Lung Epithelium Releases Growth Differentiation Factor 15 (GDF15) In Response To Pathogen-Mediated Injury Including By SARS-CoV-2
Nikhil Prasad Fact checked by:Thailand Medical News Team Feb 08, 2024 2 months, 2 weeks, 5 days, 51 minutes ago
COVID-19 News: Growth Differentiation Factor 15 (GDF15), initially identified as macrophage inhibitory cytokine-1, belongs to the transforming growth factor (TGF) superfamily. Recognized by various names such as NAG-1, MIC-1, and others, GDF15 is a stress cytokine expressed by diverse cell types, with its levels increasing during cellular stress, aging, injury, and inflammation. While its roles encompass metabolic regulation, inflammation modulation, and support for stress erythropoiesis, the understanding of GDF15's implications during lung disease and critical illness is evolving. Despite its association with diseases such as cardiovascular disease, diabetes mellitus, and malignancy, there is limited knowledge about its involvement in pneumonia and pathogen-mediated lung injury, the primary risk factor for Acute Respiratory Distress Syndrome (ARDS).
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Global deficiency of Gdf15 is marked by an altered airspace cytokine profile during lung injury induced byP. aeruginosa exoproducts. In two experiments, wildtype- (WT; N=19) and Gdf15-/--mice (N=16) were intra-tracheally inoculated with Pseudomonas aeruginosa cell-free supernatant (PA SN) and broncho-alveolar lavage (BAL) fluid and plasma was collected 20 hours post-infection. (A) Gross images of BAL hemorrhage from each experiment. (B) BAL OD540 normalized to WT median value to compare across experiments, (C) BAL immunoglobulin M (IgM) normalized to WT median value to compare across experiments, (D)Plasma tumor necrosis factor-alpha (TNF-α),(E) BAL TNF-α,(F) plasma granulocyte-colony stimulating factor (G-CSF), (G) BAL G-CSF, (H) BAL polymorphonuclear leukocytes counts normalized to WT median to compare across experiments, and (I) BAL neutrophil elastase activity in WT- (N=24) and Gdf15-/--mice (N=21) normalized to WT median to compare across experiments. Each tube or point represents a single mouse. Groups were compared using Mann-Whitney Test. Non-significant comparisons are not displayed
This
COVID-19 News report explores a groundbreaking translational investigation conducted by the University of Pittsburgh Medical Center, Division of Pulmonary, Allergy, and Critical Care Medicine, shedding light on the release of GDF15 by lung epithelium in response to pathogen-mediated injury, including that caused by SARS-CoV-2.
GDF15 in Lung: A Pleiotropic Player
GDF15 has been previously linked to various lung diseases, such as pulmonary vascular disease, chronic obstructive pulmonary disease, and pulmonary fibrosis. Despite this, its involvement in pneumonia and pathogen-induced lung injury remained largely unexplored until now. In a prior observational study, elevated circulating GDF15 levels were observed in patients with ARDS, indicating its potential prognostic value in acute respiratory failure. To delve deeper into the cellular sources and downstream effects of GDF15 during pathogen-mediated lung injury, the researchers utilized biospecimens from patients with acute respiratory failure, analyzed publicly available data from SARS-CoV-2 infection, and employed mouse models of acute lung injury caused by Pseudomonas aeruginosa exoproducts.
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GDF15 Levels Correlate with Severity in Human Patients
The study revealed higher levels of GDF15 in the plasma of patients at-risk for or diagnosed with ARDS, particularly in non-survivors. Strikingly, GDF15 levels in the lower respiratory tract correlated with plasma levels, marking a crucial connection between local and systemic GDF15 release. Further analysis of publicly available data demonstrated that SARS-CoV-2 infection induced GDF15 expression in human lung epithelium, with elevated GDF15 levels in the lower respiratory tract observed in non-survivors of severe COVID-19. This reinforces the notion that GDF15 serves as a biomarker for severe lung injury and underscores its potential significance in infectious contexts.
Mouse Models Unveil Lung Epithelium as a Primary Source
Mouse models of acute lung injury mediated by P. aeruginosa exoproducts provided valuable insights into the role of GDF15. Intra-tracheal administration of P. aeruginosa Type 2 secretion system exoproducts induced both airspace and plasma release of GDF15 in mice. Notably, epithelial-specific deletion of Gdf15 attenuated this response, highlighting the lung epithelium as a primary source of GDF15 during pathogen-mediated injury. Global deficiency of Gdf15 in mice resulted in decreased airspace hemorrhage, an altered cytokine profile, and transcriptional differences in lung tissues during P. aeruginosa exoproduct-induced injury. Surprisingly, these effects were not replicated in mice deficient for Gfral, the putative receptor for GDF15 in the central nervous system.
GDF15's Novel Role in Erythropoiesis
Reconstitution of recombinant GDF15 into Gdf15-deficient mice during pathogen-mediated injury did not significantly modulate lung cytokine levels. However, it significantly increased plasma GDF15 levels and erythrocyte counts, pointing towards a previously unrecognized lung-blood communication pathway involving GDF15. The study suggests that lung-derived GDF15 may act as a hormone to support stress erythropoiesis in mice, providing a novel perspective on GDF15's multifaceted functions.
Unraveling GDF15's Mechanisms and Limitations
Despite the intriguing findings, the study acknowledges limitations, such as the undefined receptor(s) for GDF15 outside of the brain and the need for further research to elucidate its intricate roles. The lack of a well-defined receptor in extra-pulmonary sites hinders a comprehensive understanding of GDF15's pleiotropic functions. The study proposes that future research should explore the potential bifurcation of GDF15's roles between the cleaved, mature, secreted extracellular hormone and the intra-cellular full-length pro-peptide, the latter's functions remaining poorly defined.
Conclusion
In conclusion, this comprehensive investigation reveals the significant role of lung epithelium in transcribing and releasing GDF15 during pathogen-mediated lung injury. The correlation between lower respiratory tract and circulating GDF15 levels in both humans and mice suggests a systemic response to lung injury. The study's innovative findings shed light on GDF15's involvement in stress erythropoiesis, introducing a novel lung-blood signaling pathway. Despite existing limitations, this research paves the way for future studies to unravel the intricate mechanisms of GDF15 in lung disease and critical illness, offering potential therapeutic avenues and diagnostic markers for severe respiratory conditions.
The study findings were published in the peer reviewed American Journal of Respiratory Cell and Molecular Biology.
https://www.atsjournals.org/doi/10.1165/rcmb.2023-0429OC
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