The extracellular matrix protein fibulin-1 in idiopathic pulmonary fibrosis

Abstract

One of the most pressing issues in the clinical management of patients with idiopathic pulmonary fibrosis (IPF) is how a clinician can respond when asked “how long do I have?” IPF has a varied clinical course and the only available treatments, aside from lung transplantation, are corticosteroids and immunosuppressants. The side effects of both corticosteroids and immunosuppressants may actually outweigh the benefits for use in IPF. Biomarkers of disease progression are often unable to predict acute lung function decline. This is possibly because the underlying mechanisms driving the disease are poorly understood and little attention has been paid to how intrinsic differences in resident lung fibroblasts may be contributing to this disease. In this thesis, extracellular matrix (ECM) molecules that are both found in the blood and released by resident lung fibroblasts were investigated for their utility as biomarkers of disease progression in IPF. The primary focus was on the ECM protein fibulin-1, an essential constituent of elastic fibres, which has not previously been studied in the context of interstitial lung disease. This thesis investigated the relationship between fibulin-1, and disease severity in patients with and without pulmonary fibrosis. In addition, the utility of fibulin-1 as a biomarker of disease progression was compared against other previously described components of the ECM, namely periostin, tenascin-C and fibronectin, in the same patients. Lastly, the effect of the profibrotic cytokine transforming growth factor-beta-1 (TGFβ1) on fibulin-1 levels in resident lung fibroblasts from patients with and without IPF was interrogated.