Decoding Type 2 Inflammation in COPD: An Expert’s Perspective

Author: Sanofi Editorial Team

Sanofi Editorial Team

Understanding type 2 inflammation is the key to managing symptoms and exacerbations of COPD.

What is the role of type 2 inflammation in COPD?

A deeper look into the underlying pathophysiology and drivers of chronic inflammation, particularly type 2 inflammation, can help us better understand COPD. The key cytokines involved in type 2 inflammation are elevated during acute exacerbations of COPD, and can play a role in mucus hypersecretion in lungs.

Watch the video below to get an understanding on type 2 inflammation and its role in COPD.

Read podcast transcript

My name is Surya Bhatt. I'm a professor of Medicine at the University of Alabama at Birmingham and I'm a COPD researcher.

This talk is sponsored by Sanofi and Regeneron and you won't get any (CME) credit. In response to any kind of insult. For example, cigarette smoke, viral infections, bacterial infections, pollution, there is some element of epithelial injury and epithelial damage. And the first response to this usually is once there is enough epithelial damage, there is release of damage associated molecular patterns or (DAMPs) which are now perhaps more popularly called alarmins and these are IL-33, IL-25 and TSLP or thymic stromal lymphopoietin. So all these can be released and they all have specific roles in terms of furthering inflammation. And IL-33 is perhaps best understood and some people consider it the master inflammation switch where once it's activated, it stays activated for a long time. It promotes both type 1 and type 3 inflammation as well as type 2 inflammation.

The traditional thinking has been that the prime driver of type two inflammation is IL-5, which causes eosinophilic inflammation. But now we understand that both IL-4 and IL-13 are important in driving type 2 inflammation. And here's a list of all the things that they can do. lL-4 and IL-13:

Can both cause epithelial barrier disruption.
They can cause B cell class switching and enhance an increased production of IgE
They can cause mast cell degranulation
They can cause basophil degranulation
And also eosinophilic inflammation just like IL-5.
They can also result in goblet cell hyperplasia and mucus production especially IL-13.
And as a consequence of these, they can cause significant airway remodeling as well as alveolar destruction.

IL-4 and IL-13 levels are also elevated during an acute exacerbation as opposed to in the stable state or patients without COPD. So this is also important to note that these pathways are activated in patients with acute exacerbation of COPD and they present and important in COPD.

And then, you know, we all know that there's been a lot of understanding of mucin and mucus production in COPD. And one of the prime drivers of that is MUC5A and IL-4 can induce increased expression of MUC5AC in human epithelial cells. And there's also a dose dependent response almost of IL-13 on MUC5A as well as increased mucus production. So, especially IL-13 has been found to be an important driver of mucus production in patients with COPD.

The Genesis of Inflammation in COPD

COPD is traditionally associated with exposure to harmful stimuli such as cigarette smoke, air pollution, and respiratory infections. Dr. Bhatt explains that these insults lead to epithelial damage in the respiratory tract, which is the first step in a cascade of inflammatory responses. "In response to any kind of insult, there is some element of epithelial injury and damage," Dr. Bhatt notes, outlining the release of damage-associated molecular patterns (DAMPs), also known as alarmins. These include IL-33, IL-25, and TSLP (thymic stromal lymphopoietin), each playing a crucial role in the amplification of inflammation.

Type 2 Inflammation: Beyond Eosinophils

While eosinophilic inflammation (driven by IL-5) has been the traditional focus in Type 2 inflammation, Dr. Bhatt emphasizes the significant roles of IL-4 and IL-13. These interleukins contribute to various pathological processes in COPD:

Epithelial Barrier Disruption: IL-4 and IL-13 can compromise the integrity of the epithelial barrier, making it more susceptible to environmental insults.
B Cell Class Switching and IgE Production: These cytokines facilitate B cell transformation and increase IgE levels, which are critical in allergic responses and may exacerbate respiratory symptoms.
Mast Cell and Basophil Degranulation: This leads to further release of inflammatory mediators, worsening inflammation and symptom severity.
Goblet Cell Hyperplasia and Mucus Overproduction: Particularly driven by IL-13, this results in excessive mucus production, a hallmark of COPD that contributes to airway obstruction and difficulty clearing infections.
Airway and Alveolar Remodeling: Chronic inflammation driven by these cytokines can lead to structural changes in the lung, reducing its functionality over time.

Acute Exacerbations and Mucus Production in COPD

Dr. Bhatt notes that IL-4 and IL-13 levels are elevated during acute exacerbations of COPD compared to stable states, underscoring the activation of these pathways during flare-ups. He also addresses the role of mucins in COPD, particularly MUC5AC, which is induced by IL-4 in human epithelial cells. IL-13 also shows a dose-dependent effect on MUC5A and enhances mucus production, marking it as a significant factor in COPD exacerbations.

The MUC5AC Connection

A significant aspect of Dr. Bhatt’s discussion revolves around mucin production, specifically driven by MUC5AC and its regulation by IL-4 and IL-13. "IL-4 can induce increased expression of MUC5AC in human epithelial cells," he explains, highlighting a dose-dependent increase in mucus production driven by IL-13. This pathway is particularly important as it contributes to the characteristic mucus hypersecretion observed in COPD patients.

In Summary

Dr. Surya Bhatt’s insights into the role of Type 2 inflammation in COPD underscore the complexity of this disease and the multifaceted nature of its inflammatory processes. Understanding these mechanisms not only sheds light on the pathophysiology of COPD but also opens new avenues for targeted treatments that could potentially modulate these inflammatory pathways, offering hope for better management of this debilitating disease.

As the field of COPD research continues to evolve, it is clear that integrating insights from experts like Dr. Bhatt will be crucial in developing more effective therapeutic strategies that address the underlying inflammation and its diverse manifestations in COPD patients.

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