Refining models of fibrotic lung disease

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic lung disease of unknown aetiology with a median survival of less than 3 years and no proven, effective therapy. Furthermore, there has been a progressive increase in the incidence of IPF since the early 1980s. A major bottleneck in IPF research is the absence of a pre-clinical model that accurately predicts the response to treatment in IPF.

Current models have been effective in understanding various mechanisms involved in IPF pathogenesis, but the data have been poorly translatable into the clinical domain. The aim of these studies is to develop translation pre-clinical models of IPF whilst refining, reducing and eventually replacing the use of existing animal models of disease. We will achieve this by 1) refining our current rodent lung slice model so that it can model lung fibrosis, 2) optimise imaging modalities that are clinically translatable and non-terminal thus reducing the numbers of animals required and 3) develop a human lung slice model of fibrosis such that the rodent model may eventually be replaced completely. Specifically we will harvest lung tissue slices and injure them ex-vivo, as well as injuring the lungs of rodents in vivo prior to harvesting slices to perform ex vivo experiments. Having developed the lung slice model of fibrosis ex vivo we will cross validate the data with conventional models of fibrosis, and optimise functional MRI technology to permit non-terminal imaging and lung-function measurements.

These studies will also generate more translatable outcome measures than conventional histological and biochemical measures of pulmonary fibrosis. Finally, in collaboration with the Manchester Lung Transplant Centre we will develop a human lung slice model of fibrosis analogous to the rodent slice model. These studies will facilitate improved translation of pre-clinical studies as well as reducing the number of animals required in these studies.

Tatler AL, Habgood A, Porte J, John AE, Stavrou A, Hodge E, Kerama-Likoko C, Violette SM, Weinreb PH, Knox AJ, Laurent G, Parfrey H, Wolters PJ, Wallace W, Alberti S, Nordheim A, Jenkins G (2016). Reduced Ets domain-containing protein Elk1 promotes pulmonary fibrosis via increased Integrin αvβ6 expression. J Biol Chem. 291(18): 9540-53 doi: 10.1074/jbc.M115.692368

Tatler AL, Barnes J, Habgood A, Goodwin A, McAnulty RJ, Jenkins G (2016). Caffeine inhibits TGFβ activation in epithelial cells, interrupts fibroblast responses to TGFβ, and reduces established fibrosis in ex vivo precision-cut lung slices. Thorax (6): 565-7 doi: 10.1136/thoraxjnl-2015-208215

Lilburn DM, Tatler AL, Six JS, Lesbats C, Habgood A, Porte J, Hughes-Riley T, Shaw DE, Jenkins G, Meersmann T (2016). Investigating lung responses with functional hyperpolarized xenon-129 MRI in an ex vivo rat model of asthma. Magnetic Resonance in Medicine 76(4): 1224-35 doi: 10.1002/mrm.26003

Porte J, Jenkins G (2014). Assessment of the effect of potential antifibrotic compounds on total and αVβ6 integrin-mediated TGF-β activation. Pharmacol Res Perspect. 2(4): e00030 doi: 10.1002/prp2.30

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Project grant

Grant reference number

G1100564/1

Award date:

Nov 2011 - Feb 2015

Grant amount

£443,881