The role of sphingosine kinases in pulmonary fibrosis

Pulmonary Fibrosis is defined by the development of excessive connective tissue as a response to injury. One of the major mechanisms of fibroblast accumulation is epithelial-mesenchymal transition (EMT) and the Transforming Growth Factor-β1 (TGF-β1) is one of the growth factors that regulate this transition. Sphingosine kinases (SK) are promising new targets for pulmonary fibrosis as they regulate the balance between the proapototic ceramides and prosurvival sphingosine 1-phosphate. Sphingosine kinase 1 has a profibrotic role whilst the role of sphingosine kinase 2 is not defined. The objective of this project was to establish the effect of a range of previously reported as well as new SK isoform selective inhibitors and substrates and to analyse their effects on the human alveolar epithelial type II cell line, A549. In this study, results showed that TGF-β1 induced EMT and apoptosis concurrently, most likely in sub-populations of cells at different points in the cell cycle. The EMT process is not affected by the SK inhibitors/substrates suggesting that SK1 and SK2 are not involved in EMT, although there is some effect on apoptosis. Furthermore, results also indicate that SK2 inhibitors block extracellular regulated kinase (P-ERK) signalling, suggesting that ERK 1 and 2 are involved in SK2 mediated signalling at high concentrations of TGF-β1, although the functional consequence requires further study.

Name dc:type.qualificationname

mres

Level dc:type.qualificationlevel

masters-pg

Grantor dc:publisher.institution

University of Strathclyde

Year dc:date.issued

2015

Author dc:creator

• Gauci, Lara Anne

DOI

10.48730/zy3c-8a74

Identifier

T13980

OAI identifier oai:identifier

oai:strathclyde:m613mx58n