Lung Epithelium Releases Growth Differentiation Factor 15 in Response to Pathogen-mediated Injury.

Growth differentiation factor 15 (GDF15) is a stress cytokine with several proposed roles including support of stress erythropoiesis. Higher circulating GDF15 levels are prognostic of mortality during acute respiratory distress syndrome, but the cellular sources and downstream effects of GDF15 during pathogen-mediated lung injury are unclear. We quantified GDF15 in lower respiratory tract biospecimens and plasma from patients with acute respiratory failure. Publicly available data from SARS-CoV-2 infection were re-analyzed. We utilized mouse models of hemorrhagic acute lung injury mediated by P. aeruginosa exoproducts in wildtype mice and mice genetically deficient for Gdf15 or its putative receptor, Gfral . In critically-ill humans, plasma levels of GDF15 correlated with lower respiratory tract levels and were higher in non-survivors. SARS-CoV-2 infection induced GDF15 expression in human lung epithelium and lower respiratory tract GDF15 levels were higher in COVID-19 non-survivors. In mice, intra-tracheal P. aeruginosa Type 2 secretion system exoproducts (PA SN) were sufficient to induce airspace and plasma release of GDF15, which was attenuated with epithelial-specific deletion of Gdf15 . Mice with global Gdf15 deficiency had decreased airspace hemorrhage, an attenuated cytokine profile, and altered lung transcriptional profile during PA SN injury, which was not recapitulated in mice deficient for Gfral . Airspace GDF15 reconstitution did not significantly modulate key lung cytokine levels but increased circulating erythrocyte counts. Lung epithelium releases GDF15 during pathogen injury, which associates with plasma levels in both humans and mice and can increase erythrocyte counts in mice, suggesting a novel lung-blood communication pathway. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).