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The lactoperoxidase (LPO) antimicrobial system has been shown to play an important role in maintaining sterile conditions in several tissues including the mammary gland, the salivary gland, and the airway. The LPO system in the airway consists of the enzyme LPO and its substrates hydrogen peroxide and an anion. LPO catalyzes the oxidation of a halide or pseudohalide ion for example SCN-or I- by hydrogen peroxide producing a product, OSCN- or OI- which have antibacterial, antifungal, and antiviral properties. In order to have a functional antimicrobial system all the components need to be present at appropriate concentrations. The LPO system has been suggested to be deficient in cystic fibrosis. There are three possible regulatory mechanism of this antimicrobial system and these involve the secretion and availability of the three components of the LPO system in the luminal fluid. The studies presented in this dissertation examine two of the possible regulatory mechanisms of the LPO system in the airway; the availability and transport of SCN- to the luminal surface, and the expression of LPO. The knowledge obtained from these studies could be utilized to develop treatments to control infection in diseases characterized by chronic infections such as cystic fibrosis.

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Endokrin aktive Substanzen (EACs) sind exogene Substanzen natürlichen oder synthetischen Ursprungs, die mit der Feedbackregulation hormoneller Netzwerke interferieren können und somit deren Homöostase beeinflussen. Störungen der Hypothalamus-Hypophysen-Schilddrüsenachse (HPT-Achse) haben weitreichende Konsequenzen, da Schilddrüsenhormone essentiell für die Regulation von Entwicklung, Wachstum und Stoffwechsel sind. In der vorliegenden Arbeit wurde das Wirkprofil potenter Inhibitoren der thyreotropen Achse am Beispiel von 4-Methylbenzyliden-campher (4-MBC) und Genistein (GEN) untersucht. Der UV-Filter 4-MBC wurde in der ovariektomierten Ratte als goitrogene Substanz identifiziert. 4-MBC interferiert auf Ebene von Hypothalamus und Hypophyse mit der Expression Feedback-assoziierter Gene und beeinflusst daher die Feedbackregulation der thyreotropen Achse. Darüber hinaus wird die Biosynthese von Schilddrüsenhormonen durch Inhibition des Iodidtransports bei gleichzeitig erhöhter messenger RNA (mRNA)-Konzentration des Natrium-Iodid-Symporters (NIS) durch 4-MBC beeinträchtigt. Parallel dazu lässt die verstärkte Expression des Angiogenesemarkers vascular endothelial growth factor (VEGF) nach subakuter Exposition auf die Entstehung einer Hypothyreose schließen. Die damit einhergehenden Veränderungen sind auch in peripheren Organen durch die Analyse 3,3‘,5-Triiod-L-thyronin (T3)-regulierter Zielgene dokumentiert. Zudem wurden diese Effekte maßgeblich durch die Expositionszeit beeinflusst, da nach chronischer Exposition vermutlich auch kompensatorische Prozesse eine wichtige Rolle spielen. Die gezeigten speziesspezifischen Effekte lassen sich möglicherweise auf Unterschiede in der Pharmakokinetik zurückführen, z.B. in Folge differentieller Expression von Cytochrom P450-Genen. / Endocrine active compounds (EACs) can be of natural or synthetic origin and show hormone-like effects that interfere with feedback regulation of hormonal networks. Interferences with the hypothalamic-pituitary-thyroid axis (HPT-axis) result in extensive consequences as thyroid hormones are essential for regulation of development, growth, and metabolism. In the work presented here, the active profile of potent inhibitors of the HPT-axis namely 4-methylbenzylidene-camphor (4-MBC) and genistein (GEN) was investigated. 4-MBC, a UV filter used in sunscreens and various cosmetics, was identified as a goiter causing agent using ovariectomized rats. 4-MBC acts at the level of hypothalamus and pituitary gland by modulating the expression of thyrotropin-releasing hormone (TRH) as well as thyroid-stimulating hormone (TSH) that regulate feedback on the HPT-axis. Furthermore, biosynthesis of thyroid hormones was impaired by 4-MBC secondary to the inhibition of iodide transport with concomitantly increased messenger RNA (mRNA)-levels of the sodium-iodide symporter (NIS). In parallel expression of the angiogenesis marker vascular endothelial growth factor (VEGF) was increased, indicating hypothyroidism. After the application of 4-MBC the expression of L-3,3’,5-triiodothyronine (T3)-regulated target genes was reduced in the periphery both on the mRNA and protein level. The documented species-specific effects indicate a difference in pharmacokinetics, possibly secondary to differential expression of cytochrome P450 genes. GEN is contained in soy and red clover and its mechanistic analysis was carried out in thyroid hormone receptor (TR) deficient mice (TRα0/0). The gender-dependent effects of GEN on tissue specificity did not follow an obvious pattern and warrant continuative analysis. The work presented here supports the assumption that EACs can interfere with function and regulation of the HPT-axis at levels that were previously considered safe.

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