Die Schädigung der viszeralen Organe Leber, Magen/Darm und Pankreas durch Ischämie und Reperfusion lässt sich als ein Geschehen verstehen, dessen Ereignisse Knotenpunkte in pathogenetischen Netzwerken darstellen. In der Phase der Ischämie steht die Schädigung von Zellen durch Sauerstoffmangel im Vordergrund. Initiales Ereignis ist die verminderte mitochondriale Energiebereitstellung. Veränderungen im Ionenhaushalt, die Aktivierung von Hydrolasen sowie die Bildung großer Poren in den Mitochondrienmembranen, der sog. mitochondriale Permeabilitätsübergang, sind weitere wichtige Ereignisse im Netzwerk der hypoxischen Zellschädigung. Die Zellschädigung in der Phase der Reperfusion ist entweder eine Folge von aus der Phase der Ischämie stammenden Veränderungen in den Zellen oder das Resultat einer inflammatorischen Gewebereaktion. In beiden Fällen sind reaktive Sauerstoffspezies wichtige Auslöser der Zellschädigung. Zu den Ereignissen im Netzwerk der Zellschädigung gehören in dieser Phase Störungen des Glutathion-Gleichgewichts und im Kalzium-Haushalt sowie erneut der mitochondriale Permeabilitätsübergang und die Aktivierung von Hydrolasen. Mehr noch als die intrazellulären Ereignisse der Zellschädigung sind die Ereignisse der inflammatorischen Gewebereaktion netzartig miteinander verknüpft. Ausgehend von bereits geschädigten Zellen bilden die vermehrte Freisetzung reaktiver Sauerstoffspezies, von Stickstoffmonoxid und anderen Botenstoffen, die Aktivierung von Makrophagen, Neutrophilen, Endothelzellen, Lymphozyten und des Komplementsystems sowie Störungen der Mikrozirkulation ein Netzwerk an interagierenden Ereignissen, das zu einer Perpetuierung der Gewebeschädigung führt. Aufgrund der netzartigen Verknüpfung der Ereignisse der Zell- und Gewebeschädigung lässt sich eine Vielzahl von Schädigungswegen konstruieren. Eine wichtige Konsequenz, die sich aus dem Konstrukt der pathogenetischen Netzwerke ergibt, ist deshalb die Forderung, dass eine effektive Therapie der Ischämie-Reperfusionsschädigung viszeraler Organe nur durch Blockade mehrerer zentraler Knotenpunkte zu erreichen ist.
Abstract
The injury of the visceral organs liver, stomach/intestine and pancreas by ischemia and reperfusion can be understood as a process, the events of which represent junctions in pathogenetic networks. In the phase of ischemia, damage of cells by oxygen deficiency is the center of the injurious process. The initial event is the decreased mitochondrial energy supply. Changes in ion homeostasis, activation of hydrolases as well as formation of large pores in the mitochondrial membranes, the so-called mitochondrial permeability transition, are other decisive events in the network of the hypoxic cell injury. Cell damage in the phase of reperfusion is either a consequence of changes in the cells, originating from the phase of ischemia, or the result of an inflammatory tissue reaction. In both cases reactive oxygen species are important triggers of the cell damage. Disturbances of the glutathione equilibrium and of the calcium balance as well as again the mitochondrial permeability transition and the activation of hydrolases belong to the events in the network of cell injury in this phase. Even more than the intracellular events of the cell damage, the events of the inflammatory tissue reaction are linked netlike with one another. Initiated by cells already damaged, an increased release of reactive oxygen species, nitrogen monoxide and other mediators, activation of macrophages, neutrophils, endothelial cells, lymphocytes and the complement system as well as disturbances of the microcirculation form a network of interacting events, which leads to a perpetuation of the tissue damage. A multiplicity of injurious pathways can be designed due to the netlike linkage of the events of the cell and tissue damage. An important consequence, which results from the construct of the pathogenetic networks, is therefore the demand that an effective therapy of the ischemia-reperfusion injury of visceral organs can be attained only by blockade of several central junctions.
1
Anadol A Z, Bayram O, Dursun A, Ercan S.
Role of endogenous endothelin peptides in intestinal ischemia-reperfusion injury in rats.
Prostaglandins Leukot Essent Fatty Acids.
