57*
0/1/2*
1/1/2*
1/1/2*
3222±368*
242±70*
2/3/4
2/3/4
3/3/3
5260±371
426±59
0/1/2*
0/1/2*
0/1/2*
3128±397*
202±42*
3/4/4
3/4/5
2/3/3
9123±582
505±47
0/1/2*
1/1/2*
1/1/2*
7387±494*
313±58*
0/1/2*
1/2/3*
1/2/3*
7460±504*
333±38*
3/4/4
3/4/5
2/3/3
9348±608
516±56
1/1/2*
1/1/2*
0/1/2*
7692±556*
342±42*
530
The following parameters investigated esophageal motility: the
length, pressure, and the ability to relax the upper and lower
esophageal sphincter, values of contraction amplitude in the
upper, lower and middle esophagus and peristaltic wave velocity
along the body of the esophagus as described before (10, 11).
Statistical analyses
Statistical analysis was performed by a non-parametric
Kruskal-Wallis ANOVA and subsequent Mann-Whitney U-test
to compare groups. Values of P<0.05 were considered
statistically significant.
RESULTS
We investigated the detrimental relation between
sphincters/esophagitis/pancreatitis and possible therapy effect
using the combination of the methods previously applied to
particularly induce esophagitis/sphincter failure or acute
pancreatitis (1, 3, 4, 7) and various BPC 157 regimens application.
Commonly, the rats subjected to tube insertions into the
sphincters (esophagitis/sphincter failure-method (4)) and/or bile
duct ligation (acute pancreatitis (1)) presented in any case, both
significant esophageal and pancreatic damage. Advanced
esophagitis was present with the marked necrotic pancreatitis
damage (Fig. 1). Microscopically, extensive epithelial defects,
leukocyte infiltrates in lamina propria, and sub-mucosa as well
as oedema was along with necrotic pancreas areas ranged to
extensive necrotic areas including whole lobes, prominent
edema and advanced granulocyte infiltration. All BPC 157 rats
exhibited grossly less esophageal and less pancreatic lesions,
and microscopically, almost no such changes in esophagus, less
edema, less granulacytes, more mononuclears and less pancreas
necrosis (i.e., monoacinar necrosis) (Table 1).
Along with this, the failure of both sphincters seems to be
commonly involved (Table 2). For instance, the acute
pancreatitis procedure (i.e., bile duct ligation) produced besides
Table 2. Procedures, therapy regimens, pressure assessment. After initial surgery, at 30 min, rats received (i) intraperitoneally, one
bolus application of saline (5.0 ml/kg) or pentadecapeptide BPC 157 (10 µg/kg, 10 ng/kg) (ii) per-orally, since the 30 min throughout
the next 24 hours, drinking water only (control) or pentadecapeptide BPC 157 in drinking water (10 µg/kg, 0.16 µg/ml, 12 ml/day)
until they randomly underwent a second operation under deep anesthesia to directly assess lower esophageal sphincter and pyloric
sphincter pressure before sacrifice. Alterantively, to assess the immediate effect of bile duct ligation on sphincter function (i) saline
(5.0 ml/kg) or pentadecapeptide BPC 157 10 µg/kg or 1 ng/kg i.p. application was immediately given after bile duct ligation and 5
min thereafter, a manometrical evaluation was performed as before.*P<0.05, at least vs. control.
Procedures, therapy regimens, pressure assessment
Pressure assessed in sphincters,
procedures
therapy
cm H2O, means±S.D.
used
regimens
Lower esophageal Pyloric
sphincter
sphincter
Saline
40±2
35±2
24 hours- esophagitis
5 ml/kg i.p.
procedure
BPC 157
70±3*
62±3*
(tube into LES+tube into PS)
10 µg/kg i.p.
BPC 157
65±4*
55±3*
10 ng/kg i.p
Drinking water
45±2
33±2
12 ml/day p.o.
BPC 157
10 µg/kg p.o
70±2*
60±1*
24 hours- pancreatitis
procedure
(bile duct
ligation)
Combined procedure
(24 hours- esophagitis
procedure
(tube into LES+tube into PS)
+
24 hours- pancreatitis
procedure
(bile duct
ligation))
5 min- pancreatitis
procedure
(bile duct
ligation)
Saline
5 ml/kg i.p.
BPC 157
10 µg/kg i.p.
