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Στην παρούσα διατριβή μελετήθηκε η έκφραση του παράγοντα αναστολής της μετανάστευσης των μακροφάγων (MIF) στον ιστό από ρινικό πολύποδα αλλά και στον φυσιολογικό ρινικό βλεννογόνο, καθώς και η ικανότητα αυτού να εξουδετερώνει την ανασταλτική δράση των γλυκοκορτικοειδών (ΓΚ) στην επαγόμενη από διάφορους αυξητικούς παράγοντες παραγωγή διαμεσολαβητών, όπως η IL-6 η MMP-1, η MMP-3 το κολλαγόνο τύπου-Ι και ο TIMP-1, που εμπλέκονται στη παθογένεια του ρινικού πολύποδα (ΡΠ). Ο MIF ανιχνεύθηκε στο μέσο καλλιέργειας όλων των ιστών και σε όλα τα εκχυλίσματα. Η έκφρασή του ήταν αυξημένη στον ρινικό πολύποδα σε σχέση με τον φυσιολογικό ρινικό βλεννογόνο. O TGF-β1 προκάλεσε δοσο- και χρονο-εξαρτώμενη αύξηση των επιπέδων της IL-6 του TIMP-1 και του κολλαγόνου τύπου-Ι, και παράλληλα ο TNF-α προκάλεσε δοσο- αλλά και χρονο-εξαρτώμενη διέγερση στην παραγωγή της IL-6 του TIMP-1 και των μεταλλοπρωτεασών MMP-1 και MMP-3. Η δεξαμεθαζόνη προκάλεσε στατιστικά σημαντική και δοσοεξαρτώμενη μείωση της επαγόμενης από τον TGF-β1 και TNF-α, παραγωγής της IL-6 του TIMP-1 του κολλαγόνου τύπου-Ι και των μεταλλοπρωτεασών MMP-1 και MMP-3. Διερευνώντας τον μηχανισμό μέσω του οποίου η δεξαμεθαζόνη ασκεί την κατασταλτική της δράση στην επαγόμενη τόσο από τον TGF-β1 όσο και από τον TNF-α, παραγωγή της IL-6, φάνηκε πως αυτή εκδηλώνεται κυρίως μέσω της επαγωγής αλλά και της προστασίας της ΜΚΡ-1 και κατά συνέπεια της καταστολής του μονοπατιού των ΜΑΡΚ και της ενεργοποίησης του ΑΡ-1, και λιγότερο μέσω της καταστολής της ενεργοποίησης του NF-κB. Ο ISO-1, ένας αναστολέας της δράσης του MIF, ενίσχυσε σημαντικά την κατασταλτική επίδραση της δεξαμεθαζόνης στα επίπεδα της IL-6 και του TIMP-1 στο μέσο καλλιέργειας ιστού από ΡΠ, ενώ αντίθετα προκάλεσε αναστροφή της κατασταλτικής δράσης της δεξαμεθαζόνης, η οποία ήταν στατιστικά σημαντική για την ΜΜΡ-1 όχι όμως και για την ΜΜΡ-3. Η ενίσχυση της κατασταλτικής δράσης της δεξαμεθαζόνης παρουσία του ISO-1, που κυμάνθηκε από 15.0% έως 20.5% θα πρέπει μάλλον να οφείλεται στην αναστολή του ενδογενούς MIF από τον ISO-1. Συμπερασματικά, η παρουσία του MIF στον ιστό του ρινικού πολύποδα, φαίνεται να εξασθενίζει το κατασταλτικό αποτέλεσμα της δεξαμεθαζόνης στην παραγωγή IL-6 και TIMP-1 από αυτόν τον ιστό, ενώ η ταυτόχρονη χρήση του αναστολέα του MIF, ISO-1 οδηγεί σε μια περαιτέρω ενίσχυση της κατασταλτικής δράσης της δεξαμεθαζόνης. Έτσι, είναι λογικό κατ΄αρχήν, να προταθεί πως η δημιουργία ενός φαρμακευτικού σχήματος που περιέχει κορτιζόλη και ένα αναστολέα του MIF, θα μπορούσε να είναι πιο αποτελεσματικό στην θεραπεία της ΡΠ. Απαιτούνται περαιτέρω πειράματα με συνδυασμό ΓΚ και αναστολέων του MIF για να μελετηθεί η επίδρασή τους στη παραγωγή και άλλων παραγόντων που εμπλέκονται στη παθογένεια της ΡΠ προκειμένου να εξαχθούν ασφαλέστερα συμπεράσματα. / In the present study we investigated the expression of macrophage migration inhibitory factor (MIF) in nasal polyp tissues and also in normal nasal mucosa. The ability of MIF to neutralize the inhibitory effect of glucocorticoids on various growth factors induced expression of IL-6, TIMP-1, collagen type-I and matrix metalloproteinases MMP-1 and MMP-3, involved in the pathogenesis of nasal polyps, was studied. MIF was detected in all polyp tissue extracts and tissue culture conditioned media and its expression was increased in nasal polyps compared with normal nasal mucosa. TGF-b1 caused a dose-and time-dependent increase in levels of IL-6 of TIMP-1 and collagen type-I, while the TNF-a induced a dose-and time-dependent stimulation in the production of IL-6 of TIMP-1 and metalloproteinases MMP-1 and MMP-3. Dexamethasone caused a