Asthma affects more than 300 million people worldwide, and while many can control their symptoms with inhaled steroid medications, about 10% develop a more severe form that does not respond well to these treatments. This steroid-resistant asthma is one of the most difficult forms of the disease to manage.
“We wanted to find new ways to help patients manage their condition,” said corresponding author Dr. David Corry , Fulbright Endowed Chair in Pathology and Immunology and Medicine and professor of medicine – immunology, allergy and rheumatology at Baylor College of Medicine. “To develop new treatments, we needed to identify the biological pathways and players that may help explain the steroid-resistant nature of their condition.” The findings are published in Mucosal Immunology.
The researchers began by developing a mouse model that would recapitulate severe human steroid-resistant asthma. In people, this form of the disease has a characteristic immune profile that includes abundant immune T helper type 2 cells and numerous neutrophils.
The team tested different factors known to play a role in the development of asthma, focusing on the contributions of airway fungal infections and exposure to bacterial substances known as lipopolysaccharides (LPS). LPS are molecules found on the outer surface of many bacteria and can trigger strong immune responses.
Corry and his colleagues found that exposure to the common fungus Aspergillus niger caused asthma-like disease in mice, including airway inflammation and airway hyperresponsiveness, a condition in which the airway becomes overly sensitive and narrow too easily. Surprisingly, steroid treatment reduced some signs of inflammation but did not correct the airway dysfunction that causes breathing problems.
When small amounts of LPS were added along with the fungal exposure, the disease became even more severe. The mice developed a form of asthma that resembled severe human asthma, with both allergic inflammation and increased numbers of neutrophils. Again, steroid treatment reduced inflammation but failed to restore normal airway function.
With a mouse model of severe steroid-resistant asthma in hand, the researchers then looked for the biological reasons behind steroid resistance. They focused on substances called fibrinogen cleavage products, or “cryptokines.”
Fibrinogen is a soluble blood-clotting protein that converts into insoluble fibrin to form a stable meshwork that stops bleeding when an injury occurs. Fibrin also can be in the lungs where it can form fibrin plugs that clog the airways, making it difficult to breathe. When fungal enzymes in the lungs break down fibrin, they produce smaller fragments – cryptokines – that contribute to airway hyperresponsiveness by activating a receptor called Toll-like receptor 4 (TLR4).
Steroids did not prevent the activation of this pathway. Mice lacking TLR4 did not develop the same severe airway responses, demonstrating that the receptor is essential for the disease process observed in the study.
Another important finding was that airway epithelial cells, the cells lining the airways, can produce clotting-related proteins such as fibrinogen and prothrombin. The researchers discovered that cryptokines stimulate these cells to produce even more of these proteins, creating a self-reinforcing cycle. More fibrinogen can lead to more cryptokines, which may further worsen airway disease.
“Overall, the findings support that severe steroid-resistant asthma may be driven by fungal activity, bacterial products such as LPS and clotting-related proteins that activate TLR4,” said Corry a member of the Dan L Duncan Comprehensive Cancer Center at Baylor. “These pathways appear capable of causing airway dysfunction that does not respond to steroid treatments and should be considered when planning therapies.”
Other contributors to this work include Y. Zeng, X Huang, G. Liang, K. Tang, K.E. Mauk, H. Sun, Y. Zhang, Z. Zeng, L. Song, K. Polsky, Y. Wu, C.T. Landers, E.Z. Otukoya, L.H. Bimler, F. Kheradmand, A.U. Luong, Y. Guo and J.M. Knight. The authors are affiliated with one or more of the following institutions: Baylor College of Medicine, the First Affiliated Hospital of Sun Yat-sen University, Michael E. DeBakey VA Center for Translational Research on Inflammatory Diseases and the University of Texas Health Science Center at Houston.
This project was funded by the National Institutes of Health (NIH) (grants R01HL117181, HL140398, R01AI135803, R41AI124997 and T32GM136554), VA Office of Research and Development (grant I01BX004828), the National Natural Science Foundation of China (grant 81770024) and the Project of Department of Finance of Guangdong Province (grant 20160907). This project was further supported by the Cytometry and Cell Sorting Core at Baylor College of Medicine with funding from the CPRIT Core Facility Support Award (CPRIT-RP180672) and the NIH (CA125123 and RR024574).
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Mucosal Immunology
Experimental study
Animals
Fibrinogen and lipopolysaccharide promote TLR4-dependent glucocorticoid resistance in airway mycosis-driven allergic airway disease
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