Unit:
Library of the School of Health SciencesFaculty of MedicineΤομέας Χειρουργικής
Author:
Paronis Efthymios
Dissertation committee:
Ανδρέας Λάζαρης, Αναπληρωτής Καθηγητής, Ιατρική, ΕΚΠΑ
Ιωάννης Κακίσης, Καθηγητής, Ιατρική, ΕΚΠΑ
Γεώργιος Γερουλάκος, Καθηγητής, Ιατρική, ΕΚΠΑ
Πηνελόπη Μπουζιώτη, Ερευνήτρια Α, Εργαστήριο Ραδιοχημικών μελετών, ΕΚΕΦΕ ΔΗΜΟΚΡΙΤΟΣ
Ουρανία Τσιτσιλώνη Καθηγήτρια, Βιολογία, ΕΚΠΑ
Δημήτριος Θάνος Ερευνητής Α, Κέντρο βασικής και μεταμεταφραστικής έρευνας, ΙΙΒΕΑΑ
Σπυρίδων Βασδέκης, Καθηγητής, Ιατρική, ΕΚΠΑ
Original Title:
Μελέτη της θεραπευτικής επίδρασης της σιλοσταζόλης στη φλεγμονώδη απόκριση και την εξέλιξη της ισχαιμίας άκρου σε μύες
Translated title:
The effect of Cilostazol in the immune responses and inflammation during the acute phase of hind limb ischemia in a mouse model
Summary:
Introduction: Angiogenesis is a physiological process involving the growth of new blood vessels from pre-existing vessels, with macrophages, and T cells playing an important role in the development of this phenomenon. These cells are also affected by various drugs administered for the treatment of diseases related to the pathological obstruction of blood vessels which, initially target molecules, like the phosphodiesterase inhibitor family.
Cilostazol is a selective inhibitor of phosphodiesterase 3A (PDE-3Α), with proven effectiveness in the treatment of intermittent claudication (IC), increasing the distance walked by patients with IC. The drug acts on platelets, vascular smooth muscle cells and endothelial cells by increasing the levels cyclic adenosine monophosphate (cAMP) via the concomitant intracellular PDE-3A inhibition and extracellular adenosine uptake.
Using a Peripheral Arterial Disease (PAD) mouse model, the purpose of this study was to investigate the revascularization of ischemic muscles after the induction of surgical hind limb ischemia, as well as the interactions between cilostazol and innate immunity cells, and the effects of the drug on the profile of cytokines produced.
Methods: A total of 108 NOD.CB17-Prkdcscid/J and 108 CB17 male mice were used. All animals underwent hind limb ischemia. At the day of surgery (D0), 60 mg/kg of cilostazol were administered to all animals which continued receiving a daily dosage of 30 mg/kg for the next 7 postoperative days. Vehicle was administered daily in the control groups. Serum concentrations of IL-2, IL-4, IL-6, IL-10, IL-17A, TNF and IFN-gamma were measured by flow cytometry on post-surgery days D1, D3, D5, and D7. On D7 Post-mortem Analysis was performed after the administration of 68Ga-RGD. The gastrocnemius muscle was obtained for histological evaluation.
Key findings: There was a statistically significant augmentation (p < 0.05) in the concentrations of IL-4, IL-10, IL-6 and IFN-g in cilostazol treated wild type animals while IL-2 was significantly suppressed. In treated immunodeficient animals, TNF, IL-6 and IFN-g presented significant augmentation while the uptake of 68Ga-NODAGA-RGDfK was found significantly lower for both legs in comparison with the control group. No significant difference in the uptake of 68Ga-NODAGA-RGDfK was found in wild type animals.
Significance: Cilostazol seems to significantly influence immunity cells in cytokine production altering the type of immunity response by promoting the production of anti-inflammatory cytokines in wild type animals while it helps toward the improvement of immunity response in immunodeficient animals.
Conclusions: In conclusion, cilostazol seems to significantly impact on immune cells, mainly affecting cytokine production, thus altering the type of immune response; cilostazol seems to promote the production of anti-inflammatory cytokines and the suppression of IL-2 in wild-type animals, while it helps towards the improvement of immune responses in immunodeficient animals by increasing the secretion of proinflammatory cytokines and IFN-γ, an indication that needs to be further investigated. Regarding the effects of cilostazol on angiogenesis, our results indicate reduced expression of αvβ3 integrin and CD31 receptor in immunodeficient mice, while cilostazol seems to significantly increase angiogenesis in wild type animals during the first post operational week.
Main subject category:
Health Sciences
Keywords:
Angiogenesis, Cilostazol, Cytokine profile, Mouse model, Peripheral ischemia
Number of references:
248