statistically significant and dose-dependent reduction induced by TGF-b1 and TNF-a, production of IL-6 of TIMP-1 of collagen type-I and the metalloproteinases MMP-1 and MMP-3. Investigating the mechanism by which dexamethasone exercises the suppressive action on both induced by TGF-b1 and by TNF-a, production of IL-6, showed that this occurs mainly through the induction and protection of MKP-1 and hence the suppression of the MAPK pathway and activation of AP-1, and less through the suppression of the activation of NF-kB. The ISO-1, an inhibitor of the action of MIF, significantly enhanced the suppressive effect of dexamethasone on the levels of IL-6 and TIMP-1 in tissue culture medium from nasal polyps. In contrary, ISO-1 induced inversion of the suppresive action of dexamethasone, which was statistically significant for MMP-1 but not for MMP-3. Enhancing of the suppresive action of dexamethasone in the presence of ISO-1, which ranged from 15.0% to 20.5% would probably be due to inhibition of endogenous MIF by ISO-1. In conclusion, the presence of MIF in nasal polyp tissue, appears to attenuate the suppressor effect of dexamethasone on the production of IL-6 and TIMP-1by this tissue, while simultaneously using the inhibitor of MIF, ISO-1 leads to an enhancement of dexamethasone activity. Therefore, it is reasonable to propose that the creation of a pharmaceutical regimen containing cortisol and an inhibitor of MIF, might be more effective in the treatment of nasal polyposis. Of course, requires further experiments with a combination of glucocorticoids and MIF inhibitors to study their effect on production of other factors involved in the pathogenesis of nasal polyposis in order to draw safer conclusions.

Diversas doenças estão associadas com a formação de novos vasos a parti vasos pré-existentes, ou angiogênese. Dentre elas está a aterosclerose (Griffioen & Molema, 2000). Pesquisas recentes demonstram que a hipercolesterolemia, que têm um papel importante na fisiologia da aterosclerose, também pode prejudicar a ação de fatores angiogênicos (Jang et.al., 2000). A hipercolesterolemia que é decorrente de aumento de LDL no plasma ocasiona um aumento no tempo de permanência desta partícula na circulação (Yasunobu, 2001). Contudo, a LDL pode sofrer modificação na circulação, dando origem a uma subfração mais eletronegativa da LDL, a LDL (-). A LDL (-) pode prejudicar cada etapa da angiogênese, desregulando a função endotelial (Tai et. al., 2006). Em nosso estudo, vimos que apesar da LDL (-) ter estimulado a miga celular, esta partícula inibiu a formação de túbulos in vitro. A LDL (-) não foi capa afetar a angiogênese in vivo. / A large number of diseases is associated with formation of new blood vessels out of pre-existing capillaries, or angiogenesis. These diseases include the atherosclerosis (Griffioen & Molema, 2000). Resents researches demonstrate that the hypercholesterolemia, that have a important role in the physiology of the atherosclerosis, can impaired the angiogenesis (Jang et. al., 2000) . The hypercholesterolemia that is decurrente of high levels of LDL in the plasma causes an increase in the time of permanence this particle in the circulation (Yasunobu, 2001). However, the LDL can to suffer modification in the circulation, giving rise to a subfration more eletronegative from LDL, the LDL (-). The LDL (-) could impair each one of the steps of the angiogenesis, thereby dysregulating endothelial function (Tai et. al., 2006). In our study, see that despite the LDL (-) have stimulated the cell migration, this particle inhibited the Tube formation in vitro. The LDL (-) didn\'t affect the angiogenesis in vivo.

