Nature: Reveals that excessive fibroblast activation impairs lung function through ADAMTS4

In a new study, researchers from st. Jude Children's Research Hospital in the United States and the First Affiliated Hospital of Guangzhou Medical University in China identified fibroblasts as playing an important role in the inflammatory immune response of the lungs after infection with influenza viruses and other respiratory pathogens.
they are conducting further research to translate these findings into treatments that protect lung function and improve patient survival.
study was recently published in the journal Nature under the title "Exuberant fibroblast activity compromises lung function via ADAMTS4".
images from Nature, 2020, doi:10.1038/s41586-020-2877-5.
fibroblasts are the cells needed to ensure that the lungs function properly, and they help coordinate the immune response.
the researchers found that viral infections can induce some lung fibroblasts to increase the production of cytokines and enzyme ADAMTS-4.
cytokines drive inflammation, and ADAMTS-4 degrades a key lung protein.
these changes promote inflammation and extensive tissue recombination, however, this can sacrifice lung function.
when the researchers eliminated ADAMTS-4, survival rates improved in mice infected with the flu virus.
in children and adults hospitalized for seasonal influenza and avian influenza, ADAMTS-4 levels in the lower respiratory tract were also associated with the severity of respiratory symptoms.
patients with higher levels of ADAMTS-4 had more severe symptoms, were more likely to need mechanical breathing support, and were at greater risk of death.
Paul Thomas, author of the paper and in the Department of Immunology at St. Jude Children's Research Hospital, said, "People who die from influenza tend to have taken control of the virus, but suffer from extensive lung damage."
damage is caused by the response of immune cells soaked into the lungs to the infection, but the mechanism is unclear.
by focusing on the interaction between the immune response and lung function, we have found not only a mechanism, but also a promising treatment that does not yet exist.
" fibroblasts and a successful immune response requires a delicate balance.
this immune response must eliminate viruses or other pathogens without collateral damage caused by causing out-of-control inflammation.
Thomas and his colleagues used a variety of methods to prove that fibroblasts play an important role during influenza virus infection.
found that respiratory viral infections can trigger a deadly inflammatory response by activating lung fibroblasts called damaged reactive fibroblasts.
these fibroblasts release cytokines and ADAMTS-4 that trigger inflammation, while ADAMTS-4 degrades the structural pulmonary protein versican.
, lead author of the study and a postdoctoral researcher at Thomas Labs, said, "This study found that ADAMTS-4 is the primary regulatory factor for the degradation of versican in the lungs of mice infected with influenza viruses.
the degradation of the versican has a significant effect on lung function.
" fibroblasts are best known as part of connective and supporting tissue, but in this new study they play an important role in inflammatory responses.
researchers used techniques such as single-cell and spatial transcriptomics to reveal the key role of these cells in balancing inflammation and lung function.
"These next-generation technologies allow us to finely match gene expression patterns to specific locations in individual cells and lungs," said co-author Dr. Jeremy Chase Crawford of the Department of Immunology at St. Jude Children's Research Hospital.
space transcriptomics has greatly increased the amount of information we get from our organization, so we are pleased that we are not only working on this project, but also providing technical work for other researchers at St. Jude Children's Research Hospital.
" new method shows that the activation of fibroblasts varies in different areas of the lungs, and that this activation is associated with severe lung damage.
in the same area where extreme tissue damage occurs, ADAMTS-4 is always in the vicinity.
the researchers reported that when ADAMTS-4 was eliminated, the vesican structure of the mice's lungs was preserved and the mice lived longer.
complete vesican has a variety of roles in maintaining lung health and function.
data from adult and child influenza patients hospitalized at three different medical centers around the world show that ADAMTS-4 concentrations in lung tissue are a powerful indicator of the severity of influenza.
transformational studies have begun and Thomas and his colleagues are now developing small molecules to suppress ADAMTS-4 and limit excessive inflammation and lung damage.
candidates include a compound being developed by a pharmaceutical company as a potential drug to treat rheumatoid arthritis.
Thomas said, "Our goal is to develop a drug that helps protect lung function, not just against influenza viruses, but also against other acute viral respiratory infections, including the COVID-19 pandemic virus."
" Reference: 1. David F. Boyd et al. Exuberant fibroblast activity compromises lung function via ADAMTS4. Nature, 2020, doi:10.1038/s41586-020-2877-5.2.Research advances understanding of life-life-lung following the flu This article is from Bio Valley, for more information please download Bio Valley APP (