BPC 157
10 ng/kg i.p.
Drinking water
12 ml/day p.o.
BPC 157
10 µg/kg p.o.
Saline
5 ml/kg
i.p.
BPC 157
10 µg/kg i.p.
BPC 157
10 ng/kg i.p.
Drinking water
12 ml/day p.o.
BPC 157
10 µg/kg p.o.
Saline
5 ml/kg i.p.
BPC 157
10 µg/kg i.p.
BPC 157
10 ng/kg i.p.
48±1
36±3
5±3*
65±2*
70±4*
62±1*
48±2
36±2
75±4*
65±3*
45±2
35±2
65±3*
60±2*
61±3*
62±2*
47±2
33±1
65±1*
60±2*
35±2
20±2
50±3*
45±1*
52±3*
43±2*
531
esophagitis-sphincter failure and acute pancreatitis, we
investigate whether acute pancreatitis patients have lower
pressure in esophageal sphincters compared to healthy subjects.
These results show that patients with acute pancreatitis had
significantly lower mean pressure at rest in both the lower and
upper esophageal sphincter, compared to a control group of healthy
subjects. There were no statistically significant differences in other
parameters studying esophageal motor function between compared
groups (Table 3). Interestingly, acute pancreatitis patients were
presented with esophagitis (LA score 2 (2 male, 2 female), LA
score 1 (1 male, 3 female) and LA score 0 (1 male, 1 female)).
Fig. 1. Characteristic presentation when procedures (bile duct
ligation (acute pancreatitis) and tube insertion into the sphincters
(esophagitis/sphincter failure) were combined and
simultaneously carried out. Advanced esophagitis was present
with the marked necrotic pancreatitis damage in controls (B, left,
down). All BPC 157 rats exhibited grossly apparently less
esophageal and less pancreatic lesions (C, right, upper).
Presentation at 24 hours after surgery, providing advanced fall of
pressure in sphincters in controls, and preserved pressure values
in sphincters of BPC 157-treated rats.
esophagitis, sphincter failure as evidenced by decreased pressure
within the sphincters 24 h post-surgery (Table 1, Table 2).
Furthermore, bile duct ligation alone immediately results in a
decline of the pressure in both lower esophageal and pyloric
sphincters. Vice versa, the esophagitis but also sphincter failure
procedure (i.e., insertion of the tubes into the sphincters) alone
produced acute pancreatitis. What's more, these lesions
(esophagitis, sphincter failure, acute pancreatitis when
combined) could aggravate each other as seen in rats with
inserted tubes into their sphincters and ligated bile duct (Table 1,
Table 2). Commonly it has been noted that the pyloric sphincter
seems to be the most affected. Counteraction occurred by BPC
157 therapy, both µg- and ng-regimens given either
intraperitoneally or in drinking water (Table 2).
Thereby, since this experimental evidence may suggest a
novel causative and mutually detrimental relation between
DISCUSSION
We focused on esophagitis-sphincter failure-acute pancreatitis
relation and a possible therapy that may be pentadecapeptide BPC
157. By combining esophagitis-sphincters failure (tubes into the
sphincters) (4) - and acute pancreatitis (bile duct ligation) (1)
models, we found a novel causative and mutually detrimental
relation between sphincters/esophagitis/pancreatitis. For instance,
the acute pancreatitis procedure produced esophagitis and
sphincter failure (i.e., ligation of bile duct immediately produced
a rapid and profound fall in pressure in both lower esophageal and
pyloric sphincter that could be not further rescued), and vice versa.
Counteraction occurred by the administration of BPC 157 therapy
(given either intraperitoneally or in drinking water (note, BPC 157
is suitably stable, intact in human gastric juice for more than 24 h
(7)). Furthermore, it was found that these lesions (esophagitis,
sphincter failure, acute pancreatitis) could further aggravate each
other and counteraction occurred again after BPC 157 regimens
administration. Obviously, these esophagitis, sphincter failure,
acute pancreatitis may be complex healing failures, but not only a
simple sum of separate damaging effects since sphincteric failure
may be essential. Also to oversee a practical implication, we show
that the acute pancreatitis patients have markedly lower pressure
in esophageal sphincters.
Previously, these sphincters may act as a biofeedback loop
critical for corresponding tissue integrity maintenance (i.e., pyloric
sphincter dysfunction exhibits prolonged esophagitis with a
constantly lowered pressure not only in the pyloric, but also in the
lower esophageal sphincter and a failure of both sphincters) (3, 4).
