Tez özetleri Astronomi ve Uzay Bilimleri Anabilim Dalı 2

The Effects of Tyrosıne Kınase Inhıbıtors on Myofıbroblast Actıvatıon ın Mıce Lung wıth Fıbrosıs: Therapeutıc Approach
Pulmonary fibrosis (PF) is characterized by an increase in number of fibroblasts/myofibroblasts and excessive accumulation of extracellular matrix components. The precise effective therapeutic agent for this disease has not been discovered yet. Cytokines and growth factors lead to PF, by inducing the proliferation of fibroblasts/myofibroblasts and excessive synthesis of extracellular matrix via tyrosine kinase receptors. Dasatinib, tyrosine kinase inhibitor, is used in cancer treatments due to its anti-angiogenic and anti-proliferative properties. It is known that the release of angiogenic and proliferative agents from injured lung have resulted in PF. In this study, the effects of dasatinib on the myofibroblast activation and the synthesis of collagen-I, as well as mutual relationship between these effects and PI3K/Akt and/or MAPK/ERK signalling pathways in mice with bleomycin- induced PF were investigated for the first time.
In the study, PF was induced by intratracheal bleomycin (0.08 mg/kg) instillation into mice lung. Adult mice were divided 4 groups: mice dissected on the 21^st days after the first bleomycin injection (I) and their controls (II), mice treated with dasatinib (8 mg/kg) for one week following 14 days after the first bleomycin injection and dissected on the 21^st days of experiment (III) and their controls (IV). Fibrosis score, fibroblast proliferation and myofibroblast differentiation in the lung were determined using microscopic techniques, while the expression of collagen-I, PTEN (phosphatase and tensin homologue deleted on the 10^th chromosome), Abelson kinase (c-Abl) and molecules which play a role in PI3K/Akt ve MAPK/ERK signaling pathways were analyzed by Western blotting.
Bleomycin treatments resulted in the formation of numerous fibrotic areas (avarage fibrosis score: 5), increase in the fibroblast proliferation and alpha-smooth muscle actin expressions in these areas, bleomycin-induced expressions of collagen-I, phospho-platelet derivated growth factor receptor-alpha (PDGFR-α), -ERK, -Akt and –c-Abl proteins in the fibrotic lung, whereas it downregulated the PTEN expressions in mice lung. Dasatinib treatments significantly attenuated these microscopic and biochemical alterations and upregulation of PTEN (inhibitor protein of PI3K/Akt and MAPK/ERK signalling pathways) expressions in mice lung with bleomycin-induced fibrosis. Thus fibrotic areas decreased and the fibrosis score decreased from 5 to 3. Dasatinib treatments limited the effects of PI3K/Akt and MAPK/ERK signaling pathways on fibroblast proliferation, fibroblast/myofibroblast differentiation and collagen-I synthesis, via the PDGFR-α and cytoplasmic c-Abl inhibition and the overexpression of PTEN protein in PF. The current study showed that dasatinib can be used as a novel tyrosine kinase inhibitor with anti-fibrotic effects for the regression of PF.

  

ÖVET Hale

Danışman : Doç. Dr. Füsun ÖZTAY

Anabilim Dalı : Biyoloji

Programı : Zooloji

Mezuniyet Yılı : 2014

Tez Savunma Jürisi : Doç. Dr. Füsun ÖZTAY

Prof. Dr. Şehnaz BOLKENT

Prof. Dr. Gül ÖNGEN

Prof.Dr. Refiye YANARDAĞ

Doç. Dr. Selda GEZGİNCİ OKTAYOĞLU