Multi-modal Discovery of Mechanistic Drivers of Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive lung condition characterised by scarring (fibrosis) of the lungs. This scarring deforms the lungs and reduces the ability of the lungs to take in oxygen, which causes a person to feel breathless and cough. It is not clear why some people develop IPF, but people with IPF often progress quickly to death and there is no cure. Each year 6000 people in the UK die of IPF, more than deaths from most cancers, and more than ovarian, cervical and thyroid cancers combined. This makes IPF an important disease to research.

It is currently thought that genetic changes in the cells that line the lung (epithelial cells) make them susceptible to injury and scar formation, although, how these genetic changes promote scarring remains unknown. The main feature of lung scarring is that the lungs become small and stiff due to the abnormally high activity of cells that make scar tissue.

It is known that genetic changes in cells that line the small airways lead to the production of increased mucous which we believe makes the cells that line the airsacs (alveoli) stiffer and unable to respond to injury in a normal way. When the lung is damaged the injured cells die and need to be replaced by new cells that originated from a special type of airsac cell called (an alveolar type 2 cell) however in scarred lung these cells begin to change to the lining cells but get stuck in a transitional state that is neither a specialised nor lining cell which we believe is related to the build up of mucous and increased stiffness of the lung.

Research has shown that when lung cells grow in stiff surroundings, such as that within a scarred lung, they become even more active and produce more scar tissue. However, how mechanical forces affect cells with genetic changes found in IPF, or how the genetic changes affect the signals the that epithelial cells send and the fate that injured epithelial cells undergo remains unknown. Importantly it is possible to change the cell fate through adapting the mechanical forces within the lung is not currently known.

This programme of work will use a number of distinct but complementary scientific techniques including genetics, cell and molecular biology, bioinformatics, bioengineering and biophysics to understand these interactions and determine whether we can alter the fate of lung cells and reprogram them by changing the mechanical environment they exist.
This study will bring world leading scientist from a wide range of disciplines to try and find new insights to alleviate the suffering from this devastating disease. The programme will focus on a key cellular process which could link the known genetic, molecular, cellular and mechanical faults that are associated with IPF. The aim of this project is to understand 1) whether a process called cellular extrusion by which abnormal, or excess cells are squeezed out of cell layers occurs in the small airsacs of the lung 2) understand how this process is altered in scarred lung and whether it can be changed to promote lung healing 3) understand the environment in which the cells live can affect how they behave 4) use artificial intelligence and deep learning algorithms to both learn from and inform our experiment in aims 1 to 3.

Idiopathic Pulmonary Fibrosis (IPF) is a severe, progressive, fatal disease with no cure. The current pathogenic paradigm proposes dysregulated epithelial repair following micro-injury in genetically susceptible individuals leading perpetual, abnormal, stiffened, extracellular matrix production. Loss of normal alveolar architecture is accompanied by replacement of epithelial alveolar type 1 (AT1) and type 2 (AT2) cells with an accumulation of atypical transitional 'fibrotic' epithelial cells. Cellular extrusion is a key regulator of cell fate and epithelial barrier integrity, but it role in alveolar homeostasis or IPF pathogenesis is unknown. Strikingly, multiple signals regulating the extrusion pathway are abnormal in IPF, yet how dysregulated extrusion might impact IPF has not been explored.

We propose the novel hypothesis that damage to genetically-primed alveolar cells leads to failed extrusion and a feed-forward cycle of increasing matrix deposition and stiffness, exacerbating defective extrusion instead of regenerative turnover.

This hypothesis will be tested through co-creation of a human tissue-based platform exploiting human precision cut lung slices, novel lung organoids derived from patients with and without IPF combined with synthetic extracellular matrices to address three specific aims:

1) Define the role of alveolar epithelial cell extrusion in normal and fibrotic human lung.

2) Explore the effects of matrix composition on alveolar epithelial extrusion.

3) Integrate multidimensional data from Idiopathic Pulmonary Fibrosis patients to inform mechanistic studies and promote clinical translation.

Our approach will develop novel ways to model, and measure, lung fibrosis and scales from reductionist biology to big data analytics. It brings together world-leading expertise in IPF pathobiology, engineering, medical physics, optical imaging and cell biology to maximise discoveries that will translate into clinical practice.