Table 3. Patients with acute pancreatitis underwent endoscopy and esophageal manometry compared control with healthy subjects with
normal esophageal manometry values and normal esophagogastroduodenoscopy findings Parameters investigated esophageal motility:
the length, pressure, and the ability to relax the upper and lower esophageal sphincter, values of contraction amplitude in the upper,
lower and middle esophagus and peristaltic wave velocity along the body of the esophagus, according to standard protocol as described
before (10, 11), means ±S.D., *P<0.001 vs. control.
Parameters assessed
Lower esophageal
sphincter (LES)
Esophageal corpus
Mean pressure of
peristaltic peak
(mmHg)
Esophageal corpus
Upper esophageal
sphincter (UES)
LES total lenght (mm)
Mean pressure at rest
(mmHg)
Swallowing relaxation
(mmHg)
Upper esophagus
Middle esophagus
Lower esophagus
Mean velocity of
peristaltic wave (cm/s)
UES total lenght (mm)
Mean pressure at rest
(mmHg)
Swallowing relaxation
(mmHg)
Acute pancreatitis
(n=10)
37.2±2.25
Control group
(n=30)
38.8±2.08
7.9±3.59*
20.4±3.8
0.6±0.7
0.5±0.69
84.1±11.56
88.9±14.86
90.0±11.3
94.0±14.44
93.3±13.39
96.7±10.29
3.3±0.35
3.5±0.36
28.9±3.33
30.7±2.27
47.1±12.52*
108.8±19.83
4.9±0.98
5.3±1.01
532
Now, even before tissue damage with simple bile duct ligation the
pressure within both the lower esophageal and pyloric sphincter
immediately reduces, thus causing abrupt sphincteric failure
(shown to be regularly irreparable), and thereby uncontrolled
continuous delivery to the duodenum and exocrine pancreas
resulting in acute pancreatitis (2) (and suportingly, tubes into the
sphincters induced acute pancreatitis even without bile duct
obstruction). Therefore, an extended sphincteric biofeedback loop,
esophagitis-sphincter failure-acute pancreatitis may be suggested.
On the other hand, with respect to BPC 157 involvement, all
of these damages were apparently mitigated by BPC 157 therapy
and thereby, its ability to rescue sphincter function (both lower
esophageal and pyloric sphincter) may be essential. Previously,
BPC 157 exhibited a particular anti-reflux mechanism and
sphincter balance in normal healthy rats (i.e., increasing lower
esophageal sphincter while decreasing pyloric sphincter
pressure) as well as sphincter pressure increase in pathological
conditions and failed sphincter pressure, which is a particular
recovery towards normal values. Otherwise, the decreased
values of both sphincters pressure remained in esophagitis (3, 4),
and now also in acute pancreatitis and bile duct obstruction. A
further fall in pyloric sphincter pressure found to be important
also for lower esophageal sphincter failed function (3) and
rescue by BPC 157 therapy (along with recovery of lower
esophageal sphincter and both esophageal and pancreatic tissues
lesions markedly attenuated) (3) are in accordance with
particular pyloric sphincter function (3), especially when
confronted with bile duct obstruction and/or acute pancreatitis
and successful effects of BPC 157 therapy (1, 3, 4, 7).
Thus seen from this viewpoint, it is probably more than a
coincidence that firstly, BPC 157 has anti-inflammatory effects
in the acute, subacute and chronic inflammation models (12),
BPC 157 therapy has an effect in preventing and reversing acute
pancreatitis, as well as esophagitis (including esophago-jejunal
anastomosis-esophagitis), has a particular anti-inflammatory
effect modulating inflammatory cells (polymorphonuclearssuppression; mononuclears (attraction) that may be able to
reduce local inflammation in bile duct ligation-pancreatitis along
with reduced edema and necrosis and reduced serum enzymes
values) (1), reduces LTB4, TXB2, and MPO in serum and
inflamed tissues (13, 14). Furthermore, BPC 157, could
significantly influence afferent nerve function (i.e., as seen in
capsaicin studies, it interacts and recovers somatosensory
neurons system function, in both adult and new born rats (15)
and has likely a neuroprotective effect (16, 17).
