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COVID-19-News - Post-COVID Lung Fibrosis - Maladaptive Signals Drive Fibroproliferation  Jun 20, 2023  1 year, 3 months, 3 weeks, 5 days, 2 hours, 58 minutes ago

Unraveling the Enigma of Post-COVID Lung Fibrosis: Maladaptive Signals Drive Fibroproliferation, Cedars-Sinai Researchers Reveal

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Unraveling the Enigma of Post-COVID Lung Fibrosis: Maladaptive Signals Drive Fibroproliferation, Cedars-Sinai Researchers Reveal
COVID-19-News - Post-COVID Lung Fibrosis - Maladaptive Signals Drive Fibroproliferation  Jun 20, 2023  1 year, 3 months, 3 weeks, 5 days, 2 hours, 58 minutes ago
By Discovering How Maladaptive TGF-β Signals To The Alveolar Epithelium Drive Fibrosis After COVID-19 Infection, Proper Therapeutics Could Be Developed.

COVID-19 News: The long-term effects of COVID-19, known as post-acute sequelae of SARS-CoV-2 infection (PASC) or Long COVID, continue to perplex the medical community. Among the various persistent symptoms experienced by individuals recovering from severe COVID-19, chronic lung fibrosis has emerged as a significant concern as reported in various studies, case reports and COVID-19 News coverages. However, the underlying mechanisms responsible for this condition, referred to as PASC lung fibrosis, have remained elusive. A recent breakthrough study conducted by researchers at Cedars-Sinai Medical Center in California sheds new light on this enigma and points towards maladaptive signaling pathways as major drivers of fibrosis in post-COVID individuals.


 
Unveiling the Cellular Dynamics of PASC Lung Fibrosis
To understand the mechanisms behind PASC lung fibrosis, the study team utilized a cutting-edge technique called single-cell RNA sequencing (scRNA-seq). They analyzed lung tissue samples from individuals with PASC and compared them with samples from individuals with idiopathic pulmonary fibrosis (IPF), a chronic lung disease characterized by progressive fibrosis. The findings revealed a decrease in the alveolar type 2 (AT2) cell fraction in fibrotic conditions, accompanied by compensatory increases in other types of epithelial cells.
 
Additionally, a decrease in the population of alveolar macrophages, specifically those expressing FABP4, was observed in PASC conditions. The researchers found a similar pattern of upregulation in profibrotic pathways across various epithelial cell types in both PASC lung fibrosis and IPF, indicating common molecular signatures associated with fibrogenesis.
 
Transitional Cells and Cellular Senescence: Key Players in Fibrosis
Notably, the study team discovered an increase in transitional cells (KRT8+, KRT17+, KRT5-) in the lungs of individuals recovering from severe COVID-19. These cells have garnered attention due to their presence in both acute respiratory distress syndrome (ARDS) and IPF. Strikingly, there were significant similarities between PASC and IPF in terms of the upregulation of fibrogenic signals such as TGF-beta, p53, and cellular senescence.
 
Moreover, the analysis revealed a cellular senescence signature progressively increasing from PASC to IPF conditions. This suggests that cellular senescence may be a prerequisite for the development of fibrosis. In contrast, transitional cells observed in lungs from individuals who succumbed to COVID-19 lacked the signatures of cellular senescence, suggesting a correlation between senescence and organized fibrosis.
 
The Dominance of TGF-β Signaling and Macrophages in PASC Lung Fibrosis
The dysregulation of TGF-beta signaling, a well-known driver of lung fibrosis, was found to affect the immunologic response to a cute SARS-CoV-2 infection and correlated with the severity of COVID-19. Utilizing an inferred communication network of aggregate TGF-beta signals, the syudy team discovered that these signals originated from macrophages in all conditions. Interestingly, the target of TGF-beta signals shifted from plasmacytoid dendritic cells (pDCs) in healthy lungs to both pDCs and transitional cells in IPF, while primarily concentrating on the transitional cell population in PASC lung fibrosis.
 
The loss of FABP4+ macrophages appeared to be the primary driver of reduced TGF-beta signaling between macrophages and pDCs. Furthermore, the probability of putative TGF-beta signaling between macrophage subpopulations and transitional cells was highest in PASC lung fibrosis compared to IPF. Monocyte-derived macrophages (Mo-AMs), known for their pro-fibrotic properties and their production of TGF-beta, were found to accumulate in the lungs of individuals with COVID-19 ARDS.
 
Conclusion
By unraveling the maladaptive mechanisms underlying PASC lung fibrosis, the researchers at Cedars-Sinai Medical Center have taken a significant step towards understanding the long-term effects of COVID-19 on lung health. Their findings suggest that PASC lung fibrosis shares common features with IPF, a chronic and progressive interstitial lung fibrosis, providing valuable insights into the broader understanding of fibroproliferative diseases.
 
While further research is needed to explore other cellular compartments, such as mesenchymal cells, the study offers a crucial foundation for future investigations into therapeutic interventions and preventive measures. By shedding light on the intricate cellular dynamics and communication networks involved in fibroproliferation, this research opens up new avenues for targeted treatments that could potentially mitigate the devastating impact of PASC lung fibrosis and related lung diseases.
 
The study findings were published as a correspondence in the peer reviewed American Journal of Respiratory and Critical Care Medicine.
https://www.atsjournals.org/doi/abs/10.1164/rccm.202302-0264LE
 
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