Understanding Airway Remodeling From Asthma May Help to Shape Future Treatment

Airway remodeling is not always an inflammatory response to asthma. It also may occur in parallel with chronic inflammation among patients who have the respiratory disorder, according to study results published in Frontiers in Medicine.

Asthma affects up to 13% of adults in the United States, the study authors said, and airway remodeling affects both large and small airways and is especially prevalent in individuals who have mild asthma. However, it also can worsen in conjunction with increasing disease severity, they wrote. The accompanying structural changes can help classify asthma endotypes.

The team of international investigators explored the mechanisms of action of airway remodeling, focusing on 3 distinct processes:

1. Initiation by epithelial cells
2. Amplification by immune cells
3. Mesenchymal effector functions

Epithelial cells can be disrupted by trigger allergens and can subsequently induce apoptosis, the study authors said. This response and activation of the immune system can result in activation of the submucosal mesenchyme that includes resident airway smooth muscle (ASM) cells and fibroblasts. These fibroblasts can contribute to worsening lung function as well as airway remodeling, the study authors explained.

Cells that produce cytokines also can promote airway inflammation and remodeling in allergic asthma, they added. And although immune cells in the lungs promote pulmonary tissue homeostasis, these same immune cells in patients with asthma may not function correctly and that can lead to prolonged airway inflammation.

Research shows that resident ASM cells and fibroblasts are behind some airway remodeling, because ASM mass and subepithelial fibrosis both increase, the study authors wrote. They also said the combination of ASM and fibroblasts plus malfunctioning epithelial-mesenchymal tropic unit and inflammatory stimuli can contribute to airway remodeling pathology.

The study authors said that some published literature support targeting the mesenchymal remodeling component through the use of corticosteroids, because these “can mitigate chronic inflammation which secondarily contributes to airway remodeling.” They also noted there is an interest in the development of therapies to target airway fibrosis. There is only 1 current approved biologic that targets the cellular components of airway remodeling, the study authors added.

Literature dating back to the 1950s suggests that the reactive oxygen species (ROS) can contribute to age-induced molecular alterations. As tissues age, including the lung, progressive metabolic dysfunction and physiological decline occurs, the study authors said. Mitochondrial dysfunction, hyperlipidemia, and increased production of ROS can all contribute to the inflammatory process, they added, which is why more research is needed to understand the pathology of chronic lung inflammation.

CT scans are quickly emerging as an increasingly useful method to assess airway remodeling in adults, the study authors wrote, 40% of whom first report symptoms of the condition after age 40. Whereas most cases of childhood-onset asthma occur before age 12. Both types seem to present airway remodeling, but incidence in adult cases is not as well characterized.

Today, there is a broader understanding of asthma, including the genetic, environmental, and host-related factors that contribute to the declining lung function of the patient, the study authors concluded.

“Recognizing that airway remodeling may occur in parallel with chronic inflammation, and not simply as a (serial) consequence of the inflammatory response, will be critical to developing novel therapeutic strategies,” they wrote. “Over the past several years, we have witnessed intensified efforts by both academia and industry to more specifically target airway remodeling events in disease pathogenesis. It is our hope that such efforts will lead to the discovery and development of more effective therapies for severe, steroid-resistant asthma.”

Reference

Hough KP, Curtiss ML, Blain TJ, et al. Airway remodeling in asthma. Front Med (Lausanne). Published online May 21, 2020. doi:10.3389/fmed.2020.00191