Unmanned, as well as manned space missions have seen a high failure rate in the early era of space technology. However, this decreased a lot since technology advanced and engineers learnt from previous experiences and improved critical real time systems with fault detection mechanisms. Fault detection, isolation and recovery, nowadays, is generally available in every flying device. However, the cost of hardware can bottleneck the process of creating such a system that is both robust and responsive. This thesis analyses the possibility of implementing a fault detection, isolation and recovery system inside of a single-threaded, cooperative scheduling operating system. The thesis suggests a cooperative implementation of such a system, where every task is responsible for parts of the fault detection. The analysis is done from both the integration layer, across the operating system and its tasks, as well as from the inside of the detection system, where two key components are implemented and analyzed: debug telemetry and operation modes. Results show that it is possible to implement a fault detection system that is spread across all the components of the satellite and acts cooperatively. Furthermore, the comparison with a traditional, dedicated fault detection system proves that errors can be caught faster with a cooperative mechanism. / Obemannade såväl som bemannade rymduppdrag har sett ett högt misslyckande i rymdteknikens tidiga era. Detta har dock förbättrats mycket sedan ingenjörer började lära sig av sina tidigare erfarenheter och utrustade kritiska realtidssystem med feldetekteringsmekanismer. Idag är alla flygande enheter utrustade med feldetekterings-, isolerings- och återställningsmekanismer. Däremot kan kostnaden för hårdvara vara ett problem för processen att skapa ett sådant system som är både robust och mottagligt. Denna uppsats analyserar möjligheten att implementera ett feldetekterings-, isolerings- och återställningssystem inuti ett enkelgängat samarbetsplaneringssystem. Denna uppsats föreslår ett samarbete för implementering av ett sådant system, där varje uppgift ansvarar för delar av feldetekteringen. Analysen görs från både integrationsskiktet, över operativsystemet och dess uppgifter, samt från insidan av detekteringssystemet, där två nyckelkomponenter implementeras och analyseras. Resultaten visar att det är möjligt att implementera ett feldetekteringssystem som täcker alla satellitkomponenter och som är mottaglig. Dessutom visar jämförelsen med ett traditionellt, dedikerat feldetekteringssystem att fel kan fångas snabbare med en mottagligmekanism. / Misiunile spat,iale cu oameni, atât cât s, i fara oameni, au avut o rata a es, ecurilor destul de ridicata în perioada init,iala a erei tehnologiei spat,iale. În schimb, aceasta a scazut semnificativ odata cu dezvoltarea tehnologiei, dar s, i datorita faptului ca inginerii au învat,at din experient,ele precendente s, i au îmbunatat, it sistemele critice în timp real cu mecanisme de detect,ie a erorilor. Sisteme de detect,ie, izolare s, i recuperare din erori sunt disponibile astazi în aproape toate sistemele spat,iale. Însa, costul echipamentelor poate împiedica crearea unor astfel de sisteme de detect,ie, care sa fie robuste s, i responsive. Aceasta teza analizeaza posibilitatea implementarii unui sistem de detect,ie, izolare s, i recuperare de la erori într-un satelit care este echipat cu un procesor cu un singur fir de execut,ie, care are un sistem de planificare cooperativ în sistemul de operare. Aceasta teza sugereaza o implementare cooperativa a unui astfel de sistem, unde fiecare proces este responsabil de câte o parte din detectarea erorilor. Analiza este realizata atât din perspectiva integrarii în sistemul de operare s, i procesele acestuia, cât s, i din interiorul acestui sistem de detect,ie, unde doua elemente importante sunt implementate s, i analizate: telemetria de depanare s, i modurile de operare. Rezultatele arata faptul ca este posibila implementarea unui sistem de detect,ie care este împart, it în toate componentele sistemului unui satelit s, i se comporta cooperativ. Mai departe, comparat,ia cu un sistem tradit,ional, dedicat, de detect,ie a erorilor arata ca erorile pot fi detectate mai rapid cu un sistem cooperativ.

