Chronic stress sensitizes rats to pancreatitis induced by cerulein: Role of TNF-&alpha;

doi:10.3748/wjg.v16.i44.5565

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Nov 28, 2010 (publication date) through Jan 27, 2025

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World Journal of Gastroenterology

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1007-9327

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

Original Article

World J Gastroenterol. Nov 28, 2010; 16(44): 5565-5581
Published online Nov 28, 2010. doi: 10.3748/wjg.v16.i44.5565

Table 1 Relevant parameters in serum (mean ± SE)

Group	Amylase (IU/L)	Lipase (IU/L)	TNF-α (pg/mL)	LDH (IU/L)
Stress (-)
Veh	402 ± 23	12 ± 2	BD	299 ± 21
Cer	569 ± 31	44 ± 3	BD	358 ± 23
Anti-TNF-α + Cer	572 ± 43	42 ± 5	BD	327 ± 27
Stress (+)
Veh	475 ± 21	21 ± 3	12 ± 2^a	612 ± 41
Cer	3997 ± 226^a	1793 ± 118^a	42 ± 4^a	3410 ± 218^a
Anti-TNF-α + Cer	1895 ± 103^c	714 ± 45^c	16 ± 2^c	1534 ± 121^c

^aP < 0.05 vs control-vehicle Stress (-) group;

^cP < 0.05 vs Stress (+) plus Cer group. BD: Below detection limit; LDH: Lactate dehydrogenase; TNF-α: Tumor necrosis factor-α.

Table 2 Histopathological score in pancreatic tissue (mean ± SE)

Group	Edema	Hemorrhage	Leukocyte infiltrate	Necrosis
Stress (-)
Veh	0.00 ± 0.00	0.00 ± 0.00	0.00 ± 0.00	0.00 ± 0.00
Cer	0.00 ± 0.00	0.00 ± 0.00	0.00 ± 0.00	0.00 ± 0.00
Anti-TNF-α + Cer	0.00 ± 0.00	0.00 ± 0.00	0.00 ± 0.00	0.00 ± 0.00
Stress (+)
Veh	0.49 ± 0.06	0.00 ± 0.00	0.39 ± 0.05	0.00 ± 0.00
Cer	1.28 ± 0.11^a	3.11 ± 0.17^a	2.19 ± 0.10^a	3.12 ± 0.15^a
Anti-TNF-α + Cer	2.19 ± 0.17^c	1.21 ± 0.17^c	1.32 ± 0.10^c	1.37 ± 0.19^c

^aP < 0.05 vs control-vehicle Stress (-) group;

^cP < 0.05 vs Stress (+) plus Cer group. TNF-α: Tumor necrosis factor-α.

Table 3 Inflammatory parameters in pancreatic tissue (mean ± SE)

Group	TNF-α (ng/mg DNA)	HIF-1α (ng/mg DNA)	Active trypsin (nmol/mg DNA)	NF-κB (p65) (μg/mg DNA)	NF-κB (p50) (μg/mg DNA)	MPO (U/mg DNA)	LPO (nmol/mg DNA)	MDA (μmol/mg DNA)
Stress (-)
Veh	BD	BD	0.11 ± 0.02	43 ± 5	0.48 ± 0.04	0.00 ± 0.00	BD	0.71 ± 0.03
Cer	BD	BD	0.23 ± 0.04	46 ± 6	0.51 ± 0.05	0.00 ± 0.00	BD	0.89 ± 0.05
Anti-TNF-α + Cer	BD	BD	0.22 ± 0.05	44 ± 3	0.50 ± 0.03	0.00 ± 0.00	BD	0.84 ± 0.05
Stress (+)
Veh	1.6 ± 0.2^a	0.9 ± 0.1^a	0.37 ± 0.06	72 ± 6	0.84 ± 0.07	1.41 ± 0.07	27 ± 2	2.05 ± 0.11
Cer	5.4 ± 0.3^a	3.6 ± 0.3^a	4.15 ± 0.32^a	389 ± 25^a	5.54 ± 0.35^a	15.90 ± 0.66^a	316 ± 20^a	22.16 ± 0.69^a
Anti-TNF-α + Cer	2.0 ± 0.2^c	1.5 ± 0.3^c	1.79 ± 0.21^c	221 ± 18^c	2.65 ± 0.24^c	7.14 ± 0.38^c	171 ± 14^c	12.38 ± 0.47^c

^aP < 0.05 vs control-vehicle Stress (-) group;

^cP < 0.05 vs Stress (+) plus Cer group. BD: Below detection limit; TNF-α: Tumor necrosis factor-α; HIF-1α: Hypoxia inducible factor-1α; NF-κB: Nuclear factor-κB; MPO: Myeloperoxidase; LPO: Lipid hydroperoxide; MDA: Malondialdehyde.

