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.

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Jenkins RG et al. (2017). An Official American Thoracic Society Workshop Report: Use of Animal Models for the Preclinical Assessment of Potential Therapies for Pulmonary Fibrosis. American Journal of Respiratory Cell and Molecular Biology 56(5):667-79. doi: 10.1165/rcmb.2017-0096st

John AE et al. (2017). Methods for the Assessment of Active Transforming Growth Factor-β in Cells and Tissues. In: Rittié L. (eds) Fibrosis. Methods in Molecular Biology, vol 1627. Humana Press, New York, NY doi: 10.1007/978-1-4939-7113-8_23

Habgood AN et al. (2016). Secretory leukocyte protease inhibitor gene deletion alters bleomycin-induced lung injury, but not development of pulmonary fibrosis. Laboratory Investigation 96(6):623-31. doi: 10.1038/labinvest.2016.40

John AE et al. (2016). Loss of epithelial Gq and G11 signaling inhibits TGFβ production but promotes IL-33-mediated macrophage polarization and emphysema. Science Signaling 9(451):ra104. doi: 10.1126/scisignal.aad5568

Lilburn DM et al. (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

Tatler AL et al. (2016). Amplification of TGFβ Induced ITGB6 Gene Transcription May Promote Pulmonary Fibrosis. PloS One 11(8):e0158047. doi: 10.1371/journal.pone.0158047

Tatler AL et al. (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

Tatler AL et al. (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

Porte J and 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

Status

Closed

Principal investigator

Dr Gisli Jenkins

Institution

University of Nottingham

Co-Investigator

Professor Ian Hall
Dr Simon Johnson
Dr Robin John McAnulty
Professor Thomas Meersmann

Grant reference number

G1100564/1

Award date

Nov 2011 - Feb 2015

Grant amount

£443,881