IPF: Stubborn Scars in Stiff Lungs

Written and illustrated by: Fa Wang

Edited by: Jennifer Baker, Zechariah Pfaffenberger, Olivia Pifer Alge, & Madeline Barron

Imagine a healthy 50-year-old man had a dry cough that wouldn’t go away. His cough disrupted meetings, interviews, and even prevented him from getting sleep. He visited his doctor, who diagnosed him with a cold and sent him home with antibiotics. Not only did his cough persist, the man also started having an insidious shortness of breath with activity, and occasional severe chest pain. He went back to the doctor, who sent him home with more antibiotics. Months later, his symptoms still were not better, and he started having trouble walking up stairs because he felt like he couldn’t breathe. He went back to the doctor, time after time, for additional tests. After 18 months, he was finally diagnosed with idiopathic pulmonary fibrosis (IPF), a disease he had never heard of before. He was shocked to realize that he had only 3 to 5 years to live.

IPF is not cancer, but it sounds just as scary. Despite IPF’s often grave outcomes, many people have never heard of this disease. Let’s look at what IPF is, and what can be done about it.

What is idiopathic pulmonary fibrosis (IPF)?

IPF is a rare and fatal lung disease that causes scarring in the lungs. To understand what goes wrong in IPF lungs, we need to start with normal lung structure and function. The lung is a sponge-like organ sitting in our chest. It expands while we breathe in and shrinks down when we breathe out. The functional units of the lung are called alveoli, the air sacs at the tips of the lung’s branching windpipe. The alveoli are delicate and stretchy “bubbles” constructed from a single layer of epithelial cells. The epithelial cell layer is flat and thin and serves as a protective barrier in lungs. A thin layer of fibers created by cells called fibroblasts supports these delicate air sacs; this layer of fibers is called the matrix. The matrix also anchors blood vessels to the air sacs, which ensures sufficient gas exchange between the air sacs and blood and provides oxygen to all vital organs (Figure 1, left, healthy lung). 

There are two types of cells in this thin alveolar cell lining: Type I and Type II cells. Type I cells are thin and flat, cover 95% of the barrier surface, and are easily injured when exposed to hazards. This is because the same thin structure of the alveoli “bubbles” that enables gas exchange also makes them easy to break. Type II cells are shaped like cubes, and responsible for replacing Type I cells after injury. When the damage is mild, the Type II alveolar cells turn into new Type I cells, allowing the lung to regenerate and heal. However, when the damage is beyond the Type II alveolar cells’ capacity to regenerate, the fibroblasts in the surrounding matrix step in and create scars from matrix fibers to fill in the gaps where the Type I epithelial cells have died. In healthy lungs, the matrix fibers go away–like scabs on the skin–when new epithelial cells grow back. In IPF lungs, however, these small scars progress into larger scarring areas, causing the sponge-like tissue to lose its stretchiness. This makes the alveolar barriers thicker, which prevents oxygen-rich air from crossing over to the bloodstream (Figure 1, right, IPF lung). Reduced lung stretchiness and gas exchange rate increase the severity of coughing, shortness of breath, fatigue and eventually, death.

Three challenges of IPF management

There are three main challenges for IPF management: lack of a cure, early diagnosis, and prevention.

Lack of a Cure

Currently, IPF has no cure, since simply removing the scars from the lungs of patients with IPF is not possible with currently existing medication.  When patients are diagnosed with IPF, they have, on average, 3-5 years to live without a lung transplant.  But remember, every patient is different. Even though severe disease eventually develops in all patients with IPF, some may progress slowly, while others may get worse quickly. Although no medication can make the lung work normally again, there are still ways to manage IPF symptoms. Doctors can help determine their patient’s best options for slowing IPF severity, which include oxygen therapy, pulmonary rehabilitation, and FDA-approved anti-fibrotic drugs (which slow, but don’t stop, progression). 

Early Diagnosis

While interventions to slow IPF progression work best during the early stages of IPF, it is challenging to catch cases early because we don’t have any cost-effective screening tests, like the ones for colon and breast cancer. Additionally, IPF symptoms are non-specific. IPF shares many common symptoms with other benign respiratory diseases, such as colds and the flu. Patients usually do not realize they have lung problems until they develop flu-like symptoms, chest pain and severe shortness of breath, when the best time for antifibrotic drugs has passed. Confirming a diagnosis commonly takes months or years and multiple hospital visits, even when patients are symptomatic, and IPF will keep progressing during this time. It is important for IPF patients to get their doctor’s attention as early as possible to gain valuable time for early IPF management with existing strategies.

