Development and evaluation of two mouse models for endometriosis focused on the involvement of the immune system in endometriosis establishment

Natalia Nowak, Nowak, Nicola
2008 · doi:10.17169/refubium-12324 · W1777653212
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⚙ AI-generated summary by claude@2026-06, 2026-06-06 ⓘ

This study developed and evaluated two mouse models for endometriosis, finding that the injection model induced peritoneal inflammation and that a pre-inflamed environment reduced lesion burden, unlike immunosuppression.

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This dissertation developed and evaluated two mouse models of endometriosis to study immune involvement in lesion establishment, using either an autologous transplantation approach (uterine biopsies sutured to peritoneum and intestine mesenteries) or an intraperitoneal injection approach with EGFP-expressing endometrial fragments. Histology showed lesions resembling human endometriotic lesions in both models, and the transplantation model displayed estrogen dependency via reduced lesion size after anti-estrogen treatment; a time-course in the injection model showed tissue reorganization and time-varying angiogenic processes. As a limitation, the models’ reproductive cycle differs from humans, and inflammatory effects were assessed in the peritoneal cavity rather than defining mechanistic immune pathways. Relevance to endometriosis: the entire work is centrally about endometriosis in mice, including experimentally probing peritoneal inflammation and immune suppression effects on lesion number and disease burden.

