Research blast on... the ABC of the CF lung

Feature -

The build-up of thick, sticky mucus and difficulty in clearing away infections in the lungs are some of the detrimental symptoms of cystic fibrosis (CF). Understanding what’s going wrong in the lung and causing these symptoms may give us clues about how best to treat them. This was the topic of our early Strategic Research Centre (SRC) on innovative alternatives to CFTR (INOVCF) led by Dr Mike Gray at the University of Newcastle. Here we look down the microscope into the lining of the lungs to give you an update on their results.

A is for acidity

Getting the acid-alkali balance right in the lungs is vital for keeping the mucus thin and clearing away infections. There are two types of proteins in lung cells that control this acid-alkali balance. These proteins act as gates allowing through chemicals that make the surface of the cells either more acidic or more alkali. One of the ‘alkali-producing gates’ is CFTR, the protein that is either absent or doesn’t work properly in cystic fibrosis. The ‘acid-producing gates,’ collectively known as proton pumps, continue to work in CF, but with no counter-balance from the alkali-producing CFTR protein the lung environment is too acidic.

Dr Vinciane Saint-Criq, who worked on the INOVCF SRC at the University of Newcastle, investigated whether existing ‘proton pump inhibitor’ drugs used for correcting stomach acid, could be an effective way of correcting the acid-alkali balance in the lungs. This is the first time such an approach has been tested, and although it’s early days, Dr Saint-Criq’s research has shown that it works in the lab. This is also a treatment that could work for everyone with CF, irrespective of their genotype.

B is for bacteria

Above the cells that line the surface of our lungs is a liquid layer called the ‘airway surface liquid’ or ASL (part of this is the mucus we cough up). The role of the ASL is to trap any unwanted things we inhale, for example particulates in the air and bacteria, and to clear the debris out of our lungs. Within the ASL there are over 100 proteins. Some of these help to keep it sticky and give it the right properties to be swept away, and others are involved in killing bacteria or reducing their activity.

In CF, the ASL becomes dehydrated and too sticky, and it also loses some of its anti-bacterial properties. This means that mucus can’t be cleared out of the lungs and bacteria stay in the lungs and grow, ultimately causing lung damage.

Professor Rob Tarran and Dr Saira Ahmad based at the University of North Carolina at Chapel Hill in the USA, who are working on the INOVCF SRC, have been looking at the role of a specific protein found in the ASL called SPLUNC1. They have shown that it doesn’t work properly in CF and are now investigating whether it can be rescued, restoring some of the properties of the ASL back to normal. They’ve recently shown that SPLUNC1 loses its antibacterial properties in the acidic environment of the CF lung. By adapting the protein in the lab it can be made ‘acid-resistant’ and its antibacterial properties can be protected. This offers another potential area to develop new drugs to treat cystic fibrosis.

C is for chloride

One of the roles for the CFTR protein is to move chloride from the inside of the lung cells to the ASL on the outside of the cells. In CF, the movement of chloride is blocked by the faulty CFTR protein or the lack of CFTR protein altogether. It is important to have chloride in the ASL as this helps to keep it hydrated, and allows the mucus to be sticky enough to trap the bacteria and hold its shape, but thin enough that it doesn’t stick to the epithelial cells and not move at all.

As well as the CFTR protein, there are other proteins within the lung cells that allow the movement of chloride into the ASL, helping to keep it hydrated. Another area of the INOVCF SRC was to investigate whether increasing the activity of a protein called ANO1 (also known as TMEM16A) could be an effective way to treat CF, by increasing the movement of chloride into the ASL. If this works, it would be a treatment for everyone with CF, irrespective of their genotype. Dr Mike Gray and colleagues at the Universities of Newcastle, Lisbon and Regensburg have begun a new SRC programme to investigate this in more detail last year.

Find out more about Dr Gray's Restoring airway function SRC or donate today to help support ground-breaking research like this.

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