1998;
59
279-283
2
Angermüller S, Schunk M, Kusterer K.
Alteration of xanthine oxidase activity in sinusoidal endothelial cells and morphological changes of Kupffer cells in hypoxic and reoxygenated rat liver.
Hepatology.
1995;
21
1594-1601
3
Anundi I, de Groot H.
Hypoxic cell death in isolated hepatocytes: Critical Po2 and dependence of cell viability on the glycolytic capacity.
Am J Physiol.
1989;
257
G 58-G 64
4
Arumugam T V, Shiels I A, Woodruff T M, Reid R C, Fairlie D P, Taylor S M.
Protective effect of a new C5a receptor antagonist against ischemia-reperfusion injury in the rat small intestine.
J Surg Res.
2002;
103
260-267
5
Atalla S L, Toledo-Pereyra L H, MacKenzie G H, Cederna J P.
Influence of oxygen-derived free radical scavengers on ischemic livers.
Transplantation.
1985;
40
584-590
6
Austen W G, Kyriakides C, Favuzza J, Wang Y, Kobzik L, Moore F D, Hechtman H B.
Intestinal ischemia-reperfusion injury is mediated by the membrane attack complex.
Surgery.
1999;
126
343-348
8
Ayub K, Serracino-Inglott F, Williamson R C, Mathie R T.
Expression of inducible nitric oxide synthase contributes to the development of pancreatitis following pancreatic ischaemia and reperfusion.
Br J Surg.
2001;
88
1189-1193
9
Bajt M L, Farhood A, Jaeschke H.
Effects of CXC chemokines on neutrophil activation and sequestration in hepatic vasculature.
Am J Physiol.
2001;
281
G1188-G1195
10
Baldwin W M, Pruitt S K, Brauer R B, Daha M R, Sanfilippo F.
Complement in organ transplantation. Contributions to inflammation, injury, and rejection.
Transplantation.
1995;
59
797-808
11
Benz S, Obermaier R, Wiessner R, Breitenbuch P V, Burska D, Weber H, Schnabel R, Mayer J, Pfeffer F, Nizze H, Hopt U T.
Effect of nitric oxide in ischemia/reperfusion of the pancreas.
J Surg Res.
2002;
106
46-53
12
Berger M L, Reynolds R C, Hagler H K, Bellotto D, Parsons D, Mulligan K J, Buja L M.
Anoxic hepatocyte injury: role of reversible changes in elemental content and distribution.
Hepatology.
1989;
9
219-228
13
Blanc M C, Housset C, Lasnier E, Rey C, Capeau J, Giboudeau J, Poupon R, Vaubourdolle M.
Direct cytotoxicity of hypoxia-reoxygenation towards sinusoidal endothelial cells in the rat.
Liver.
1999;
19
42-49
15
Calabrese F, Valente M, Pettenazzo E, Ferraresso M, Burra P, Cadrobbi R, Cardin R, Bacelle L, Parnigotto A, Rigotti P.
The protective effects of L-arginine after liver ischaemia/reperfusion injury in a pig model.
J Pathol.
1997;
183
477-485
16
Caraceni P, Ryu H S, Thiel D H van, Borle A B.
Source of oxygen free radicals produced by rat hepatocytes during postanoxic reoxygenation.
Biochim Biophys Acta.
1995;
1268
249-254
17
Carini R, Bellomo G, Benedetti A, Fulceri R, Gamberucci A, Parola M, Dianzani M U, Albano E.
Alteration of Na+ homeostasis as a critical step in the development of irreversible hepatocyte injury after adenosine triphosphate depletion.
Hepatology.
1995;
21
1089-1098
19
Colantoni A, de Maria N, Caraceni P, Bernardi M, Floyd R A, Thiel D H Van.
Prevention of reoxygenation injury by sodium salicylate in isolated-perfused rat liver.
Free Radic Biol Med.
1998;
25
87-94
20
Cottart C H, Do L, Blanc M C, Vaubourdolle M, Descamps G, Durand D, Galen F X, Clot J P.
Hepatoprotective effect of endogenous nitric oxide during ischemia-reperfusion in the rat.
Hepatology.
1999;
29
809-813
23
Cursio R, Gugenheim J, Ricci J E, Crenesse D, Rostagno P, Maulon L, Saint-Paul M C, Ferrua B, Auberger A P.
