Was der Chirurg über grundlegend neue Konzepte zur Entzündung und deren therapeutische Konsequenzen wissen sollte: Die Ausheilung der Entzündung ist kein passiver, sondern ein durch Lipidmediatoren regulierter aktiver Prozess^[*]

Zusammenfassung

Die akute Entzündung als physiologische Antwort auf schädigende Reize ist u. a. durch komplex regulierte Wirkungen pro- und antiinflammatorischer Mediatoren charakterisiert. Die Forschung der letzten Jahrzehnte hat die Wechselwirkungen dieser Mediatoren weitgehend aufgeklärt und zur Entwicklung antiinflammatorisch wirksamer Medikamente geführt. Allerdings wurde die endgültige Abheilung der akuten Entzündung bis vor wenigen Jahren als passiver Prozess angesehen. Es ist daher nicht verwunderlich, dass die Mechanismen weitgehend unbekannt waren, die entweder zur vollständigen Abheilung mit Wiederherstellung der normalen Funktion oder zur chronischen Entzündung mit Gewebeschädigung und eingeschränkter Funktion führen. Vor allem im letzten Jahrzehnt wurden die sogenannten entzündungsauflösenden Lipidmediatoren (ELM) identifiziert, die in verschiedenen Zellen aus essenziellen Fettsäuren gebildet werden. Diese Mediatoren – Lipoxine, Resolvine, Protektine und Maresine – beenden die akute Entzündungsantwort und stimulieren deren vollständige Abheilung. ELM wirken somit sowohl antiinflammatorisch als auch entzündungsauflösend, indem sie die proinflammatorischen Zytokine hemmen, die Gewebseinwanderung der Neutrophilen eindämmen, die Aufnahme der Makrophagen im entzündeten Gewebe fördern, eine nonphlogistische Aktivierung der Makrophagen bewirken und schließlich die Beseitigung apoptotischer Neutrophilen und mikrobieller Partikel stimulieren. Es konnte in verschiedenen Tiermodellen der humanen chronischen Entzündung nachgewiesen werden, dass z. B. die Atherosklerose, der Diabetes und die chronisch-entzündlichen Darmerkrankungen durch erniedrigte Spiegel der entzündungsauflösenden Lipidmediatoren gekennzeichnet waren und dass deren Substitution zu einer Regression der Krankheitserscheinungen führte. Zukünftige Studien sollen untersuchen, ob die bei den Tiermodellen gewonnenen Erkenntnisse auch auf Entzündungsprozesse des Menschen übertragbar sind und ob die ELM und deren stabile Analoga therapeutisch zur Behandlung akuter und chronischer Entzündungen und deren Komplikationen eingesetzt werden können.

Abstract

The acute inflammatory response as a physiological programme that protects the organism against injurious pathogens is characterised by highly regulated actions of pro- and anti-inflammatory mediators. Intensive investigations during the last decades have led to the identification of these mediators and their complex interplay as well as the design and development of anti-inflammatory therapies. However, the resolution of acute inflammation has long been considered to be a passive process. In consequence, little was known about the mechanisms which guide acute inflammation either to complete resolution, repair of inflamed tissue and restoration of normal function or to a chronic inflammatory process characterised by persistent signs of inflammation, tissue damage and impaired function. Predominantly during the last decade the so-called specialised proresolving mediators (SPM) have been identified. These essential fatty acid-derived mediators – lipoxins, resolvins, protectins, and maresins – terminate the acute inflammatory responses and stimulate their complete resolution. SPM possess both anti-inflammatory and proresolving activities in that they inhibit pro-inflammatory cytokines, limit infiltration of neutrophils, enhance macrophage uptake, and finally stimulate their non-phlogistic activation and clearance of apoptotic neutrophils and microbial particles. It has been demonstrated in multiple animal models of human inflammatory diseases that, e.g., atherosclerosis, diabetes, and inflammatory bowel diseases are caused by a decreased synthesis and/or an impaired signal transduction of the proresolving mediators. Future studies are warranted to clarify whether these proresolving lipid mediators will participate in healing human inflammatory diseases and their complications.

Schlüsselwörter

Inflammation - Lipidmediatoren - Lipoxygenase - Cyclooxygenase - Lipoxine - Resolvine - Protektine - Maresine - Zytokine

Key words

inflammation - lipid mediators - lipoxygenase - cyclooxygenase - lipoxins - resolvins - protectins - maresins - cytokines

^* Prof. Dr. Dr. H. Lippert gewidmet

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