Dokument

Zusammenfassung:
Zielsetzung dieser Arbeit war die Charakterisierung der äußerst komplexen und vielseitigen Wirkungen, die durch den PAR-2 im Gastrointestinaltrakt vermittelt werden. Hier wurde vor allem der regulatorische Einfluss des PAR-2 (Protease aktivierter Rezeptor 2) auf die intestinale Ionensekretion und die Permeabilität im unteren Intestinaltrakt untersucht. Die Ausbildung der inneren intestinalen Barriere ist zu einem bedeutenden Anteil von Proteasen abhängig. Entscheidend im Prozess einer regelhaften Reifung und Ausbildung der Zell-Zell-Verbindungen ist nach Bacher jedoch vor allem der andauernde, intraluminale (apikale) Einfluss der Proteasen (Bacher A et al, 1992). Im Hinblick auf die Tatsache, dass eine Inhibition der Proteasen intraluminal eine verminderte Bildung eines transepithelialen Widerstandes (TER) zur Folge hat (Bacher A et al, 1992), sind hier die kurzfristigen Veränderungen des TER und des Kurzschlussstromes durch Trypsin und das PAR-2-AP untersucht worden. Hinweise auf eine evtl. protektive Funktion i.S. einer Steigerung des transepithelialen Widerstandes durch Proteasen erhielt man durch die Arbeiten von Lynch (Lynch RD et al, 1995), der zeigen konnte, dass durch eine basolaterale Stimulation von Zellen mittels Trypsin tight-junction-Komplexe (vor allem ZO-1-Proteine) neu formiert werden. Über welche Rezeptoren dieser Vorgang reguliert wird, wurde in der damaligen Arbeit nicht untersucht. Entscheidend war, dass eine basolaterale Stimulation zu einem ca. 1 stündigen Anstieg des TER (transepithelialen Widerstandes) auf über 190% des Ausgangswertes geführt hatte. In der nun vorliegenden Arbeit konnte durch die Versuchsreihe mit der Protease Trypsin und dem PAR-2-aktivierenden Peptid der Mechanismus der kurzfristig adaptiven (und vielleicht auch der permanenten) Vorgänge der tight-junction-Regulation an den Darmepithelien noch ein wenig besser charakterisiert und verstanden werden. Ein wichtiger Kandidat für diese Rezeptoren, die an der Regulation der hochkomplexen Organisation der Interzellularbrücken beteiligt sind, könnte tatsächlich der PAR-2 sein. Dass (besser Satz so umstellen, dass er nicht mit dass beginnt) es sich bei den gezeigten Veränderungen des transepithelialen Widerstandes nicht nur um unspezifische Effekte des Trypsins über diverse andere Rezeptoren an Darmepithelien handelt, sondern tatsächlich PAR-2 vermittelte Wirkungen vorliegen, konnte schließlich dadurch bewiesen werden, dass gleichsinnige Effekte in der gleichen Versuchsreihe durch das aktivierende Peptid mit der spezifischen Aminosäuresequenz erzielt wurden. Zwar blieb die Effektivität des PAR-2-AP deutlich hinter der des Trypsins zurück, jedoch ist dieses Phänomen durch den besonderen Rezeptoraktivierungsmechanismus der PARs erklärt (ein Molekül Trypsin vermag mehrere PARs in Serie zu aktivieren, wohingegen ein PAR-2-aktivierendes Peptid jeweils nur einen Rezeptor aktiviert und dann internalisiert wird). Die Erkenntnis, dass körpereigene Proteasen die Permeabilität des Gastrointestinaltraktes beeinflussen können und dass es sich beim transepithelialen Widerstand eher um eine dynamische, und nicht um eine statische Eigenschaft des Intestinums handelt, bietet neben der genaueren Sichtweise und dem besserem Verständnis, auch einen potenziellen pharmakologischen Ansatzpunkt in der Medizin. Von Interesse wären hier z.B. Krankheitsbilder, die durch eine gesteigerte Permeabilität der intestinalen Barriere entweder die Ursache oder auch die unmittelbare Folge eine Erkrankung darstellen, und so zu einer weiteren Zustandsverschlechterung des Organismus beitragen können. In diesem Zusammenhang sind die chronisch-entzündlichen Darmerkrankungen von Interesse, bei denen eine erhöhte Permeabilität nachgewiesen werden kann. Genauso wäre es z.B. denkbar, dass bei akuten Darminfektionen eine Keiminvasion in den Organismus therapeutisch durch Erhöhung des transepithelialen Widerstandes vermindert werden könnte. Durch Entwicklung von geeigneten Agonisten in der Zukunft könnten hier beispielsweise supportive Medikamente entwickelt werden.

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