Refining models of fibrotic lung disease

Lead Research Organisation: University of Nottingham
Department Name: School of Life Sciences

Abstract

Idiopathic pulmonary fibrosis (IPF) is a disease where the fine, delicate structure of the lungs is replaced by a hard, concrete-like substance called fibrous matrix. This prevents the normal functions of the lung, such as the transfer of oxygen from the air to the body, as well as an irritating persistent cough. At the current time there are no treatments that can improve the outlook for people with IPF. There are, however, many potential new therapies that might have a beneficial effect on this terrible disease. Predicting which potential therapy might work requires careful testing, because it is not possible to test all the alternatives in people with disease. The aim of this study is to develop a way to predict which new therapies might work in people with IPF. This information will ensure the most promising therapies can be assessed in clinical trials for IPF, which will be crucial in the development of new treatments so urgently needed for this condition.

Technical Summary

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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