Die Schädigung viszeraler Organe durch Ischämie und Reperfusion. Abläufe in pathogenetischen Netzwerken

Zusammenfassung

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.

Ischämie - Reperfusion - Leber - Pankreas - Magen - Darm - Pathogenese - Netzwerk

ischemia - reperfusion - liver - pancreas - stomach - intestine - pathogenesis - network

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1 7 mmHg entspricht ca. 1 % O₂.

2 Der Punkt in den Molekülformeln steht für ein ungepaartes Elektron und zeigt damit eine radikalische Spezies an.

3 Stickstoffmonoxid (^.NO) wird hier gesondert aufgeführt, da es sehr intensiv untersucht worden ist und nicht nur Mediatorfunktion besitzt.