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The Role and Function of Clusterin in Normal and Fibrotic Lung.

Peix, L; (2017) The Role and Function of Clusterin in Normal and Fibrotic Lung. Doctoral thesis , UCL (University College London).

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Abstract

Pulmonary fibrosis is a progressive scarring disorder of the lung with a dismal prognosis and no curative therapy. Clusterin, a multifunctional glycoprotein with extracellular chaperone activity and involved in regulating cell function, is reduced in bronchoalveolar lavage fluid of patients with pulmonary fibrosis. However, its distribution and role in normal and fibrotic lung are incompletely characterised. Immunohistochemical localisation of clusterin in human lung revealed strong staining associated with fibroblasts in control lung and morphologically normal areas of fibrotic lung but weak or undetectable staining in fibroblasts in fibrotic regions and particularly fibroblastic foci. Clusterin also co-localised with elastin in vessel walls and additionally with amorphous elastin deposits in fibrotic lung. Analysis of primary lung fibroblast isolates in vitro confirmed the down-regulation of clusterin expression in fibrotic compared with control lung fibroblasts and further demonstrated that TGF-β1 is capable of down-regulating fibroblast clusterin expression. shRNA-mediated down-regulation of clusterin did not affect TGF-β1-induced fibroblast-myofibroblast differentiation but inhibited fibroblast proliferative responses and sensitised to apoptosis. Together, these data demonstrate that clusterin promotes lung fibroblast proliferation and survival. Down-regulation of clusterin in fibrotic lung fibroblasts at least partly due to increased TGF-β1 may, therefore, represent an appropriate but insufficient response to limit fibroproliferation. Reduced expression of clusterin in the lung may also limit its extracellular chaperoning activity contributing to dysregulated deposition of extracellular matrix proteins. Alveolar macrophages express clusterin receptor LRP2, suggesting that these cells are responsive to altered clusterin in the lung. In vitro studies with human alveolar and blood-derived macrophages, demonstrate that exogenous clusterin induces the secretion of pro-inflammatory cytokines/chemokines, including TNFα, suggesting a clusterin-mediated polarisation towards an “M1-like” phenotype. Reduced levels of secretory clusterin in the fibrotic lung may, therefore, benefit polarisation towards “M2-like” macrophages, which produce pro-fibrotic mediators, including TGF-β1, resulting in further clusterin reduction and progression of pulmonary fibrosis.

Type: Thesis (Doctoral)
Title: The Role and Function of Clusterin in Normal and Fibrotic Lung.
Language: English
UCL classification: UCL > School of Life and Medical Sciences
UCL > School of Life and Medical Sciences > Faculty of Medical Sciences
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URI: http://discovery.ucl.ac.uk/id/eprint/1546574
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