Severe Asthma: What Causes Airway Remodeling?

As I discussed in my post, “What is Airway Remodeling?” some asthmatics, about 5-10%, develop airway changes called remodeling. This may contribute to Severe Asthma. I thought it would be neat to further investigate this issue to gather a better understanding of what might cause these changes to occur.

What is airway remodeling?

As I noted in previous posts, this is when abnormal changes occur in cells lining airways. Essentially, it’s when airway walls become abnormally thick. This makes airways abnormally narrow and increasingly hypersensitive to asthma triggers.

Why does this happen?

Some researchers think it may be initiated by an abnormal immune response to allergens, although others think it may be initiated during a severe cold early in life, such as caused by the Rhinovirus. Of course, there is also the potential that it’s caused by certain asthma genes. So, at this point, it’s difficult to say exactly why it happens. 1, 2

What are some theories?

Researchers like to come up with theories to explain things. They then perform experiments and studies to either prove or disprove these theories. For instance, one theory explaining why airway remodeling occurs in asthma is uncontrolled asthma. They think that prolonged and untreated airway inflammation may impair the airway cell healing process, resulting in scarring.

What is some basic anatomy?

To fully understand the theories I’m about to explain, you may want to review my post, “Anatomy 101: Airway Walls.” Or, better yet, I will just give you a quick review here. Or, if you want, you can just skip forward to my next question.

For those still here, think of an airway as a pipe. Lining the inside walls of the pipe you have a single layer of ciliated columnar epithelial cells. Squeezed between these cells are goblet cells that secrete mucus. Under these, you have a thin basement membrane. This membrane becomes abnormally thick. Then you have connective tissue that contains blood vessels. These blood vessels increase in number. Wrapped around the outside of this pipe you have bundles of smooth muscle cells that become abnormally large. Together these make your airway walls abnormally thick. Airway cells now become hypersensitive (extra twitchy) to asthma triggers.

What are the theories?

Here is what researchers are presently thinking.

Mast Cells.These are white blood cells that are randomly scattered throughout airways among connective tissue and smooth muscles. Asthmatics usually have more of these than non-asthmatics. They also may be more sensitive in asthmatics to asthma triggers. This exposure triggers them to release proteins that cause inflammation. One such protein is Mast Cell Tryptase.

Mast Cell Tryptase. It plays a key role in airway inflammation. However, it also may tell fibroblasts in airway connective tissue to secrete proteins.1

Fibroblasts. These are the most common cells found in airway connective tissue. They secrete proteins (such as collagen) that make connective tissue. When triggered to do so by mast cells tryptase, they secrete collagen. When you have an injury, this is what forms the scar. It’s possible that this is what causes the basement membrane to become abnormally thick (scarred, fibrotic).1, 3

Eosinophils. They play a key role in asthma, and their numbers are almost always elevated during asthma episodes. They come into contact with airway cells and release small proteins that cause persistent airway inflammation. Some researchers think they might cause fibroblasts to reproduce, causing an abnormal number of them in asthmatic airways, which may lead to a thicker basement membrane.1

Viruses. These are the number one cause of asthma symptoms. Some even speculate that viruses, particularly the Rhinovirus, may cause the release of proteins that cause airway remodeling.2

Bronchospasm. During asthma attacks, smooth muscles spasm and constrict, thereby narrowing airways and making you feel short of breath. When this happens, these smooth muscles may release a substance called “Spasmogen Methacholine.” This substance may cause a thickening of the basement membrane.2

Some researchers think this may happen regardless of whether eosinophils are present, perhaps making it look like eosinophils by themselves do not cause airway remodeling. However, further studies are needed to be sure this is the case.3,5

Another similar theory suggests that bronchospasm might stimulate epithelial cells to release a protein called TGF-β in an attempt to repair damaged cells.5

Transforming growth factor beta. (TGF-β). It’s a tiny protein called a cytokine. It causes smooth muscle cells to increase in number and become larger than normal, making smooth muscle bundles thicker. It causes fibroblasts to secrete more collagen. It also recruites cells called fibrocytes from blood vessels. 3,4

Fibrocytes. They are cells that also secrete proteins for making connective tissue. Their numbers are elevated in smooth muscles of asthmatics to participate the healing process of cells damaged due to inflammation.

The combination of all these proteins for making connective tissue causes a thickening of the basement membrane. A combination of these and other effects cause a cascade of events resulting in thicker airway walls causing asthma to become increasingly severe (Severe Asthma) 3,5

What to make of this?

So, as you can see, there are some theories researchers have to go by. Ideally, ongoing research will help researchers sort out all this information, thereby leading them to better strategies and medicines for preventing and treating asthma. And, maybe someday, the quest to understand this will lead to a cure.

This article represents the opinions, thoughts, and experiences of the author; none of this content has been paid for by any advertiser. The team does not recommend or endorse any products or treatments discussed herein. Learn more about how we maintain editorial integrity here.
View References
  1. Lazarus, Stephen, "Airway remodelling in asthma," Medscape, 2017, September 14,, accessed 9/14/17
  2. Berair, et al, "Origins of increased airway smooth muscle mass in asthma," BMC Medicine, 2013,, accessed 8/9/17
  3. "What are fibroblasts?",, accessed 9/17/17
  4. Bentley, J. Kelley, Marc B. Hershenson, "Airway Smooth Muscle Growth in Asthma," Proceedings of the American Thoracic Society, 2008, January,, accessed 8/9/17
  5. Grainge, Christopher L., "Effect of Bronchoconstriction on Airway Remodelling in Asthma," The New England Journal of Medicine, 2011,, 9/17/17
  6. Keglowich, L.F., P. Borger, "The Three A's In Asthma -- Airway Smooth Muscle, Airway Remodelling & Angiogenesis," Respiratory Medicine Journal, 2015,, accessed 8/9/17