A caspase inhibitor fully protects rats against lethal normothermic liver ischemia by inhibition of liver apoptosis.
FASEB J.
1999;
13
253-261
24
de Groot H, Littauer A.
Reoxygenation injury in isolated hepatocytes: Cell death precedes conversion of xanthine dehydrogenase to xanthine oxidase.
Biochem Biophys Res Commun.
1988;
155
278-282
26
Dhar D K, Nagasue N, Kimoto T, Uchida M, Takemoto Y, Nakamura T.
The salutary effect of FK506 in ischemia-reperfusion injury of the canine liver.
Transplantation.
1992;
54
583-588
29
Farhood A, McGuire G M, Manning A M, Miyasaka M, Smith C W, Jaeschke H.
Intercellular adhesion molecule 1 (ICAM-1) expression and its role in neutrophil-induced ischemia-reperfusion injury in rat liver.
J Leukoc Biol.
1995;
57
368-374
30
Ferguson D, McDonagh P F, Biewer J, Paidas C N, Clemens M G.
Spatial relationship between leukocyte accumulation and microvascular injury during reperfusion following hepatic ischemia.
Int J Microcirc Clin Exp.
1993;
12
45-60
31
Fiegen R J, Rauen U, Hartmann M, Decking U K, de Groot H.
Decrease of ischemic injury to the isolated perfused rat liver by loop diuretics.
Hepatology.
1997;
25
1425-1431
32
Frank A, Rauen U, de Groot H.
Protection by glycine against hypoxic injury of rat hepatocytes: inhibition of ion fluxes through nonspecific leaks.
J Hepatol.
2000;
32
58-66
33
Fujimoto K, Hosotani R, Wada M, Lee J, Koshiba T, Miyamoto Y, Doi R, Imamura M.
Ischemia-reperfusion injury on the pancreas in rats: identification of acinar cell apoptosis.
J Surg Res.
1997;
71
127-136
34
Gasbarrini A, Borle A B, Farghali H, Bender C, Francavilla A, Thiel D Van.
Effect of anoxia on intracellular ATP, Nai+, Cai2+, Mgi2+, and cytotoxicity in rat hepatocytes.
J Biol Chem.
1992;
267
6654-6663
35
Goto M, Takei Y, Kawano S, Nagano K, Tsuji S, Masuda E, Nishimura Y, Okumura S, Kashiwagi T, Fusamoto H, Kamada T.
Endothelin-1 is involved in the pathogenesis of ischemia/reperfusion liver injury by hepatic microcirculatory disturbances.
Hepatology.
1994;
19
675-681
36
Grotz M R, Deitch E A, Ding J, Xu D, Huang Q, Regel G.
Intestinal cytokine response after gut ischemia: role of gut barrier failure.
Annals Surg.
1999;
229
478-486
37
Gujral J S, Bucci T J, Farhood A, Jaeschke H.
Mechanism of cell death during warm hepatic ischemia-reperfusion in rats: apoptosis or necrosis?.
Hepatology.
2001;
33
397-405
38
Gunel E, Caglayan F, Caglayan O, Dilsiz A, Duman S, Aktan M.
Treatment of intestinal reperfusion injury using antioxidative agents.
J Pediatr Surg.
1998;
33
1536-1539
40
Hakguder G, Akgur F, Ates O, Olguner M, Ozer E.
Short-term intestinal ischemia-reperfusion alters intestinal motility that can be preserved by xanthine oxidase inhibition.
Dig Dis Sci.
2002;
47
1279-1283
41
Harbrecht B G, Wu B, Watkins S C, Billiar T R, Peitzman A B.
Inhibition of nitric oxide synthesis during severe shock but not after resuscitation increases hepatic injury and neutrophil accumulation in hemorrhaged rats.
Shock.
1997;
8
415-421
42
Heuser M, Pfaar O, Gralla O, Grone H J, Nustede R, Post S.
Impact of gastrin-releasing peptide on intestinal microcirculation after ischemia-reperfusion in rats.
Digestion.
2000;
61
172-180
43
Hill J, Lindsay T F, Ortiz F, Yeh C G, Hechtman H B, Moore F D.
Soluble complement receptor type 1 ameliorates the local and remote organ injury after intestinal ischemia-reperfusion in the rat.