Table 4 Inflammatory parameters in blood (mean ± SE)

Group	Leukocytes (ng/mL)	CRP (mg/dL)	HSP-72 (pg/mL)	IL-6 (pg/mL)	IL-10 (pg/mL)	MIP-1α (pg/mL)
Stress (-)
Veh	5900 ± 240	0.0 ± 0.0	558 ± 27	BD	BD	7 ± 1
Cer	6111 ± 248	0.0 ± 0.0	866 ± 32	BD	BD	9 ± 1
Anti-TNF-α + Cer	6005 ± 244	0.0 ± 0.0	817 ± 49	BD	BD	8 ± 1
Stress (+)
Veh	7139 ± 250	1.5 ± 0.2^a	899 ± 63	66 ± 6^a	75 ± 5^a	54 ± 4^a
Cer	21 222 ± 976^a	24.9 ± 1.3^a	2648 ± 159^a	1115 ± 54^a	1404 ± 148^a	318 ± 23^a
Anti-TNF-α + Cer	12 733 ± 586^c	12.4 ± 0.8^c	1805 ± 112^c	417 ± 38^c	596 ± 68^c	127 ± 11^b

^aP < 0.05 vs control-vehicle Stress (-) group;

^cP < 0.05 vs Stress (+) plus Cer group. CRP: C-reactive protein; HSP: Heat shock protein; IL: Interleukin; MIP-1α: Macrophage inflammatory protein-1α; TNF-α: Tumor necrosis factor-α; BD: Below detection limit.

Table 5 General biochemical assays in blood (mean ± SE)

Group	Glucose (mg/dL)	Urea (mg/dL)	Creatinine (mg/dL)	Calcium (mg/dL)	Proteins (g/dL)	AST (IU/L)	ALT (IU/L)	Hematocrit (%)
Stress (-)
Veh	139 ± 13	39 ± 4	0.48 ± 0.03	13.02 ± 0.57	8.51 ± 0.39	192 ± 21	88 ± 7	40 ± 5
Cer	153 ± 14	55 ± 4	0.65 ± 0.09	11.08 ± 0.48	7.46 ± 0.28	298 ± 32	155 ± 14	42 ± 4
Anti-TNF-α + Cer	148 ± 12	52 ± 5	0.67 ± 0.08	10.91 ± 0.70	7.51 ± 0.43	293 ± 20	149 ± 9	41 ± 5
Stress (+)
Veh	118 ± 11^a	38 ± 5	0.50 ± 0.05	11.72 ± 0.61	8.48 ± 0.22	201 ± 26	95 ± 9	36 ± 5^a
Cer	294 ± 26^a	105 ± 9^a	1.94 ± 0.50^a	9.03 ± 0.33^a	6.02 ± 0.19^a	432 ± 35^a	219 ± 19^a	41 ± 3
Anti-TNF-α + Cer	189 ± 16^c	73 ± 8^c	1.14 ± 0.24^c	9.63 ± 0.58	6.76 ± 0.35^c	356 ± 29^c	187 ± 19^c	39 ± 4

^aP < 0.05 vs control-vehicle Stress (-) group;

^cP < 0.05 vs Stress (+) plus Cer group. ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; TNF-α: Tumor necrosis factor-α.

Table 6 Pancreatic caspases (mean ± SE)

Group	CASP-2	CASP-3	CASP-8	CASP-9
Stress (-)
Veh	34 ± 6	25 ± 2	45 ± 5	40 ± 7
Cer	56 ± 12	63 ± 9	87 ± 11	82 ± 8
Anti-TNF-α + Cer	50 ± 7	39 ± 5	72 ± 7	68 ± 9
Stress (+)
Veh	124 ± 15	118 ± 10	189 ± 11	158 ± 16
Cer	995 ± 88^a	838 ± 74^a	1123 ± 103^a	1079 ± 70^a
Anti-TNF-α + Cer	696 ± 47^c	544 ± 58^c	887 ± 65^c	679 ± 48^c

Pancreatic caspases are expressed as pmol/min per milligram protein.

^aP < 0.05 vs control-vehicle Stress (-) group;

^cP < 0.05 vs Stress (+) plus Cer group. TNF-α: Tumor necrosis factor-α; CASP: Caspase.