Prevention

To prevent a disease, we look for the causes. For example, if we know that coronavirus causes COVID, we wear masks and avoid being exposed to it. However, the I in IPF stands for “idiopathic,” which means that we don’t know the cause of IPF, and therefore we can’t prevent the disease before it occurs. While targeted prevention for IPF is impossible, patients are advised to avoid being exposed to risk factors associated with IPF, such as tobacco, environmental dusts, and viruses to prevent exacerbation. IPF can also run in families, so patients are advised to report their family history to their doctor. Regular exercise makes the lung stronger and is beneficial for quality of life in patients with and without IPF.

Researchers are seeking new IPF management strategies

Researchers are working hard to tackle the challenges of managing IPF. Epidemiologists are looking for more clues to pin down potential causes for IPF, biologists are looking for biomarkers for early detection and novel therapies, and physicians are applying new technologies to improve IPF diagnosis and treatment. As a cell biologist, I view IPF development as a series of cellular events. IPF starts with the injury of lung epithelial cells, insufficient repair of injured cells, and scarring from overproduced fibers in matrix. Because of this, both strategies I research involve managing IPF through cell-targeted prevention. First, we investigate lung epithelial cell response after injury and identify events that ensure normal epithelial repair. We can then use this knowledge to accelerate the normal repair process, so the fibroblasts won’t have the chance to make excessive fibers and deposit scars, which would prevent lung fibrosis at a cellular level. Our second strategy is to identify cellular mistakes that trigger fibroblasts to deposit scars and thus initiate fibrosis. We are investigating how lung epithelial cells and fibroblasts interact with the hope of finding a biological switch that is mistakenly turned on in fibrotic lungs. If we can identify this biological switch, we can then design treatments to turn the switch back off in IPF patients.

While determining the biological switch to turn off fibrosis and accelerate healing is important for IPF patients, it also can be applied to circumstances where we know the cause of fibrosis, such as severe COVID infection. During COVID, SARS-CoV-2 infects and kills lung epithelial cells, leaving big holes in the alveolar cell layer. Many people have a proper healing response that leads to recovery, but not all patients recover their lung function. These non-recovering patients develop lung scarring. Though fibrosis in COVID patients occurs more quickly than in IPF (i.e., over weeks instead of years), our research group believes that IPF and non-recovering COVID share a specific type of abnormal lung repair. In one study of non-recovering COVID patients, we observed that cellular regeneration “stalls” at an intermediate stage, where the Type II cells have replicated but failed to flatten out and cover the holes in the alveolar cell layer. We think this stalled healing response causes scarring to patch the holes in the alveoli when the normal healing response fails. Since these cellular changes are indistinguishable from IPF, figuring out how to prevent or treat this abnormal lung repair response could help both patients in the clinic with IPF and in the ICU with severe COVID.

“Life is always terminal, and I choose to manage the chronic part.”

To close, I want to share this quote from an IPF patient, who views IPF as a chronic disease rather than a terminal disease. I am really touched by her positive attitude and glad to know that she has survived beyond the 5-year milestone after diagnosis. While scientists keep looking for a cure, doctors will help IPF patients find the best way to relieve symptoms and use medication or physical therapy to slow down IPF progression. Patients are also encouraged to seek help from friends, families, and other support groups for psychological and emotional assistance. Even though the disease has no cure for now, scientists like me will never stop seeking new strategies to make these stubborn scars go away.

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Fa Wang is a Research Fellow in Internal Medicine, Division of Pulmonary and Critical Care Medicine, working with Dr. Rachel Zemans. Her research interest is to investigate the mechanism of physiological and pathological alveolar repair, with a special focus on finding novel therapeutic targets of idiopathic pulmonary fibrosis. Prior to coming to Michigan, Fa completed her PhD degree in Biochemical and Molecular Nutrition Science at Purdue University. Outside of the lab, she is active in K-12 science communication by attending scientist spotlight events organized by University of Michigan Museum of Natural History. She also enjoys hiking, traveling, and attending symphony orchestra with her family.