alteration of intestinal permeability and effect of drugs on...
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Alteration of intestinal permeability and effect of drugs on postoperative ileus in a guinea pig model
Young Min Kim, Zahid Hussain, Young Ju Lee, Hyojin Park
Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
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Introduction (1)
Related to alteration of intestinal permeability• Inflammatory bowel disease
• Functional gastrointestinal disease
• Malignancy
• Obesity-associated with metabolic diseases
• Allergic disease
Mechanisms• Gut inflammation
• Dysregulation for tight junction (TJ) proteins
• Gut dysbiosisGut 2007;56:61-72
Intest Res 2016;14:297-304Front Med 2018;5:349
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Introduction (2)
Postoperative ileus (POI)
: Transient cessation of coordinated bowel motility after surgical procedure
Hypothesis I
: POI is associated with alteration of intestinal permeability.
J Neurogastroenterol Motil 2018;24:147-158
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Mosapride Glutamine
Gut 2011;60:638-647Int J Mol Sci 2017;12:18
Introduction (3)
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Introduction (4)Ketotifen
Hypothesis II: Mosapride, glutamine, and ketotifen have an effect on intestinal permeability.
Block the release of mast cell granules (tryptase, histamine, PG) following activation
Front Immunol 2015;6:238
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Aims
Characterize the alteration of intestinal permeability in POI
Investigate whether mosapride, glutamine, and ketotifen have an effect on intestinal permeability in POI
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Experimental POI model
Mosapride (0.3 and 1mg/kg, per oral)
POI 3H POI 6H
-1hr +1hr
Adult male guinea pigs, 250-350g
Harvest tissue (ileum & proximal colon)
Method
Glutamine (500mg/kg, per oral)
Ketotifen (1mg/kg, per oral)
-4D -1D-2D-3D
Measurements• Permeability
: Ussing chamber (differences in optical translucency)• Inflammatory markers
: Leukocyte count, calprotectin level• Tight junction proteins
: Claudin-1, 2 level
Analyses• Control vs. POI group • POI vs. Drug group
OP
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Leukocyte count (POI 3H)
* P < 0.05
POI 3H
Ileum Proximal colon
Result
0
20
40
60
80
100
Control POI 3H MOS0.3mg
MOS 1mg GLN500mg
KET 1mg
Leu
kocy
tes/
fie
ld (
x40
0)
POI 3H
0
20
40
60
80
100
Control POI 3H MOS0.3mg
MOS 1mg GLN500mg
KET 1mg
Leu
kocy
tes/
fie
ld (
x40
0)
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Leukocyte count (POI 6H)
* P < 0.05
POI 6H POI 6H
Ileum Proximal colon
0
20
40
60
80
100
Control POI 6H MOS0.3mg
MOS 1mg GLN500mg
KET 1mg
Leu
kocy
tes/
fie
ld (
x40
0)
0
20
40
60
80
100
Control POI 6H MOS0.3mg
MOS 1mg GLN500mg
KET 1mg
Leu
kocy
tes/
fie
ld (
x40
0)
Result
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Calprotectin level (POI 3H)
* P < 0.05
POI 3HPOI 3H
Ileum Proximal colon
Result
0
5000
10000
15000
20000
25000
30000
35000
Control POI 3H MOS0.3mg
MOS 1mg GLN500mg
KET 1mg
Ave
rage
inte
nsi
ty (
x20
0)
0
5000
10000
15000
20000
25000
30000
35000
Control POI 3H MOS0.3mg
MOS 1mg GLN500mg
KET 1mg
Ave
rage
inte
nsi
ty (
x20
0)
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Calprotectin level (POI 6H)
* P < 0.05
POI 6H POI 6H
Ileum Proximal colon
Result
0
5000
10000
15000
20000
25000
30000
35000
Control POI 6H MOS0.3mg
MOS 1mg GLN500mg
KET 1mg
Ave
rage
inte
nsi
ty (
x20
0)
0
5000
10000
15000
20000
25000
30000
35000
Control POH 6H MOS0.3mg
MOS 1mg GLN500mg
KET 1mg
Ave
rage
inte
nsi
ty (
x20
0)
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Claudin-1 level
* P < 0.05
POI 6H POI 6H
Ileum Proximal colon
0
10
20
30
40
50
60
70
80
90
Control POI 6H MOS 0.3mg GLN 500mg KET 1mg
Ave
rage
inte
nsi
ty (
x10
6)
0
10
20
30
40
50
60
70
80
90
Control POI 6H MOS 0.3mg GLN 500mg KET 1mg
Ave
rage
inte
nsi
ty (
x10
6)
Result
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Claudin-2 level
* P < 0.05
POI 6H POI 6H
Ileum Proximal colon
0
10
20
30
40
Control POI 6H MOS 0.3mg GLN 500mg KET 1mg
Ave
rage
inte
nsi
ty (
x10
6)
0
10
20
30
40
Control POI 6H MOS 0.3mg GLN 500mg KET 1mg
Ave
rage
inte
nsi
ty (
x10
6)
Result
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Mast cell tryptase
* P < 0.05
POI 6HPOI 6H
Proximal colon
0
5000
10000
15000
20000
25000
30000
35000
40000
45000
Control POI 3H KET 1mg POI 6H KET 1mg
Ave
rage
inte
nsi
ty (
x20
0)
0
5000
10000
15000
20000
25000
30000
35000
40000
45000
Control POI 3H KET 1mg POI 6H KET 1mg
Ave
rage
inte
nsi
ty (
x20
0)
POI 3HPOI 3H
Ileum
Result
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Permeability (POI 3H)
* P < 0.05
Ileum Proximal colon
0
100
200
300
400
500
600
Control POI 3H MOS0.3mg
MOS 1mg GLN500mg
KET 1mg
% c
han
ge f
rom
co
ntr
ol
0
100
200
300
400
500
600
Control POI 3H MOS0.3mg
MOS 1mg GLN500mg
KET 1mg
% c
han
ge f
rom
co
ntr
ol
POI 3H POI 3H
Result
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Permeability (POI 6H)
* P < 0.05
Ileum Proximal colon
0
100
200
300
400
500
600
Control POI 6H MOS0.3mg
MOS 1mg GLN500mg
KET 1mg
% c
han
ge f
rom
co
ntr
ol
0
100
200
300
400
500
600
Control POI 6H MOS0.3mg
MOS 1mg GLN500mg
KET 1mg
% c
han
ge f
rom
co
ntr
ol
POI 6H POI 6H
Result
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Alteration of intestinal permeability and change ofinflammatory markers, claudin level, and mast cell tryptasewere observed in the POI guinea pig model.
Mosapride, glutamine, and ketotifen have an anti-inflammatory effect, thereby, modulates intestinal permeability.
Notably, glutamine had an effect on tight junction proteins,and ketotifen had an effect on mast cells.
Conclusions
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Thank You for Your Attention