J Immunol.
1992;
149
1723-1728
46
Jaeschke H, Farhood A.
Neutrophil and Kupffer cell-induced oxidant stress and ischemia-reperfusion injury in rat liver.
Am J Physiol.
1991;
260
G 355-G 362
47
Jaeschke H, Farhood A, Bautista A P, Spolarics Z, Spitzer J J.
Complement activates Kupffer cells and neutrophils during reperfusion after hepatic ischemia.
Am J Physiol.
1993;
264
G 801-G 809
49
Jaeschke H, Mitchell J R.
Mitochondria and xanthine oxidase both generate reactive oxygen species in isolated perfused rat liver after hypoxic injury.
Biochemic Biophysic Res Comm.
1989;
160
140-147
51
Joh T, Ikai M, Oshima T, Kurokawa T, Seno K, Yokoyama Y, Okada N, Itoh M.
Complement plays an important role in gastric mucosal damage induced by ischemia-reperfusion in rats.
Life Sci.
2001;
70
109-117
52
Kalia N, Pockley A G, Wood R F, Brown N J.
Effects of FK409 on intestinal ischemia-reperfusion injury and ischemia-induced changes in the rat mucosal villus microcirculation.
Transplantation.
2001;
72
1875-1880
53
Kawata K, Takeyoshi I, Iwanami K, Sunose Y, Aiba M, Ohwada S, Matsumoto K, Morishita Y.
A spontaneous nitric oxide donor ameliorates small bowel ischemia-reperfusion injury in dogs.
Dig Dis Sci.
2001;
46
1748-1756
54
Kobayashi S, Miescher E, Clemens M G.
A synergistic effect of extracellular hypocalcemic condition for hyperoxic reoxygenation injury in rat hepatocytes.
Transplantation.
1999;
67
451-457
55
Koeppel T A, Thies J C, Schemmer P, Trauner M, Gebhard M M, Otto G, Post S.
Inhibition of nitric oxide synthesis in ischemia/reperfusion of the rat liver is followed by impairment of hepatic microvascular blood flow.
J Hepatol.
1997;
27
163-169
56
Koo A, Komatsu H, Tao G, Inoue M, Guth P H, Kaplowitz N.
Contribution of no-reflow phenomenon to hepatic injury after ischemia-reperfusion: evidence for a role for superoxide anion.
Hepatology.
1992;
15
507-514
59
Lehmann T G, Koeppel T A, Munch S, Heger M, Kirschfink M, Klar E, Post S.
Impact of inhibition of complement by sCR1 on hepatic microcirculation after warm ischemia.
Microvasc Res.
2001;
62
284-292
60
Lentsch A B, Kato A, Yoshidome H, McMasters K M, Edwards M J.
Inflammatory mechanisms and therapeutic strategies for warm hepatic ischemia/reperfusion injury.
Hepatology.
2000;
32
169-173
61
Littauer A, de Groot H.
Release of reactive oxygen by hepatocytes on reoxygenation: three phases and role of mitochondria.
Am J Physiol.
1992;
262
G 1015-G 1020
62
Luo C C, Chen H M, Chiu C H, Lin J N, Chen J C.
Effect of N(G)-nitro-L-arginine methyl ester on intestinal permeability following intestinal ischemia-reperfusion injury in a rat model.
Biol Neonate.
2001;
80
60-63
63
Matsumura F, Yamaguchi Y, Goto M, Ichiguchi O, Akizuki E, Matsuda T, Okabe K, Liang J, Ohshiro H, Iwamoto T, Yamada S, Mori K, Ogawa M.
Xanthine oxidase inhibition attenuates Kupffer cell production of neutrophil chemoattractant following ischemia-reperfusion in rat liver.
Hepatology.
1998;
28
1578-1587
65
Menger M D, Rucker M, Vollmar B.
Capillary dysfunction in striated muscle ischemia/reperfusion: on the mechanisms of capillary “no-reflow”.
Shock.
1997;
8
2-7
66
Natarajan R, Fisher B J, Jones D G, Ghosh S, Fowler A A.
Reoxygenating microvascular endothelium exhibits temporal dissociation of NF-kappaB and AP-1 activation.
Free Radic Biol Med.