Adipositas und ihre Folgeerkrankungen stellen eine wachsende medizinische Herausforde- rung globalen Ausmaßes dar. Im Rahmen der Adipositasforschung wurde das Fettgewebe als endokrines Organ identifiziert. Von ihm sezernierte Proteine, die sogenannten Adipo- kine, beeinflussen maßgeblich Insulinresistenz und Gefäßverletzbarkeit. Adipositas geht im Fettgewebe mit einer subklinischen chronischen Entzündung einher, die zu einer erhöhten Sekretion von proinflammatorischen Adipokinen führt. Die verstärkte Anwesenheit dieser Proteine ist mit den Komplikationen der Adipositas assoziiert. Die vorliegende Arbeit be- fasst sich mit dem Einfluss von Interleukin (IL)-1β, einem wichtigen Entzündungsmediator des Organismus, auf die Sekretion der proinflammatorischen Adipokine tissue inhibitor of metalloproteinase (TIMP)-1, serum amyloid A (SAA)-3, Lipocalin-2 und Chemerin. Die zugrundeliegenden Untersuchungen wurden mit 3T3-L1- und braunen Adipozyten durch- geführt. Es erfolgte der Nachweis auf mRNA- sowie auf Proteinebene. Der Einsatz von spe- zifischen Inhibitoren erlaubte den Rückschluss auf grundlegende Signalwege. Für alle vier untersuchten Adipokine konnte eine signifikante dosis- und zeitabhängige Steige- rung der mRNA- und Proteinexpression durch IL-1β nachgewiesen werden. Die Transduktion des IL-1β-Signals erfolgte im Falle von Lipocalin-2 und SAA-3 über nuclear factor (NF)-κB und janus kinase (Jak)-2, bei TIMP-1 lediglich über Jak-2 und in Bezug auf Chemerin über NFκB, Jak-2, p44/42 mitogen-activated protein kinase und Phosphatidylinositol-3-Kinase. Die in dieser Arbeit nachgewiesenen Expressions- und Sekretionssteigerungen von TIMP-1, SAA-3, Lipocalin-2 und Chemerin in braunen und weißen Adipozyten festigen IL-1β als einen entscheidenden Mediator proinflammatorischer Prozesse im Fettgewebe. Eine umfassende Bewertung der Funktion von IL-1β im Fettgewebe, insbesondere im Zustand der Adipositas, muss jedoch in weitergehenden Studien erfolgen.

Matrix remodeling could be an important mode of action of multipotent mesenchymal stromal cells (MSC) in extracellular matrix (ECM) disease, but knowledge is limited in this respect. As MSC are well-known to adapt their behavior to their environment, we aimed to investigate if their mode of action would change in response to healthy versus pathologically altered ECM. Human MSC-derived ECM was produced under different culture conditions, including standard culture, culture on Matrigel-coated dishes, and stimulation with the pro-fibrotic transforming growth factor-1 (TGF1). The MSC-ECM was decellularized, characterized by histochemistry, and used as MSC culture substrate reflecting different ECM conditions. MSC were cultured on the different ECM substrates or in control conditions for 2 days. Culture on ECM increased the presence of surface molecules with ECM receptor function in the MSC, demonstrating an interaction between MSC and ECM. In MSC cultured on Matrigel-ECM and TGF1-ECM, which displayed a fibrosis-like morphology, gene expression of collagens and decorin, as well as total matrix metalloproteinase (MMP) activity in the supernatant were decreased as compared with control conditions. These results demonstrated that MSC adapt to their ECM environment, which may include pathological adaptations that could compromise therapeutic efficacy.

