How does the natural chemical succinate affect lung health in people with CF

A Development Award exploring a novel role for succinate chemosensing in the pathogenesis of CF airway disease.

Summary

Treatments to improve lung health are still required for everyone living with CF. CFTR modulator medicines have been transformative for many people with CF but not everyone can benefit from them. In addition, improvements in lung function are seen for those on modulators, but they still experience ongoing infections and lung inflammation, which may lead to permanent lung damage. We know that improved treatment is a research priority for the CF community.

Scientists have recently shown that a natural chemical called succinate is linked to increasing the activity of the CF protein (CFTR) in the lungs. In this research study Dr Mike Gray and colleagues will investigate in detail: how succinate activates the CF protein, which specialised cells within the lungs this takes place in, and whether the role of succinate in the lungs changes over time. Understanding more about the activity of succinate in the lungs of people with CF could lead to new treatments for CF in the future, to improve lung health and reduce lung damage.

Below we explain more about the background to this research and the aims of this research project.

What does succinate do in the lungs?

Succinate acts as a first line of defence against infections in the lungs. It does this by triggering a sequence of events that leads to increased clearance of bugs trapped in the mucus from the lungs. The CF protein is a key part of this process and when the CF protein is faulty mucus clearance is reduced, which leads to infections.

Dr Gray and colleagues have also shown that succinate does not increase mucus clearance in CF lung cells, and that this is restored when CFTR modulators are added to the cells. 

However, there seems to be a tipping point where the actions of succinate shift from being protective to harmful, possibly when succinate is present in the lungs for a long time. 

In this Trust-funded research project the researchers will be investigating the role of succinate in more detail, both to understand its links with improving lung health and its possible harmful effects too.

  • Aim 1 What happens in detail when succinate activates the CF protein?

    So far, scientists know that succinate increases the activity of the CF protein, but they don’t know exactly how this happens. It is likely that there are a number of different steps involved. It’s important to understand these steps to understand more about CF, and work out how to use this information to develop new treatments in the future.

  • Aim 2 Which cells in the lining of the lungs are involved?

    There are different types of cells lining the lungs, and each has a different job to do in keeping the lungs healthy. As well as understanding the sequence of events that leads from succinate to the activation of the CF protein, researchers want to know where -which cell – the action takes place in. They will do different types of study to find this out.

  • Aim 3 What happens to airway cells after long term exposure to succinate?

    When succinate is present in the lining of the lungs for a short time it is beneficial. However, if it is present for a longer time, researchers believe it may become harmful. Understanding how these harmful effects are caused means that it might be possible to prevent them happening in the future.

    To understand this in more detail the researchers will look at how the lungs respond to the long-term presence of succinate and in particular, whether this leads to inflammation. They will also investigate what happens when the activities of succinate are blocked.

  • Aim 4 Does long-term succinate exposure contribute to lung damage?

    Researchers know some of the biological changes that lead to lung damage but more research is needed to understand these in detail. In the last aim of this research proposal, Dr Gray and colleagues will study whether long term exposure to succinate contributes to a specific type of lung damage called fibrosis, by looking at changes to specific types of lung cell. They will look at these changes in lung cells affected by CF and also in lung cells unaffected by CF.

Who is involved?

Principal investigator: Dr Mike Gray, University of Newcastle 

Co-investigators:

Professor Chris Ward, University of Newcastle 

Dr Iram Haq, University of Newcastle

Dr Carlos Flores, University of San Sebastien and Centre of Scientific Study, Valdivia, Chile