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Pulmonary endothelial NEDD9 and the prothrombotic pathophenotype of acute respiratory distress syndrome due to SARS-CoV-2 infection.
Alba, George A; Samokhin, Andriy O; Wang, Rui-Sheng; Wertheim, Bradley M; Haley, Kathleen J; Padera, Robert F; Vargas, Sara O; Rosas, Ivan O; Hariri, Lida P; Shih, Angela; Thompson, Boyd Taylor; Mitchell, Richard N; Maron, Bradley A.
  • Alba GA; Division of Pulmonary and Critical Care Medicine Massachusetts General Hospital Boston Massachusetts USA.
  • Samokhin AO; Division of Cardiovascular Medicine Brigham and Women's Hospital Boston Massachusetts USA.
  • Wang RS; Division of Cardiovascular Medicine Brigham and Women's Hospital Boston Massachusetts USA.
  • Wertheim BM; Division of Pulmonary and Critical Care Medicine Brigham and Women's Hospital Boston Massachusetts USA.
  • Haley KJ; Division of Pulmonary and Critical Care Medicine Brigham and Women's Hospital Boston Massachusetts USA.
  • Padera RF; Department of Pathology Brigham and Women's Hospital Boston Massachusetts USA.
  • Vargas SO; Department of Pathology Boston Children's Hospital Boston Massachusetts USA.
  • Rosas IO; Division of Pulmonary and Critical Care Medicine Baylor College of Medicine Houston Texas USA.
  • Hariri LP; Division of Pulmonary and Critical Care Medicine Massachusetts General Hospital Boston Massachusetts USA.
  • Shih A; Department of Pathology Massachusetts General Hospital Boston Massachusetts USA.
  • Thompson BT; Department of Pathology Massachusetts General Hospital Boston Massachusetts USA.
  • Mitchell RN; Division of Pulmonary and Critical Care Medicine Massachusetts General Hospital Boston Massachusetts USA.
  • Maron BA; Department of Pathology Brigham and Women's Hospital Boston Massachusetts USA.
Pulm Circ ; 12(2): e12071, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1772839
ABSTRACT
The pathobiology of in situ pulmonary thrombosis in acute respiratory distress syndrome (ARDS) due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is incompletely characterized. In human pulmonary artery endothelial cells (HPAECs), hypoxia increases neural precursor cell expressed, developmentally downregulated 9 (NEDD9) and induces expression of a prothrombotic NEDD9 peptide (N9P) on the extracellular plasma membrane surface. We hypothesized that the SARS-CoV-2-ARDS pathophenotype involves increased pulmonary endothelial N9P. Paraffin-embedded autopsy lung specimens were acquired from patients with SARS-CoV-2-​​​​​​ARDS (n = 13), ARDS from other causes (n = 10), and organ donor controls (n = 5). Immunofluorescence characterized the expression of N9P, fibrin, and transcription factor 12 (TCF12), a putative binding target of SARS-CoV-2 and known transcriptional regulator of NEDD9. We performed RNA-sequencing on normal HPAECs treated with normoxia or hypoxia (0.2% O2) for 24 h. Immunoprecipitation-liquid chromatography-mass spectrometry (IP-LC-MS) profiled protein-protein interactions involving N9P relevant to thrombus stabilization. Hypoxia increased TCF12 messenger RNA significantly compared to normoxia in HPAECs in vitro (+1.19-fold, p = 0.001; false discovery rate = 0.005), and pulmonary endothelial TCF12 expression was increased threefold in SARS-CoV-2-ARDS versus donor control lungs (p < 0.001). Compared to donor controls, pulmonary endothelial N9P-fibrin colocalization was increased in situ in non-SARS-CoV-2-ARDS and SARS-CoV-2-ARDS decedents (3.7 ± 1.2 vs. 10.3 ± 3.2 and 21.8 ± 4.0 arb. units, p < 0.001). However, total pulmonary endothelial N9P was increased significantly only in SARS-CoV-2-ARDS versus donor controls (15 ± 4.2 vs. 6.3 ± 0.9 arb. units, p < 0.001). In HPAEC plasma membrane isolates, IP-LC-MS identified a novel protein-protein interaction between NEDD9 and the ß3-subunit of the αvß3-integrin, which regulates fibrin anchoring to endothelial cells. In conclusion, lethal SARS-CoV-2-ARDS is associated with increased pulmonary endothelial N9P expression and N9P-fibrin colocalization in situ. Further investigation is needed to determine the pathogenetic and potential therapeutic relevance of N9P to the thrombotic pathophenotype of SARS-CoV-2-ARDS.
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Full text: Available Collection: International databases Database: MEDLINE Language: English Journal: Pulm Circ Year: 2022 Document Type: Article

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Full text: Available Collection: International databases Database: MEDLINE Language: English Journal: Pulm Circ Year: 2022 Document Type: Article