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Local glucocorticoid synthesis in the respiratory tract : Implications for immune homeostasis, inflammation and cancer

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2023

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Epithelial barriers are frequently affected by inflammatory diseases due to their close contact with the environment. Synthetic glucocorticoids (GCs) have been a mainstay in the treatment of these diseases for decades. Although their anti-inflammatory effects and therapeutic efficacy are undisputed, undesired side effects require alternatives. Endogenous local GCs could be one promising alternative, but their role in regulating inflammatory processes remains to be better understood. The majority of endogenous GCs is produced in the adrenal glands, but also epithelial barriers can synthesize GCs extra-adrenally. The close contact of intestine, skin and lung with the environment requires a tightly controlled immune system to allow pathogen clearance and avoid excessive and tissue-destructive reactions. Emerging research has already emphasized important regulatory functions of extra-adrenal GCs in physiological and pathological conditions of the skin and intestine, however, only little is known for the lung. Thus, this thesis aimed to investigate the specific role of lung-derived GCs under healthy conditions, in lung inflammation and cancer. To achieve this, three experimental studies were performed to answer these questions and in addition, the current knowledge was summarized in two literature reviews. We demonstrated that GCs are differentially synthesized along the murine and human respiratory tree, presumably to support immunoregulatory mechanisms according to the different physiological functions of the large and small conducting airways and the alveolar space (Chapter I). Furthermore, we revealed important immunoregulatory functions of 11b-HSD1-mediated GC reactivation in house dust mite (HDM)-induced airway hypersensitivity. The lack of locally reactivated GCs exacerbated the inflammatory phenotype which was characterized by an enhanced Th17-type immune response and associated neutrophil infiltration. Moreover, the Th2 immune response and associated eosinophilic inflammation, which was observed also in wild type animals, was markedly enhanced in 11b-HSD1-deficient mice in response to chronic HDM exposure (Chapter II). The current knowledge on a possible role of locally synthesized GCs in controlling viral infections of the lung was summarized in a literature review (Chapter III). Finally, we could provide first evidence for local GC synthesis by lung cancer cells as potential immune evasion strategy (Chapter IV). Future experiments may unravel the complex regulatory networks in the lung and place local GCs in the context of interorgan crosstalk in order to understand systemic effects of local mechanisms (Chapter V). In summary, the presented findings in this thesis provide evidence for a critical role of local GC synthesis in the lung and constitute a promising basis for future research on lung-derived GCs as a potential therapeutic target for the treatment of patients with inflammatory lung diseases or cancer.

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570 Biowissenschaften, Biologie

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ISO 690MERK, Verena M., 2023. Local glucocorticoid synthesis in the respiratory tract : Implications for immune homeostasis, inflammation and cancer [Dissertation]. Konstanz: University of Konstanz
BibTex
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  year={2023},
  title={Local glucocorticoid synthesis in the respiratory tract : Implications for immune homeostasis, inflammation and cancer},
  author={Merk, Verena M.},
  address={Konstanz},
  school={Universität Konstanz}
}
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Prüfungsdatum der Dissertation

October 20, 2023
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Konstanz, Univ., Diss., 2023
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