Can lung fibrosis be stopped?

Close to 70% of people living with systemic sclerosis (SSc) develop interstitial lung disease (ILD). ILD is an umbrella term for a range of conditions affecting the lungs, all of which affect the interstitium. This is the fluid-filled space comprised of connective tissues that extends throughout both lungs, and it provides support to the alveoli, tiny air sacs which function to exchange gases between the air in the lungs and the blood. The interstitium is such a thin network that it cannot be seen on chest X-rays or CT scans normally.

In some instances, however, the interstitium will become visible, due to the development of ILD leading to the thickening of this layer. This can be in the form of inflammation, scarring or fluid build-up, and can either be chronic or short-lived. The type of ILD that is most relevant for those with SSc is idiopathic pulmonary fibrosis (IPF), whereby there is progressive scarring of the interstitium. This is an often-fatal diagnosis, with a median survival time of 3-5 years. It is therefore critical that efforts continue to be focused into furthering understanding of why this fibrosis occurs and how it can be reduced or prevented, or potentially even cured.

Previous research has demonstrated that there are a range of molecules involved in fibrosis, which interact with eachother in a biological pathway. Of these molecules, two major drivers of lung fibrosis are TGF-β and reactive oxygen species (ROS). Fibrosis is triggered by cells called fibroblasts, which are found in every tissue in the body; the primary cell type responsible for fibrosis is a myofibroblast. Both TGF-β and ROS are necessary for the presence and action of myofibroblasts, and elevated levels of ROS and TGF-β are observed in people with SSc. Furthermore, studies following a similar line of questioning have indicated that limiting ROS production improves lung injury in mice. Also involved in this process are two proteins, NOX4 and SOD2; NOX4 is vital for the production of ROS and of myofibroblasts, but the specific role of SOD2 in pulmonary fibrosis is less well understood.

A research team based at Imperial College London hypothesized that another group of proteins called BET proteins are key factors of both ROS and myofibroblast production. These have recently emerged as a promising therapeutic target for cancer, obesity, inflammation and fibrosis. BET proteins can be inhibited by a molecule called JQ1, and this has been shown to reduce the action of myofibroblasts and have antifibrotic effects, but it is unclear how this occurs within IPF. The team therefore investigated if BET proteins are involved in the fibrotic pathway through myofibroblasts.

The collated data indicated that BET proteins are involved in this molecular mechanism regulating redox balance and myofibroblastic differentiation. The inhibition of BET proteins by JQ1 acts to decrease the level of ROS, thus limiting damage to DNA and the function of myofibroblasts. Further studies will be needed to confirm the role of BET proteins in the fibroblasts of people who have SSc and IPF, but the results for the time being are positive as BET protein inhibitors may in the future be suitable for use as therapeutic agents to treat pulmonary fibrosis.

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