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Abstract

Endometriosis is a common gynaecological disease, affecting around 10 % of women in reproductive age. It is characterised by the presence of endometrial tissue fragments outside the uterine cavity, the so called endometriotic lesions, which grow in an estrogen-dependent manner. The major symptoms like severe chronic pain, dysmenorrhea and decreased fertility have a deep impact on the quality of the women’s lives. Current therapies result in pain release and amelioration of life conditions, but the recurrence rate is very high. Thus, there is an urgent need for new, more effective therapeutics. Due to ethical concerns, drug discovery cannot be conducted in humans. Non-human primates like the baboon, which menstruate and develop endometriosis spontaneously, are the best model system. However, high costs, long time periods until endometriosis occurs and ethical considerations limit the use of these animals. Mouse models are an alternative to examine endometriosis establishment and subsequently to test new therapeutical approaches, albeit their reproductive cycle is different. In the present work, two different endometriosis mouse models were established and evaluated to demonstrate their usability for endometriosis research and drug discovery. The first endometriosis model was an autologous transplantation model where uterus biopsies were sutured onto peritoneum and intestine mesenteries. Histological analysis revealed that the developed lesions resembled human endometriotic lesions. Additionally, the lesions demonstrated estrogen dependency by decreased lesion size after treatment with an anti-estrogen. Thus, the transplantation model is suitable for investigating anti-hormonal therapeutic approaches. The second endometriosis mouse model presented in this study was induced by intraperitoneal injection of enhanced green fluorescent protein- expressing endometrium fragments (EGFP). The developed lesions could be easily detected using a fluorescence microscope and revealed histological similarities with human lesions, thus making this model applicable for endometriosis research. Furthermore, a time course experiment demonstrated that the lesions underlay tissue reorganisation and angiogenic processes were visible which varied over time. In the pathophysiology of endometriosis, one important aspect is the role of the immune system, even though its exact impact still remains enigmatic. In the present study, both models were investigated particularly with regard to inflammatory events in the peritoneal cavity. No differences could be demonstrated for the transplantation model compared to sham-operated and untreated controls. However, in the injection model increased inflammatory parameters could be detected 24 h, 72 h and even 10 days after endometriosis induction. Thus, the induction of endometriosis provoked a peritoneal inflammation in the injection model. Furthermore, the injection model was used to examine the impact of an altered immune system on endometriosis establishment. Endometriosis was induced on the one hand in a pre-inflamed peritoneal cavity and on the other hand in immunosuppressed animals. Induction of endometriosis in a pre-inflamed peritoneal cavity resulted in fewer lesions and significantly lower disease burden per mouse. Thus, a pre-existing peritoneal inflammation might not be a factor favouring the development of endometriosis. By contrast, a suppressed immune system had no significant impact on lesion number and size. In summary, the injection model can be used to investigate establishment of lesions and potentially attachment-interfering agents.
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Haupttitel: Development and evaluation of two mouse models for endometriosis focused on the involvement of the immune system in endometriosis establishment Titel übersetzt: Entwicklung und Evaluation zweier Mausmodelle für Endometriose, fokussiert auf den Einfluss des Immunsystems auf Endometriose-Etablierung Autor*in: Nowak, Nicola Erscheinungsjahr: 2008 Datum der Freigabe: 2008-11-10T13:37:25.224Z Abstract: Endometriosis is a common gynaecological disease, affecting around 10 % of women in reproductive age. It is characterised by the presence of endometrial tissue fragments outside the uterine cavity, the so called endometriotic lesions, which grow in an estrogen-dependent manner. The major symptoms like severe chronic pain, dysmenorrhea and decreased fertility have a deep impact on the quality of the women’s lives. Current therapies result in pain release and amelioration of life conditions, but the recurrence rate is very high. Thus, there is an urgent need for new, more effective therapeutics. Due to ethical concerns, drug discovery cannot be conducted in humans. Non-human primates like the baboon, which menstruate and develop endometriosis spontaneously, are the best model system. However, high costs, long time periods until endometriosis occurs and ethical considerations limit the use of these animals. Mouse models are an alternative to examine endometriosis establishment and subsequently to test new therapeutical approaches, albeit their reproductive cycle is different. In the present work, two different endometriosis mouse models were established and evaluated to demonstrate their usability for endometriosis research and drug discovery. The first endometriosis model was an autologous transplantation model where uterus biopsies were sutured onto peritoneum and intestine mesenteries. Histological analysis revealed that the developed lesions resembled human endometriotic lesions. Additionally, the lesions demonstrated estrogen dependency by decreased lesion size after treatment with an anti-estrogen. Thus, the transplantation model is suitable for investigating anti-hormonal therapeutic approaches. The second endometriosis mouse model presented in this study was induced by intraperitoneal injection of enhanced green fluorescent protein- expressing endometrium fragments (EGFP). The developed lesions could be easily detected using a fluorescence microscope and revealed histological similarities with human lesions, thus making this model applicable for endometriosis