Datta, A;
(2013)
The role of thymic stromal lymphopoietin in pulmonary fibrosis.
Doctoral thesis (PhD), UCL (University College London).
Preview |
Text
Datta_Thesis_ combined_sig_removed.pdf Download (9MB) | Preview |
Abstract
Thymic stromal lymphopoietin (TSLP) is an IL-7 like cytokine that has recently emerged as being critical in promoting T-2 mediated inflammatory responses in atopic disease via its unique activation of dendritic cells (DCs). However, its role in idiopathic pulmonary fibrosis (IPF), a non-allergen driven disease characterised by excessive fibroblast activation and a pro-fibrotic T-2 immune phenotype, is unknown. TSLP has traditionally been regarded as an epithelial-derived cytokine targeting cells of a haematopoietic lineage. However, the present work identifies fibroblasts as a potentially important source and cellular target in IPF. Primary human lung fibroblasts (pHLFs) express and release TSLP in a JNK/c-Jun dependent manner following exposure to TNF-α, a master cytokine strongly implicated in the pathogenesis of lung fibrosis. Moreover, this thesis demonstrates for the first time that lung fibroblasts express a functional TSLP-TSLPR signalling axis; following exposure to TSLP, these cells release the pro-fibrotic chemokine, CCL2, in a STAT3-dependent manner, thereby promoting chemotaxis of human monocytes. The work presented here further identifies TSLP as a key mediator of local DC activation and the generation of a T-2 immune phenotype in the bleomycin model of lung injury and fibrosis. However, neutralisation of TSLP activity in vivo did not attenuate bleomycin-induced fibrosis, suggesting that despite its essential role in DC activation and T-2 polarisation, TSLP may not play a significant role in the subsequent development of fibrosis in this model. Taken together, these studies extend our current understanding of TSLP as a master regulator of T-2 immune responses beyond that of allergic inflammatory conditions. The human expression and functional studies performed during the course of this PhD do not rule out a potential pathogenic role for TSLP in IPF. Extended studies are warranted to explore these observations further.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | PhD |
| Title: | The role of thymic stromal lymphopoietin in pulmonary fibrosis |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| UCL classification: | UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/1399221 |
Archive Staff Only
 |
View Item |
