Pathogenetische Effekte der prä- und postnatalen Inflammationsreaktion in den Lungen

Zusammenfassung

Die fetale Entwicklung der Lunge und des Immunsystems ist sehr plastisch und kann von diversen endogenen und exogenen Faktoren beeinflusst werden. In den letzten Jahren konnte mithilfe von verschiedenen Tiermodellen Erkenntnisse über die Wirkung von Chorioamnionitis auf die Lungenreifung und -entwicklung sowie auf das sich entwickelnde Immunsystem gewonnen werden. Dabei zeigte sich, dass Chorioamnionitis zu einer Verletzung der Lunge durch eine Entzündungsreaktion und sich daran anschließenden Umbauprozessen führt. Als eines der wesentlichen Zytokine, das in die Vermittlung dieser Prozesse involviert ist, konnte Interleukin-1 (IL-1) identifiziert werden. Bezüglich der Lungenreifung konnte gezeigt werden, dass Chorioamnionitis zu einer Induktion der Synthese von Surfactant Proteinen und Lipiden in der fetalen Lunge führt und somit den positiven Einfluss von Chorioamnionitis auf das Atemnotsyndrom (RDS) funktionell erklären hilft. Auf der anderen Seite kann Chorioamnionitis auch strukturelle Veränderungen in der Lunge bewirken, verbunden mit einer Modulation von Wachstumsfaktoren wie TGF-β, CTGF, FGF-10 oder BMP-4, die alle eine wesentliche Rolle in der Lungenentwicklung besitzen. Diese Veränderungen führen zu einer Vereinfachung der Alveolen und zu einer Alterierung der Blutgefäße, die den Veränderungen bei BPD sehr ähnlich sind. Chorioamnionitis beeinflusst daneben eine Vielzahl von Signalwegen der Entzündungsreaktion und embryologischen Entwicklung. Diese Signalwege beeinflussen sich gegenseitig und bilden ein fein reguliertes Netzwerk, das die Lungenentwicklung steuert. Neben Chorioamnionitis können diese Signalwege durch andere pränatale (z. B. Glukokortikoide) und postnatale Faktoren (mechanische Beatmung, Sauerstoff, Infektionen, Steroide) beeinflusst werden. Die Entwicklung der Lunge kann ebenfalls indirekt durch die Wirkung der Chorioamnionitis auf die Effizienz des fötalen Immunsystems beeinflusst werden. Chorioamnionitis kann eine Toleranz gegenüber Endotoxin (LPS Toleranz, Immunparalyse) induzieren, die wohl weiteren Schaden des Feten verhindern kann, aber auch das Risiko für postnatale Infektionen erhöht. Die postnatale Reparaturreaktion scheint in hohem Maße von pränatalen Faktoren abhängig zu sein. Daher erscheint die Hypothese von sekundären Verletzungen sehr plausibel, wobei histologische Chorioamnionitis eine Prädisposition für eine postnatal beeinträchtigte Entwicklung ist.

Abstract

The developing lung and immune systems are very plastic and their developmental pathway can be influenced by various endogenous and/or exogenous factors. In the last years translational research with various animal models has been helpful to answer some basic questions about the effect of chorioamnionitis on maturation and development of the foetal lung and immune system. Chorioamnionitis can induce a cascade of lung injury, pulmonary inflammation and remodelling in the foetal lung. Chorioamnionitis-induced IL-1 production is consistently associated with lung maturation, induced by enhancing surfactant protein and lipid synthesis. IL-1 therefore seems to be the main link between lung inflammation and lung maturation, which largely prevents RDS in preterm infants. On the other hand, chorioamnionitis can also cause structural lung changes and affect the expression of growth factors, like TGF-β, CTGF, FGF-10 or BMP-4, which are crucial for branching morphogenesis. These changes result in alveolar and microvascular simplification similar to BPD. Neonatal outcome may also be affected by chorioamnionitis by modulating the efficacy of the immune system. Chorioamnionitis can induce LPS-tolerance (endotoxin hyporesponsiveness/immunoparalysis), which may prevent further foetal lung damage but increases susceptibility to postnatal infections. The inflammatory and developmental signalling pathways affected by chorioamnionitis form delicately regulated networks, which interact with each other to control lung development. In addition to chorioamnionitis, these pathways can be affected by other prenatal (steroid) or postnatal factors (mechanical ventilation, oxygen exposure, infection, steroids). Because the postnatal response to injury appears to be highly dependent on prenatal exposures, the “secondary hit” hypothesis is very plausible, in which exposure to chorioamnionitis is a predisposition for the development of adverse neonatal outcomes.

Schlüsselwörter

Chorioamnionitis - RDS - Surfaktant - BPD - TGF-β - Toleranz

Key words

chorioamnionitis - RDS - surfactant - BPD - TGF-β - tolerance

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