Die invasiven und metastatischen Eigenschaften vieler Tumore werden mit einer Veränderung im physiologischen Gleichgewicht der Matrix Metalloproteinasen (MMP) und ihrer spezifischen und unspezifischen Inhibitoren in Zusammenhang gebracht. Das Ziel dieser Dissertation war es, die Wirkung von Batimastat, einem synthetischen Inhibitor der MMP, auf hormonabhängige und hormonunabhängige Prostatakarzinomzellinien sowie auf das Tumorwachstum im orthotopen Tumormodell des Dunning Tumor (R3327) zu untersuchen. Methoden: Im Zellkulturversuch wurde die Wirkung verschiedener Konzentrationen von Batimastat untersucht und die Proliferation mit dem MTT Test gemessen. Die Induktion des orthotopen Tumors erfolgte durch Inokulation von MATLyLu Zellen in die Rattenprostata (Dunning Tumor der Copenhagen Ratte). 10 Tiere wurden nach Tumorinduktion täglich mit 30 mg/kg Batimastat durch intraperitoneale Gabe behandelt, 10 weitere Ratten erhielten nur das Vehikel. Zehn Kontrolltiere blieben unbehandelt. Der Effekt auf des lokale Tumorwachstum wurden durch Bestimmung des Tumorgewichtes nach 20 Tagen definiert. Results:Batimastat zeigte eine dosisabhänige Hemmung des Wachstums der Prostatakarzinomzellinien in vitro. Bei 4000 ng/ml kam es zu einer eindeutigen Hemmung des Zellwachstums. Im Tierversuch fand sich nach 20 Tagen in der Kontrollgruppe ein mittleres Tumorgewicht von 18.9 ± 5,4 g, in der Vehikelgruppe von 22.3 ± 4,3 g und in der mit Batimastat behandelten Gruppe von 11.1 ± 2,6 g. Im Vergleich zur Kontroll- und Vehikelgruppe, zeigte sich in der Batimastatgruppe ein signifikant geringeres Tumorgewicht. Zusammenfassung: Batimastat kann das Tumorwachstum in einem Standardtiermodell des Prostatakarzinoms vermindern. Der Dunning Tumor der Copenhagen Ratte ist ein zuverlässiges Tiermodell zur weiteren Untersuchung von synthetischen Inhibitoren der MMP. / Background: Increased concentrations of metalloproteinases are associated with the invasive and metastatic behavior of several human malignant tumors. Normally, enzymatic activity is tightly regulated by nonspecific mechanisms and specific inhibitors. The aim of this dissertation was to determine the potential of a synthetic metallproteinase inhibitor, batimastat, to show its in vitro effect on hormonedependent and hormoneindependent prostate cancer cell lines and its in vivo effect on tumor growth in orthotopic cancer (R3327 Dunning tumor) in rats. Methods: In vitro, a dose response curve of batimastat was generated over 5 days using the MTT assay. Prostate cancer was injected in vivo in male Copenhagen rats by inoculating R3327 Dunning tumor cells (MATLyLu) into the ventral prostatic lobe of 30 rats. Each of 10 rats received batimastat (30 mg / kg / body weight) or vehicle once a day by i.p. application beginning the day of cell inoculation. Ten rats remained untreated. The effect on local tumor growth was evaluated by measuring tumor weights 20 days after tumor cell inoculation. Results: Significant inhibiton of tumor cell proliferation in vitro occurred at 4000 ng / ml batimastat. After orthotopic cell inoculation, tumors grew to mean weights of 18.9 ± 5,4 g in the control group without treatment, to 22.3 ± 4,3 g in the vehicle group, an to 11.1 ± 2,6 g in the treated group. In comparison to the control group and to the vehicle group, tumor weights increased significantly less under treatment with batimastat. Conclusions: Batimastat is able to reduce tumor growth in the standard prostate cancer model. Using this model, activity against cancer progression of future inhibitory agents can be reliably assessed.

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