We’ve Come a Long Way: Advances in ILD Treatment

To “know thy enemy” is a concept from an ancient military treatise – Sun Tzu’s The Art of War – yet modern medicine has borrowed this strategy in its own fight against disease. Understanding the complex, underlying causes of various diseases at the molecular level has led to a revolution in medicine.

For Dr. Martin Kolb and clinician-scientists like him, their “enemy” is interstitial lung disease (ILD), a group of diseases that affect the tissue and spaces around the air sacs of the lungs. The excessive growth of scar tissue causes lung capacity to decline to dangerous levels.

Ultimately, the lungs are slowly devoured by scar tissue – a process called fibrosis. This progressively makes it more difficult to breath, with symptoms such as coughing, shortness of breath, fatigue, and weight loss.

Before the late 1990s, not much was known about the underlying mechanisms of ILD. It was thought to be inflammation and therefore treated with prednisone. However, outcomes remained poor as the progression of lung fibrosis in patients continued.

Dr. Martin Kolb is a clinician-scientist at the Firestone Institute for Respiratory Health

Idiopathic pulmonary fibrosis (IPF) is the most common subgroup of ILD (“idiopathic” means that no obvious cause can be identified). IPF has been observed to affect men more often than women, and patients usually live for 2 to 6 years until succumbing to the disease.

The scientific landscape started to change in the 1990s as researchers unravelled more mysteries surrounding the biological underpinnings of IPF. Dr. Kolb was a post-doctoral fellow working in the fibrosis lab of Dr. Jack Gauldie, a renowned researcher known for his role in the founding of cytokine biology.

By 2001, the prevailing hypothesis was that IPF was caused by scar formation that does not stop – an aberrant process of wound healing as we now understand it today. Scar tissue progressively spreads long after any wounds have healed, hindering lung function.

Inflammation would soon become only a small consideration among a multitude of other factors involved in lung fibrosis. Around the world, researchers focused on different factors, with Kolb’s team at the Firestone Institute focusing on intercellular signals that promote lung fibrosis called profibrotic cytokines (including TGF-ß and others).

Researchers began to understand the role of these cytokines in lung fibrosis. Kolb and his colleagues showed that inflammatory cytokines are followed by repair cytokines, some of which persist and are associated with fibrosis. This distinction between inflammatory cytokines and fibrotic cytokines was an important milestone. With other key discoveries, a fundamental shift occurred in how scientists looked at fibrotic lung diseases.

Dr. Kolb and his team also looked at the effects of mechanical stretching on fibrosis progression – that is, breathing itself – and found that it can amplify fibrosis.

Dr. Martin Kolb

“Breathing causes mechanical forces on the tissue, and if you have stiff tissue (from IPF), those forces will aggravate the repair signals.”
A lung tissue specimen showing fibrosis around the outer edges (visible as thicker areas).

The team was able to visualize this by analyzing fibrotic tissue specimens. Since the mechanical forces are higher on the edges of the lungs compared to the middle, scarring tends to be concentrated on the outside of the lungs instead of the inside.

“The good news here is that we can interfere with those forces,” says Kolb. “We can block different mechanical stimuli with pharmacological approaches.”

These pharmacological approaches include receptor and intracellular inhibitors, many of which are currently in development and in clinical trials for patients with IPF.

Numerous other discoveries have been made since the paradigm shift in our understanding of interstitial lung diseases. By 2021, the treatment guidelines have become much more complex and now leverage advanced diagnostic tools that have also matured since the early days.

Interestingly, acid reflux medications are an important part of the treatment regimen for those with gastroesophageal reflux disease (GERD), since inhaling stomach acids can cause coughing symptoms and lead to further fibrosis progression. This was demonstrated in research from Dr. Kolb and his team.

In 2014, nintedanib was shown to reduce disease progression for those with mild disease. In patients with more severe disease, Dr. Kolb and the INSTAGE investigators found that using a combination treatment of nintedanib and sildenafil also helped reduce the progression of lung fibrosis.

Dr. Kolb estimates that about one quarter of his patients fall into the category of non-idiopathic progressive lung fibrosis, and further research has shown that IPF treatments are effective against non-idiopathic disease.

“Once patients have fibrosis and the lungs shrink, it doesn’t matter how it started,” says Dr. Kolb, noting that the same treatments for IPF have shown to be effective with other fibrotic lung diseases.

As a clinician-scientist, Dr. Kolb has studied interstitial lung diseases, including IPF, through basic research in the laboratory and through clinical research in his medical practice. To learn more about his work, be sure to watch Dr. Kolb’s McArthur Award academic presentation.

The Future of IPF Patient Care

Nationally, the Firestone Institute for Respiratory Health is a key treatment and research centre for a wide range of complex airway diseases, with a particular focus on interstitial lung diseases and IPF. Research on strategies that improve patient outcomes with a focus on clinical services are as important as pharmacological research.

In 2022, Firestone researchers announced a new collaborative research project with Boehringer Ingelheim and other partners that will address key actions related to ILD identified by the Institute for Health Economics. This includes increasing surveillance to identify those in need of services earlier, further investment in patient navigators to support patients and families, and much more.

The project will launch in the fall of 2022 – keep an eye on our website for updates.