Table 7 Energy metabolism in pancreatic tissue (mean ± SE)

Group	ATP (μmol/mg protein)	ATP loss (%)	ADP/ATP ratio
Stress (-)
Veh	9.1 ± 0.4	0.0 ± 4.4	0.32 ± 0.04
Cer	6.8 ± 0.5	25.3 ± 5.5	0.38 ± 0.05
Anti-TNF-α + Cer	6.9 ± 0.6	24.2 ± 6.6	0.36 ± 0.04
Stress (+)
Veh	7.3 ± 0.5	19.8 ± 5.5	0.40 ± 0.06
Cer	2.6 ± 0.4^a	71.4 ± 4.4^a	0.94 ± 0.11^a
Anti-TNF-α + Cer	5.3 ± 0.3^c	41.8 ± 3.3^c	0.63 ± 0.07^c

^aP < 0.05 vs control-vehicle Stress (-) group;

^cP < 0.05 vs Stress (+) plus Cer group. TNF-α: Tumor necrosis factor-α.

Table 8 Histopathological score in lung tissue (mean ± SE)

Group	Edema	Hemorrhage	Leukocyte infiltrate
Stress (-)
Veh	0.00 ± 0.00	0.00 ± 0.00	0.00 ± 0.00
Cer	0.00 ± 0.00	0.00 ± 0.00	0.00 ± 0.00
Anti-TNF-α + Cer	0.00 ± 0.00	0.00 ± 0.00	0.00 ± 0.00
Stress (+)
Veh	0.36 ± 0.04	0.00 ± 0.00	0.30 ± 0.03
Cer	1.51 ± 0.11^a	2.73 ± 0.58^a	1.63 ± 0.54^a
Anti-TNF-α + Cer	1.80 ± 0.21^c	1.21 ± 0.08^c	0.73 ± 0.05^c

^aP < 0.05 vs control-vehicle Stress (-) group;

^cP < 0.05 vs Stress (+) plus Cer group. TNF-α: Tumor necrosis factor-α.

Table 9 Inflammatory parameters in lung tissue (mean ± SE)

Group	TNF-α (ng/mg DNA)	MPO (U/mg DNA)	NF-κB (p65) (μg/mg DNA)	NF-κB (p50) (μg/mg DNA)
Stress (-)
Veh	BD	0.00 ± 0.00	23 ± 2	0.27 ± 0.02
Cer	BD	0.00 ± 0.00	24 ± 2	0.30 ± 0.02
Anti-TNF-α + Cer	BD	0.00 ± 0.00	24 ± 3	0.29 ± 0.03
Stress (+)
Veh	1.3 ± 0.1^a	0.89 ± 0.12	43 ± 5	0.51 ± 0.03
Cer	4.2 ± 0.3^a	12.10 ± 0.56^a	251 ± 19^a	2.92 ± 0.28^a
Anti-TNF-α + Cer	1.8 ± 0.2^c	5.04 ± 0.29^c	107 ± 9^c	1.13 ± 0.11^c

^aP < 0.05 vs control-vehicle Stress (-) group;

^cP < 0.05 vs Stress (+) plus Cer group. TNF-α: Tumor necrosis factor-α; MPO: Myeloperoxidase; NF-κB: Nuclear factor-κB.

Table 10 Lung caspases (mean ± SE)

Group	CASP-2	CASP-3	CASP-8	CASP-9
Stress (-)
Veh	18 ± 3	20 ± 2	21 ± 5	22 ± 4
Cer	27 ± 3	29 ± 4	32 ± 5	29 ± 3
Anti-TNF-α + Cer	26 ± 2	24 ± 3	24 ± 4	22 ± 3
Stress (+)
Veh	97 ± 11	103 ± 9	99 ± 8	104 ± 12
Cer	853 ± 81^a	912 ± 101^a	824 ± 77^a	917 ± 85^a
Anti-TNF-α + Cer	597 ± 48^c	592 ± 55^c	560 ± 45^c	568 ± 47^c

Lung caspases are expressed as pmol/min per milligram protein.

^aP < 0.05 vs control-vehicle Stress (-) group;

^cP < 0.05 vs Stress (+) plus Cer group. TNF-α: Tumor necrosis factor-α; CASP: Caspase.

