Understanding Idiopathic Pulmonary Fibrosis (IPF)

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Idiopathic pulmonary fibrosis, or IPF, is a serious lung disease that gets worse over time. It's called "idiopathic" because, at first, we didn't know what caused it, but now we know it's a complicated condition with both genetic and environmental factors playing a role.

What happens in IPF? In IPF, the lungs become scarred and damaged. This scarring, called fibrosis, makes it hard for the lungs to work properly. The lung tissue becomes thickened and stiff, making it difficult to breathe. The disease typically appears as patchy areas of fibrosis, often starting in the lower parts of the lungs. Sadly, people diagnosed with IPF often live only 3 to 5 years.

The Two-Hit theory: Scientists now think that IPF develops because of a "two-hit" process. The first hit makes the lung cells vulnerable, often because of a person’s genes. This means that they have a higher chance of developing the disease. The second hit is some kind of injury to the lung, like from pollution or smoking. This second hit triggers the lung cells to behave abnormally, which causes the fibrosis.

The role of genetics: Genetics play a significant role in making someone vulnerable to IPF. It's thought that at least 30% of IPF cases have a genetic cause. Several genes have been linked to IPF, and they affect important functions in the lungs. These include:

• Host defence: Genes like MUC5B, TOLLIP, and others are involved in protecting the lungs from harmful substances.
• Cell adhesion: Genes such as DSP, MDGA2 and others help cells stick together and maintain tissue structure.
• Telomere biology: Genes like TERC, TERT and others affect the structures called telomeres that protect the ends of chromosomes.
• Mitotic spindle assembly: Genes such as KIF15 and MAD1L1 are involved in cell division.
• Surfactant protein biology: Genes like SFTPC, SFTPA1 and others are important for lung function.
• GTPase activity regulation: Genes like FAM13A, NPRL3 are involved in cell signaling

One particular gene, MUC5B, is a major player. A change in the MUC5B gene promoter is the most common genetic risk factor for IPF, and accounts for about half of the genetic risk for the disease. This gene makes a protein called MUC5B that's important for lung protection. However, when it’s overproduced, it can disrupt the normal function of the lungs. The MUC5B protein is normally found in the airways, but in IPF patients, it’s often found in the wrong place in the lungs.

Importantly, many of these genetic changes don't automatically cause IPF. Instead, they make the lungs more vulnerable to damage. This vulnerability means that the person is more likely to develop IPF when exposed to other risk factors.

Environmental risk factors: Several environmental factors increase the risk of developing IPF. The main ones are:

• Ageing: The risk of IPF increases with age. Every year, the likelihood of having IPF goes up by about 6%.
• Smoking: Cigarette smoking increases the risk of IPF by 3 to 5 times.
• Pollution: Air pollution, such as that from wildfires, traffic, and dust, can also contribute. Things like metal dust, asbestos, and even farming and livestock are considered risk factors.

How does the damage happen? When the lungs are injured, the body tries to repair them. Special cells called progenitor cells help in this process. These cells can turn into different types of lung cells to fix the damage. However, in IPF, this repair process goes wrong. The cells don't heal properly and instead, contribute to the formation of scar tissue. There are also disruptions in how lung cells adhere to one another. There is also increased endoplasmic reticulum stress, and cell senescence (when cells stop dividing) that promote lung damage.

The role of MUC5B: The overproduction of MUC5B seems to cause problems in the lungs. This protein, when it is in the wrong place in the distal part of the lung, might interfere with how the lungs get rid of particles and how gases are exchanged. The cells that produce MUC5B must work very hard to make this protein. This can lead to stress in the cells, and can result in damage. This damage can then trigger inflammation and fibrosis.

Current treatments and future directions: Unfortunately, there's no cure for IPF yet. Current treatments, like nintedanib and pirfenidone, can only slow down the disease but they don't stop it completely, and they have side effects. So, researchers are working hard to find new treatments.

Some promising new approaches include:

• Targeting specific genes: Developing treatments that target specific genes such as MUC5B.
• Reducing cell senescence: Slowing down cell ageing with treatments that target DNA damage or by removing senescent cells.
• Blocking integrin molecules: Reducing the action of integrins, which are involved in inflammation and scar tissue formation.
• Gene editing: Using gene editing to correct the gene errors that cause the disease.
• Epigenetic approaches: Targeting the "epigenome", which are changes that affect gene expression, can help with conditions like IPF

By understanding the complex causes and mechanisms of IPF, we can develop more effective therapies. The goal is to move from just managing the disease to eventually finding a cure.

 

Additional information: Progressive lung fibrosis: reprogramming a genetically vulnerable bronchoalveolar epithelium. The Journal of clinical investigation (2025). https://doi.org/10.1172/JCI183836

Journal information: https://www.jci.org/