GEM4 Summer School OpenCourseWare
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Lecture: “The Inflammatory Cascade” by Dr. Geert Schmid-Schonbein, part II.
Given August 7, 2006 during the GEM4 session at MIT in Cambridge, MA.
Please use the following citation format:
Schmid-Schonbein, Geert. “The Inflammatory Cascade, Part II.” Lecture, GEM4 session at MIT, Cambridge, MA, August 7,
2006. http://gem4.educommons.net/ (accessed MM DD, YYYY). License: Creative Commons Attribution-NoncommercialShare Alike.
Note: Please use the actual date you accessed this material in your citation.
0%
Figure by MIT OpenCourseWare. After Kistler et al., 2000.
Skeletal Muscle
Thymus
Pancreas
Kidney
80%
Small Intestine
90%
Spleen
Liver
Brain
Heart
Aorta
Neutrophil Activation (%)
100%
Homogenate
70%
60%
50%
40%
30%
20%
10%
90%
Homogenate
80%
Homogenate with Trypsin
70%
60%
50%
40%
30%
20%
Figure by MIT OpenCourseWare. After Kistler et al., 2000.
Skeletal Muscle
Thymus
Pancreas
Kidney
Small Intestine
Spleen
Liver
Brain
0%
Heart
10%
Aorta
Neutrophil Activation (%)
100%
Pan
Pan
Liver
P
Prote
Prro
otte
Trypsinogen
Chymotrypsinogen
Proelastase
Procarboxypeptidase A
Procarboxypeptidase B
A
m yl
Amyl
Stomach
(not shown)
Colon
Pancreas underlying stomach
Figure by MIT OpenCourseWare.
Amylase
Waldo et al, 2003
Hydrolyse proteins, carbohydrates, lipids, nucleic acid
3500
3000
Fluorescence Units
2500
2000
1500
1000
500
0
I ntestinal Fluid
Plasma
Figure by MIT OpenCourseWare.
Pancreatic Enzyme Derived Inflammatory Mediators 100
100
*
50
25
0
#
2.5 x 10-7 fMLP
*
Activation (%)
75
50
25
Lipase
*
75
2.5 x 10-7 fMLP
Neutrophil Activation (%)
Chymotrypsin
0
Controls
Intestine
Controls
Intestine
Figure by MIT OpenCourseWare. After Waldo et al., 2003.
*
Organ homogenates with pancreatic enzymes produce cell death Image removed due to copyright restrictions.��
Images of cell death from Penn et al., 2006, in review.
Mean Arterial Pressure (mmHg)
MABP (mmHg)
Pancreatic Digestive Enzyme Blockade with ANGD, FOY® (Gabaxate mesilate), and Aprotinin
SAO
SAL
200
100
0
SAO
200
ANGD
SAO
200
Reperfusion
*
*
100
*
*
R-30
R-60
Control
FOY
0
*
p < 0.05 vs Control
100
Pre
Occlusion
0
PreIsch em ia
R-3 0
R-6 0
O-30
O-60
O-90
R-90
R-120
Figure by MIT OpenCourseWare. After Mitsuoka et al., 2002.
Courtesy of National Academy of Sciences, U. S. A. Used with permission.
Source: Mitsuoka, et al. "Generation of in Vivo Activating Factors in the
Ischemic Intestine by Pancreatic Enzymes." Proc Natl Acad Sci 97 (2000): 1772.
(c) National Academy of Sciences, U.S.A.
(mmHg)
Mean Arterial Blood Pressure
160
Futhan
140
Aprotinin
120
100
80
60
40
20
0
Reperfusion
Occlusion
Time
Figure by MIT OpenCourseWare. After Shimmeyer et al., in review.
Intestinal Mucosal Injury
Image removed due to copyright restrictions.
Courtesy of National Academy of Sciences, U. S. A. Used with permission.
Source: Mitsuoka, et al. "Generation of in Vivo Activating Factors in the
Ischemic Intestine by Pancreatic Enzymes." Proc Natl Acad Sci 97 (2000): 1772.
