Dokument

Zusammenfassung:
Die Prävalenz allergischer Erkrankungen hat in den letzten Jahrzehnten stetig zugenommen und stellt heute eine globale Belastung dar, die Menschen jeglichen Alters und ethnischen Hintergrundes betrifft. Aufgrund wachsender medizinischer, sozialer und wirtschaftlicher Probleme, gibt es weltweit einen dringenden Bedarf, die Allergieproblematik intensiver anzugehen. Die Suche nach Erklärungen für die beobachtete Zunahme allergischer Erkrankungen führte zu der Umwelt-Hypothese, nach der Umweltschadstoffe in der Atemluft für die steigenden Prävalenzen verantwortlich gemacht werden. Neben direkt und indirekt schädigender Wirkung auf die Atemwege können sich Luftschadstoffe auch gegen die Allergene selbst richten und luftübertragene Proteine modifizieren. In diesem Zusammenhang zeigen Experimente, dass Proteine durch atmosphärisches Stickstoffdioxid nitriert werden können und dass eine solche posttranslationale Proteinmodifikation die Immunogenität der Allergene verstärkt. Da die Lunge aufgrund ihrer großen Oberfläche in besonderem Maße gegenüber diesen Fremdstoffen exponiert wird, sind Veränderungen ihrer Struktur und Funktion zu erwarten. Weitere Angriffspunkte stellen das pulmonale Surfactant-System und das physiologische Antioxidantien-Gleichgewicht dar. 
Im Rahmen dieser Arbeit sollte an einem Mausmodell, durch Verwendung zweier Allergene in nativer und nitrierter Form (Ovalbumin und Keyhole Limpet Hemocyanin) der Einfluss der Proteinnitrierung auf verschiedene strukturelle, biochemische und molekularbiologische Parameter des allergischen Asthmas untersucht werden. Dazu wurden C57BL-6-Wildtyptiere entsprechend des Protokolls zur Induktion eines akuten allergischen Asthmas behandelt und mit PBS / (n)OVA / (n)KLH intraperitoneal sensibilisiert und inhalativ provoziert. Bei einem Teil der Tiere wurde mit Hilfe des FlexiVent®Systems die Atemwegshyperreaktivität gegenüber Methacholin gemessen und die Lungen anschließend histologisch aufgearbeitet. Bei dem anderen Teil der Tiere wurden Plasma und bronchoalveoläre Lavage (BAL) gewonnen sowie Typ-II-Pneumozyten isoliert. Im Plasma wurde die Gesamt-SOD-Aktivität gemessen, mittels Zytospin die BAL-Zytologie ermittelt und aus dem zellfreien Lavage-Überstand Gesamtprotein und Gesamtphospholipid bestimmt. Die isolierten Typ-II-Pneumozyten wurden mittels real-time RT-PCR hinsichtlich ihres mRNA-Gehalts an Phospholipid-synthetisierenden Enzymen (Cholinkinase α and β, CTP:Phosphocholinecytidylyltransferase α) und antioxidativen Enzymen der SOD-Untergruppen untersucht. Darüber hinaus wurde in den Typ-II-Zellen der Proteingehalt der MnSOD mittels Western Blot bestimmt. 
Der Vergleich der Gruppen OVA/OVA und nOVA/nOVA diente der Beantwortung der Frage, ob nitrierte Allergenen in einem kompletten Individuum eine stärkere Entzündungsreaktion hervorrufen als die entsprechenden nicht nitrierten Allergene. Als Ergebnis zeigte sich einerseits, dass die histologischen Veränderungen in Form von strukturellen Läsionen und zellulären Infiltraten in der nOVA/nOVA-Gruppe deutlicher ausgeprägter waren, als bei den OVA/OVA-Tieren. In der Zytologie wies die nitrierte Gruppe eine höhere Anzahl an Entzündungszellen auf. Darüber hinaus fand sich bei den nOVA/nOVA-Tieren als Ausdruck einer gestörten Integrität und Permeabilität des Lungenepithels ein höherer Gesamtproteingehalt in der BAL. Auf der anderen Seite zeigten sich in den Untersuchungen von Lungenfunktion, Phospholipiden und Superoxiddismutasen keine Unterschiede zwischen der nitrierten und nicht nitrierten Gruppe. Anhand des Vergleichs von nOVA/nKLH mit den Gruppen nOVA/KLH und PBS/nKLH sollte die zweite Hauptfragestellung der Arbeit beantwortet werden, ob ein Individuum bei bestehender Sensibilisierung gegen ein definiertes nitriertes Allergen auch gegen andere nitrierte Allergene reagiert. In den Versuchen zeigte die nOVA/nKLH-Gruppe im Gegensatz zu den Kontrollen sowohl in der Histologie als auch in der Zytologie eine entzündliche Reaktion. Weitere Unterschiede gegenüber den Kontrollen wies die nOVA/nKLH-Gruppe hinsichtlich ihres Gesamtproteingehalts in der BAL sowie ihres MnSOD-mRNA-Gehaltes in den Typ-II-Pneumozyten auf. Abgesehen von diesen nicht signifikanten Veränderungen entsprachen die restlichen Ergebnisse dieser Gruppe weitgehend denen der Kontrollen. 
Die Ergebnisse haben zum Verständnis der biochemischen und molekularen Mechanismen bei der Immunantwort auf native und nitrierte Allergene beigetragen. Die dabei gemachten Beobachtungen, dass eine umweltbedingte Nitrierung von Allergenen die entzündliche Reaktion gegen diese verstärkt und dass ein Individuum bei bestehender Sensibilisierung gegen ein definiertes nitriertes Allergen eine Tendenz entwickeln, auch gegen ein anderes nitriertes Allergen zu reagieren, könnten eine Erklärung für die allgemein beobachtete Zunahme von Allergien und allergischem Asthma darstellen.


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