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The influence of Rolipram on cigarette smoke exposed lung organoid formation via the cAMP pathway

Verkleij, Lars (2018) The influence of Rolipram on cigarette smoke exposed lung organoid formation via the cAMP pathway. Research Project, Pharmacy.

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[Background] Using the stemness of epithelial progenitor cells to treat chronic obstructive pulmonary disease (COPD) is one of the novel approaches in recent research. COPD, a leading cause of death worldwide, is a progressive chronic disease and is mainly induced by cigarette smoke that damages the gas exchange units in the lung called alveoli. Breakdown of the alveoli can lead to emphysema, one of the main characteristics of COPD. The effect of cigarette smoke on the lung is well known but available therapies are insufficient, hence research for new therapies is vital. The lung organoid model derived from epithelial cells, which is a novel method to study emphysema. This method is based on the capacity of the progenitor epithelial cells via self-renewal and producing differentiated structural cells. One of the targets for cigarette smoke damaged repair in the lung is the cAMP-pathway. Increased levels of cAMP could result in increased proliferation and differentiation in the cell. Therefore, inhibition of phosphodiesterase-4 (PDE4), a protein involved in the breakdown of cAMP, was selected as target to increase the cAMP levels. [Aim] Thus, the hypothesis of this study is that cigarette smoke impacts the lung organoid formation. Additionally, this study hypothesized that Rolipram could reduce cigarette smoke induced lung organoid damage by targeting the cAMP pathway. [Methods] The lung organoids were established by co-culturing epithelial cells (EpCAM+)/CD31-/CD45-) and fibroblasts (CCL206) within matrigel. In addition, the lung organoids were treated with different concentration of cigarette smoke extract (C.S.E.).[Results] The number of organoids cultured after 7 days was significant decreased by 5% C.S.E. (p<0.0001). The 5% C.S.E. significantly decreased the number of the airway/alveolar type organoids visible on day 14 (p<0.0001). Additionally, a significant reduction in size of the alveolar organoids was found by 5% C.S.E. (p<0.01). Next, an addition of 10 µM Rolipram during 14 days of lung organoid formation with 5% C.S.E. revealed an increasing trend of alveolar organoid formation compared with the corresponding control group. [Conclusion] The main outcome of this experiment is the optimal percentage of 5% C.S.E. for this lung organoid co-cultured model. Finally, the cAMP pathway revealed to be potential target for lung organoid cigarette smoke damage repair by Rolipram’s inhibition of phosphodiesterase-4.

Item Type: Thesis (Research Project)
Supervisor name: Wu, X. and Gosens, R.
Degree programme: Pharmacy
Thesis type: Research Project
Language: English
Date Deposited: 24 Jul 2018
Last Modified: 24 Jul 2018 13:31

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