2002;
32
1033-1045
67
Ohmori H, Dhar D K, Nakashima Y, Hashimoto M, Masumura S, Nagasue N.
Beneficial effects of FK409, a novel nitric oxide donor, on reperfusion injury of rat liver.
Transplantation.
1998;
66
579-585
69
Pastorino J G, Snyder J W, Serroni A, Hoek J B, Farber J L.
Cyclosporine and carnitine prevent the anoxic death of cultured hepatocytes by inhibiting the mitochondrial permeability transition.
J Biol Chem.
1993;
268
13 791-13 798
70
Pastorino J G, Wilhelm T J, Glascott P A, Kocsis J J, Farber J L.
Dexamethasone induces resistance to the lethal consequences of electron transport inhibition in cultured hepatocytes.
Arch Biochem Biophys.
1995;
318
175-181
72
Pillai S B, Hinman C E, Luquette M H, Nowicki P T, Besner G E.
Heparin-binding epidermal growth factor-like growth factor protects rat intestine from ischemia/reperfusion injury.
J Surgic Res.
1999;
87
225-231
76
Samarasinghe D A, Tapner M, Farrell G C.
Role of oxidative stress in hypoxia-reoxygenation injury to cultured rat hepatic sinusoidal endothelial cells.
Hepatology.
2000;
31
160-165
78
Saxton N E, Barclay J L, Clouston A D, Fawcett J.
Cyclosporin A pretreatment in a rat model of warm ischaemia/reperfusion injury.
J Hepatol.
2002;
36
241-247
79
Shimizu S, Kamiike W, Hatanaka N, Nishimura M, Miyata M, Inoue T, Yoshida Y, Tagawa K, Matsuda H.
Enzyme release from mitochondria during reoxygenation of rat liver.
Transplantation.
1994;
57
144-148
80
Shiraishi M, Hiroyasu S, Nagahama M, Miyaguni T, Higa T, Tomori H, Okuhama Y, Kusano T, Muto Y.
Role of exogenous L-arginine in hepatic ischemia-reperfusion injury.
J Surg Res.
1997;
69
429-434
81
Soeda J, Miyagawa S, Sano K, Masumoto J, Taniguchi S, Kawasaki S.
Cytochrome c release into cytosol with subsequent caspase activation during warm ischemia in rat liver.
Am J Physiol.
2001;
281
G1115-G1123
82
Souza D G, Cassali G D, Poole S, Teixeira M M.
Effects of inhibition of PDE4 and TNF-alpha on local and remote injuries following ischaemia and reperfusion injury.
Br J Pharmacol.
2001;
134
985-994
83
Takada D, Yamashita K, Sakurai-Yamashita Y, Shigematsu K, Hamada Y, Hioki K, Taniyama K.
Participation of nitric oxide in the mucosal injury of rat intestine induced by ischemia-reperfusion.
J Pharmac Experim Therap.
1998;
287
403-407
85
Uhlmann D, Uhlmann S, Loffler B M, Witzigmann H, Spiegel H U.
Pharmacological regulation of postischemic sinusoidal diameters in rats - a new approach for reducing hepatic ischemia/reperfusion injury.
Clin Hemorheol Microcirc.
2001;
24
233-246
86
Wheeler M D, Katuna M, Smutney O M, Froh M, Dikalova A, Mason R P, Samulski R J, Thurman R G.
Comparison of the effect of adenoviral delivery of three superoxide dismutase genes against hepatic ischemia-reperfusion injury.
Hum Gene Ther.
2001;
12
2167-2177
87
Williams J P, Pechet T T, Weiser M R, Reid R, Kobzik L, Moore F D, Carroll M C, Hechtman H B.
Intestinal reperfusion injury is mediated by IgM and complement.
J Appl Physiol.
1999;
86
938-942
89
Wu T W, Hashimoto N, Au J X, Wu J, Mickle D A, Carey D.
Trolox protects rat hepatocytes against oxyradical damage and the ischemic rat liver from reperfusion injury.
Hepatology.
1991;
13
575-580
91
Zahrebelski G, Nieminen A L, al-Ghoul K, Qian T, Herman B, Lemasters J J.
Progression of subcellular changes during chemical hypoxia to cultured rat hepatocytes: a laser scanning confocal microscopic study.
Hepatology.
1995;
21
1361-1372