(c) National Academy of Sciences, U.S.A.
Leukocyte Infiltration
Lung Wet/Dry Weight
Acute Respiratory Distress Syndrome
6
5
4
3
Courtesy of National Academy of Sciences, U. S. A. Used with permission.
Source: Mitsuoka, et al. "Generation of in Vivo Activating Factors in the
Ischemic Intestine by Pancreatic Enzymes." Proc Natl Acad Sci 97 (2000): 1772.
(c) National Academy of Sciences, U.S.A.
Intestinal Enzyme Blockade Prevents Cell Death in the Peripheral Microcirculation
Images removed due to copyright restrictions.
See figures in Fitzal, F., F. A. DeLano, C. Young, H. S. Rosario, and G. W. Schmid-Schonbein. "Pancreatic Protease Inhibition During
Shock Attenuates Cell Activation and Peripheral Inflammation." J Vasc Res 39 (2002): 320-329.
Images removed due to copyright restrictions.
See figures in Fitzal F., DeLano F. A., Young C., Rosario H. S., Schmid-Schonbein G. W. "Pancreatic Protease Inhibition During
Shock Attenuates Cell Activation and Peripheral Inflammation." J Vasc Res 39 (2002): 320-329.
What are the inflammatory mediators ?
PMN Pseudopod Formation (%)
120
Rat Pancreas
PAF (10-6 M)
Pig Pancreas
LTB4 (10-6 M)
100
80
60
40
20
0
Con
PAF
10%
20%
30%
40%
50%
60%
70%
80%
% Acetonitrile Fraction
Figure by MIT OpenCourseWare. After Schmid-Schönbein, et al., 2001.
2001
Effect of Non-Incubated Pancreatic Homogenate on
Haemodynamic Function in the Rat
Effect of Incubated Pancreatic Homogenate on
Haemodynamic Function in the Rat
Heart Rate
Mean BP
120
Heart Rate
Mean BP
90
80
300
60
200
Result - Rat Survived
Prep 2
Injection
Heart Rate (BPM)
80
Mean Blood Pressure
350
100
400
70
300
60
250
50
200
40
Result- Rat Died
Prep 2
150
20
Injection
50
20
0
5
0
0
10
20
30
40
50
60
Elapsed Time (minutes)
70
10
0
0
0
30
100
40
100
10
20
15
Elapsed Time (minutes)
25
80
Figures by MIT OpenCourseWare. After Kramp, et al., 2003.
Effect of Lipid Extract of Pancreatic Homogenate On
Haemodynamic Functions in the Rat
400
80
60
250
50
200
40
Heart Rate
Mean BP
150
100
30
Result - Rat Died
Prep 2 Incubated
20
Injection
50
10
0
0
0
5
10
15
Elapsed Time (minutes)
20
25
140
350
120
300
Mean Blood Pressure
70
300
Heart Rate (BPM)
350
400
100
250
80
200
60
Heart Rate
Mean BP
150
40
Result - Rat died
Prep 3
100
20
50
Injection
0
0
0
5
10
15
Elapsed Time (minutes)
20
25
Heart Rate (BPM)
Effect of Aqueous Extract of Incubated Pancreatic
Homogenate on Haemodynamic Functions in the Rat
Mean Blood Pressure
Mean Blood Pressure
500
100
450
400
Heart Rate (BPM)
140
600
Electrophoresis pattern of aqueous fraction of
incubated (I) and non-incubated (N) pancreatic homogenates Image removed due to copyright restrictions.
See Fig. 7 in Kramp, et al. "Characterization of Two Classes of Pancreatic Shock Factors: Functional Differences Exhibited by
Hydrophilic and Hydrophobic Shock Factors." Shock 20 (2003): 356-362.
A breach of the intestinal mucosal barrier causes
Escape of Digestive Enzymes into the
Wall of the Intestine and Auto-digestion
Cardiovascular Cytotoxicity
Destruction of the Mucosal
Epithelial Barrier
Cell Activation
Swelling of the Lung & ARDS
Images removed due to copyright restrictions.