Understanding Benign Airway Stenosis: New Insights into Causes and Treatment

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Image credit: https://openai.com/index/dall-e/

Benign airway stenosis (BAS) is a condition where the airway becomes narrowed, causing breathing difficulties. This can range from mild shortness of breath to life-threatening situations. It's often a complication for critically ill patients, especially after long periods of being on a breathing tube. This blog post will provide insights into the causes, the role of inflammation, and potential treatments for BAS, based on recent research.

What causes BAS?

BAS primarily arises from mechanical injuries to the trachea (windpipe), such as those from:

  • Post-intubation tracheal stenosis (PITS): Narrowing of the trachea after a breathing tube has been used.
  • Post-tracheotomy tracheal stenosis (PTTS): Narrowing of the trachea after a tracheotomy (a surgical opening in the neck to help with breathing).
  • Post-surgical tracheal stenosis: Narrowing after surgical procedures involving the trachea.

The rise in public health crises like COVID-19, which often require patients to be on ventilators, has led to an increased risk of BAS. Current treatments, such as stent implantation and balloon dilation, can be effective, but surgical options can sometimes cause secondary injury, leading to more scar tissue and further narrowing. It's clear that new treatments are needed.

The role of inflammation and the cGAS-STING Pathway

Recent research highlights the importance of inflammation in the development of BAS. Specifically, the cGAS-STING pathway is a key player. This pathway is part of the body's immune system and is usually activated when it detects foreign or damaged DNA. In BAS, it seems that damaged cells in the airway release their DNA, which activates the cGAS-STING pathway in immune cells called macrophages.

When the cGAS-STING pathway is activated, it produces inflammation and encourages the growth of scar tissue. This process involves:

  • The release of double-stranded DNA (dsDNA) from damaged epithelial cells in the trachea.
  • Activation of the cGAS-STING pathway in macrophages.
  • The release of an inflammatory factor called IL-6, which in turn activates STAT3 in cells called fibroblasts.
  • Fibroblasts, when activated, promote fibrosis (scarring), which contributes to the narrowing of the airway.

How macrophages contribute to BAS

Macrophages are immune cells that are essential for wound healing, but when they become overactive they can cause problems. In BAS, the research found that:

  • The cGAS-STING pathway is highly expressed in macrophages found in the granulation tissue of patients with BAS.
  • In the early stages of BAS, there are many macrophages in the airways.
  • These macrophages express the STING protein, and when it's activated, it promotes inflammation.
  • These macrophages also release inflammatory factors like IL-6, IL-1β, and CXCL10, which worsen the inflammation and promote fibrosis.

New therapeutic targets and potential treatments

The new research suggests that targeting the cGAS-STING pathway could be a good way to prevent or treat BAS. Several potential treatment strategies have shown promise:

  • Inhibiting STING: Using drugs that block the STING protein can reduce inflammation and fibrosis in mice. A drug called C176 has been used in research to effectively reduce STING expression and the level of STING phosphorylation.
  • Inhibiting cGAS: Blocking the cGAS receptor, which is part of the cGAS-STING pathway, can also alleviate the symptoms of BAS in mice.
  • Depleting Macrophages: Reducing the number of macrophages in the airways using clodronate liposomes can reduce inflammation and the formation of scar tissue.
  • Targeting IL-6 and STAT3: Blocking the activity of IL-6 and STAT3 can also help to reduce fibrosis. This was shown through the use of a STAT3 inhibitor and an IL-6 neutralizing antibody which both reduced fibrosis in research mice.

The research also showed that:

  • Inhibiting STING reduced the level of IL6, which in turn inhibited the STAT3 pathway, highlighting the link between the cGAS-STING pathway and the fibrotic process.
  • Inhibiting the cGAS-STING pathway in macrophages may result in a reduction of IL-6, thus inhibiting fibrosis through the suppression of STAT3 activation in fibroblasts.

Conclusion

This research has shown that the cGAS-STING pathway plays a significant role in benign airway stenosis. By understanding this pathway and how macrophages contribute to the inflammatory process, new treatments can be developed to prevent or minimise airway narrowing. The studies suggest that drugs targeting STING, cGAS, IL-6 or STAT3, or depleting macrophages, could be beneficial in managing and treating BAS. More research will hopefully bring these treatment strategies closer to clinical use.

 

Journal information: Macrophage STING signaling promotes fibrosis in benign airway stenosis via an IL6-STAT3 pathway. Nature communications (2024).  https://doi.org/10.1038/s41467-024-55170-5

Additional information: https://www.nature.com/ncomms/


Location: Oxford, UK

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