Table 11 Energy metabolism in lung tissue (mean ± SE)

Group	ATP (μmol/mg protein)	ATP loss (%)	ADP/ATP ratio
Stress (-)
Veh	10.3 ± 0.5	0.0 ± 4.9	0.20 ± 0.03
Cer	10.0 ± 0.3	2.9 ± 2.9	0.22 ± 0.02
Anti-TNF-α + Cer	10.1 ± 0.4	1.9 ± 3.8	0.21 ± 0.03
Stress (+)
Veh	7.9 ± 0.7	25.5 ± 6.8	0.32 ± 0.05
Cer	3.6 ± 0.4^a	66.0 ± 3.8^a	0.72 ± 0.10^a
Anti-TNF-α + Cer	6.7 ± 0.6^c	36.8 ± 5.7^c	0.49 ± 0.06^c

^aP < 0.05 vs control-vehicle Stress (-) group;

^cP < 0.05 vs Stress (+) plus Cer group. TNF-α: Tumor necrosis factor-α.

Table 12 Histopathological score in stomach tissue (mean ± SE)

Group	Edema	Hemorrhage	Leukocyte infiltrate	Necrosis
Stress (-)
Veh	0.00 ± 0.00	0.00 ± 0.00	0.00 ± 0.00	0.00 ± 0.00
Cer	0.00 ± 0.00	0.00 ± 0.00	0.00 ± 0.00	0.00 ± 0.00
Anti-TNF-α + Cer	0.00 ± 0.00	0.00 ± 0.00	0.00 ± 0.00	0.00 ± 0.00
Stress (+)
Veh	3.25 ± 0.14^b	1.55 ± 0.08^a	1.26 ± 0.19^a	0.95 ± 0.06^a
Cer	1.17 ± 0.08^a	3.23 ± 0.29^a	2.77 ± 0.16^a	3.48 ± 0.32^a
Anti-TNF-α + Cer	1.96 ± 0.17^c	2.23 ± 0.15^c	1.63 ± 0.05^c	1.57 ± 0.12^c

^aP < 0.05,

^bP < 0.01 vs control-vehicle Stress (-) group;

^cP < 0.05 vs Stress (+) plus Cer group. TNF-α: Tumor necrosis factor-α.

Table 13 Stomach caspases (mean ± SE)

Group	CASP-2	CASP-3	CASP-8	CASP-9
Stress (-)
Veh	37 ± 4	32 ± 3	48 ± 5	39 ± 5
Cer	40 ± 5	32 ± 5	51 ± 4	40 ± 3
Anti-TNF-α + Cer	33 ± 4	30 ± 3	47 ± 4	39 ± 4
Stress (+)
Veh	1358 ± 132^a	1515 ± 154^a	1479 ± 136^a	1425 ± 126^a
Cer	798 ± 87^a	824 ± 95^a	868 ± 70^a	832 ± 87^a
Anti-TNF-α + Cer	1089 ± 98^c	1203 ± 107^c	1108 ± 89^c	1144 ± 102^c

Stomach caspases are expressed as pmol/min per milligram protein.

^aP < 0.05 vs control-vehicle Stress (-) group;

^cP < 0.05 vs Stress (+) plus Cer group. TNF-α: Tumor necrosis factor-α; CASP: Caspase.

Table 14 Energy metabolism in stomach tissue (mean ± SE)

Group	ATP (μmol/mg protein)	ATP loss (%)	ADP/ATP ratio
Stress (-)
Veh	13.4 ± 0.9	0.0 ± 6.7	0.16 ± 0.02
Cer	12.9 ± 0.7	3.7 ± 5.2	0.18 ± 0.03
Anti-TNF-α + Cer	13.0 ± 0.8	3.0 ± 6.0	0.17 ± 0.02
Stress (+)
Veh	5.5 ± 0.4^a	58.9 ± 3.0^a	0.67 ± 0.07^a
Cer	2.3 ± 0.4^a	82.8 ± 3.0^a	1.14 ± 0.16^a
Anti-TNF-α + Cer	6.2 ± 0.6^c	53.7 ± 4.5^c	0.58 ± 0.06^c

^aP < 0.05 vs control-vehicle Stress (-) group;

^cP < 0.05 vs Stress (+) plus Cer group. TNF-α: Tumor necrosis factor-α.

Citation: Binker MG, Binker-Cosen AA, Richards D, Gaisano HY, de Cosen RH, Cosen-Binker LI. Chronic stress sensitizes rats to pancreatitis induced by cerulein: Role of TNF-α. World J Gastroenterol 2010; 16(44): 5565-5581
URL: https://www.wjgnet.com/1007-9327/full/v16/i44/5565.htm
DOI: https://dx.doi.org/10.3748/wjg.v16.i44.5565