Secondly, in relation to the improved sphincter function, BPC
157 may additionally rescue the function of other failed sphincters
as well (18). This may lead to strands of newly formed muscle
after intestinal anastomosis, increased anastomotic strength (and
thereby, improved ileo-ileal anastomosis healing) (19) and a
particular increase of muscle thickness (inner circular muscular
layer, more than villus height and crypt depth increased) after
massive intestine resection (besides, rescuing rats with short
bowel with BPC 157 perorally and parenterally therapy means a
constant weight gain above preoperative values eventually
reaching the level of the healthy animals) (20). In analogy to
improve sphincter function, in quadriceps muscle or
gastrocnemius muscle complex injuries, BPC 157 increases
muscle function and healing, after a complete transection or major
crush (21-23). In addition, these effects of BPC 157 (21-23) occur
concurrently with its marked neuroprotective capability (15-17).
Thirdly, pentadecapeptide BPC 157 given peripherally could
affect sphincter function through serotonin (24, 25) or dopamine
(26-28) (presenting in the same dose-range BPC 157
prevented/reversed catalepsy or stereotypy and all concomitant
gastrointestinal lesions) (26-28). Also, this could be through
nitric oxide (NO) systems (presenting an effect in different
species and disturbances, both in vivo and in vitro, modulated
NO-agonist, NO synthase (NOS)-blocker effects as well as NOsynthesis (29-35)). In addition, we should emphasize BPC 157increase of macrophage function (36) (that may markedly
increase NO output (37)), a strong angiogenic effect (21) (i.e.,
direct protection of endothelium (32)) and particular
counteraction of endothelin over-expression (34). Finally, neural
input controls lower esophageal sphincter relaxation as a
function of NANC innervation with a significant influence of
NO (38) with further gut sphincters richly innervated by
peptidergic nerves (39, 40). Since the NO-system is essential for
normal and disturbed pancreatic function as well as integrity
(41), it may also improve the course of acute pancreatitis.
Additionally, all of the patients with acute pancreatitis have
markedly reduced pressure in both upper and lower esophageal
sphincters, thus, a consistent sphincter failure. Thereby, this
supportive evidence means there is a likelihood of analogous
chains of events in acute pancreatitis patients as well. Most patients
exhibited esophagitis while two had no esophagitis signs
endoscopically. What's more, the obtained values accord with those
in esophagitis patients with increased acid exposure corresponding
with the minimum pressure to maintain competence at the cardia
(42, 43). Together, the here described esophagitis/acute
pancreatitis/sphincter failure chain of events may provide step by
step evidence needed that a connection may be fully established.
On the other hand, the lack of definable extra-esophageal link may
be responsible for the still limited significance of manometric
evaluation within esophagiteal motility abnormality (i.e., the
manometric criteria for a putative motility disorder do not establish
the clinical importance of the motility abnormality, nor the
manometric phenomena clearly considered as manifestations of a
disease process) (44), and (now introduced) definable extraesophageal link may help to establish full clinical importance of
evaluation of esophageal motility disturbances.
Until the end, regularly given without a carrier, BPC 157
may have an individual and particular peptidergic activity, since
it is; suitably stable, intact in gastric juice for more than 24 h,
there is no achievement of LD1 and exerts the same beneficial
effects through intraperitoneal regimen and administration in
drinking water (7). Besides, the role of the novel mediator of
Robert's cytoprotection and adaptive cytoprotection (7) may in
general explain the maintenance of gastrointestinal mucosa
integrity, sphincter function and additionally BPC 157's
beneficial effect on acute pancreatitis. However in conclusion,
both theoretical and practical implications provide that
pentadecapeptide BPC 157 could be helpful to cure
esophagitis/sphincter/acute pancreatitis healing failure in
patients as well as mild acute pancreatic patients, may exhibit a
fall in sphincter pressure, therefore predicting that esophagus,
sphincters and pancreas disturbance will be further elucidated.
Acknowledgements: This work is supported by a research
grant from the Ministry of Science, Education and Sports of the
Republic of Croatia.
Conflict of interests: None declared.
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R e c e i v e d : August 11, 2011
A c c e p t e d : October 3, 2011
Author's address: Prof. Dr. Predrag Sikiric, Department of
Pharmacology, Medical Faculty University of Zagreb, 11 Salata
Street, POB 916, 10000 Zagreb, Croatia; Phone: 385-1-4566-833;
E-mail: [email protected]