research. Furthermore, a time course experiment demonstrated that the lesions underlay tissue reorganisation and angiogenic processes were visible which varied over time. In the pathophysiology of endometriosis, one important aspect is the role of the immune system, even though its exact impact still remains enigmatic. In the present study, both models were investigated particularly with regard to inflammatory events in the peritoneal cavity. No differences could be demonstrated for the transplantation model compared to sham-operated and untreated controls. However, in the injection model increased inflammatory parameters could be detected 24 h, 72 h and even 10 days after endometriosis induction. Thus, the induction of endometriosis provoked a peritoneal inflammation in the injection model. Furthermore, the injection model was used to examine the impact of an altered immune system on endometriosis establishment. Endometriosis was induced on the one hand in a pre-inflamed peritoneal cavity and on the other hand in immunosuppressed animals. Induction of endometriosis in a pre-inflamed peritoneal cavity resulted in fewer lesions and significantly lower disease burden per mouse. Thus, a pre-existing peritoneal inflammation might not be a factor favouring the development of endometriosis. By contrast, a suppressed immune system had no significant impact on lesion number and size. In summary, the injection model can be used to investigate establishment of lesions and potentially attachment-interfering agents. Endometriose ist eine häufig auftretende gynäkologische Erkrankung. Von ihr betroffen sind etwa 10 % aller Frauen im reproduktiven Alter. Die Krankheit wird charakterisiert durch das Vorhandensein von endometrialen Gewebsfragmenten außerhalb der Uterushöhle, den sogennanten endometriotischen Läsionen, welche östrogenabhängig wachsen. Die Hauptsymptome wie starker chronischer Schmerz, unregelmäßige Blutungen und herabgesetzte Fruchtbarkeit haben einen großen Einfluss auf die Lebensqualität der erkrankten Frauen. Die aktuell angewendeten Therapien reduzieren die Schmerz¬symptomatik und verbessern die Lebensbedingungen, aber die Rückkehr der Erkrankung nach Absetzen der Medikamente ist hoch. Daher werden neue, effektivere Therapeutika dringend benötigt. Aufgrund ethischer Richtlinien wird die Erfoschung neuer Medikamente nicht am Menschen durchgeführt. Das beste Modellsystem für Endometriose sind momentan Altweltaffen wie z. B. der Pavian, welche menstruieren und spontan Endometriose entwickeln können. Allerdings limitieren hohe Kosten, lange Zeiträume bis zur Entwicklung der Endometriose und ethische Berücksichtigungen die Verwendung dieser Tiere. Obwohl sich der Reproduktionszyklus der Maus von dem des Menschen unterscheidet, sind Mausmodelle eine mögliche Alternative, um die Etablierung der Endometriose zu untersuchen und darauf folgend neue therapeutische Ansätze zu testen, In der vorliegenden Arbeit wurden zwei verschiedene Mausmodelle für Endometriose etabliert und evaluiert, um ihre Verwendbarkeit für Endometrioseforschung und die Entwicklung neuer Medikamente zu zeigen. Als erstes wurde ein autologes Transplantationsmodell verwendet, bei welchem Uterusbiopsien auf Peritoneum und Darmmesenterien aufgenäht wurden. Die histologische Analyse ergab, dass die entstandenen murinen Läsionen humanen Läsionen ähneln. Zusätzlich zeigten die Läsionen Östrogenabhängigkeit, da ihre Größe nach Behandlung mit einem Anti-Östrogen abnahm. Folglich scheint das murine Endometriose- Transplantationsmodell geeignet, um anti-hormonelle Therapieansätze zu testen. Das zweite in dieser Arbeit präsentierte Mausmodell wurde durch intraperitoneale Injektion von „Enhanced green fluorescent protein“ (EGFP)-exprimierenden endometrialen Fragmenten induziert. Die entstandenen Läsionen konnten unter einer Fluoreszenzlupe gut entdeckt und quantifiziert werden und zeigten ebenfalls histologische Ähnlichkeit mit humanen Läsionen. Somit ist das Injektionsmodell für Endometrioseforschung verwendbar. Darüber hinaus zeigte ein Zeitverlauf-Experiment, dass die Läsionen Gewebsreorganisation unterliegen und Angiogeneseprozesse sichbar sind, welche sich im Verlauf der Zeit verändern. Eine bedeutende Rolle in der Pathophysiologie der Endometriose spielt das Immunsystem. Allerdings ist sein genauer Einfluss bisher nicht komplett entschlüsselt worden. In der vorliegenden Arbeit wurden beide Modelle besonders unter dem Aspekt der Inflammation in der Peritonealhöhle untersucht. Im Vergleich zu Kontrollen ohne Operation und schein-operierten Tieren wurden in den Tieren mit transplantierter Endometriose keine Unterschiede in inflammatorischen Parametern gefunden. Im Injektionsmodell dagegen wurden erhöhte inflammatorische Marker 24 Stunden, 72 Stunden und 10 Tage nach Endometriose- Induktion detektiert. Folglich führt die Induktion von Endometriose durch Injektion von endometrialen Fragmenten zu einer peritonealen Entzündung. Weiterhin wurde das Injektionsmodell verwendet, um den Einfluss eines veränderten Immunsystems auf die Etablierung der Endometriose zu untersuchen. Endometriose wurde zum Einen in einer entzündeten Peritonealhöhle und zum Anderen in immunsupprimierten Tieren induziert. Herbeiführen der Endometriose in einer entzündeten Peritonealhöhle resultierte in geringeren Läsionszahlen und einer signifikant geringeren Krankheitsbelastung pro Tier. Daher scheint eine bereits bestehende peritoneale Inflammation kein krankheitsfördernder Faktor der Endometriose zu sein. Konträr zu diesen Ergebnissen hatte das supprimierte Immunsystem keinen signifikanten Einfluss auf Läsionsanzahl und -größe. Zusammenfassend ist festzustellen, dass das Injektionsmodell für die Untersuchung von Läsionsetablierung und möglichen adhäsionsvermindernden therapeutischen Agenzien sehr geeignet ist. Identifier: Sprache: Englisch Freie Schlagwörter: Endometriosis mouse model EGFP immune system mouse model EGFP immune system DDC-Klassifikation: 570 Biowissenschaften; Biologie Publikationstyp: Dissertation Fachbereich/Einrichtung: Biologie, Chemie, Pharmazie Version_4.7.08_final_ohneCV.pdf Größe: 3.295MB Format: PDF Prüfsumme (MD5): e56244ccf094803cfb3a84cbfce2c44f

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