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1.
Front Immunol ; 12: 687397, 2021.
Article in English | MEDLINE | ID: covidwho-1477818

ABSTRACT

Severe COVID-19 is characterized by acute respiratory distress syndrome (ARDS)-like hyperinflammation and endothelial dysfunction, that can lead to respiratory and multi organ failure and death. Interstitial lung diseases (ILD) and pulmonary fibrosis confer an increased risk for severe disease, while a subset of COVID-19-related ARDS surviving patients will develop a fibroproliferative response that can persist post hospitalization. Autotaxin (ATX) is a secreted lysophospholipase D, largely responsible for the extracellular production of lysophosphatidic acid (LPA), a pleiotropic signaling lysophospholipid with multiple effects in pulmonary and immune cells. In this review, we discuss the similarities of COVID-19, ARDS and ILDs, and suggest ATX as a possible pathologic link and a potential common therapeutic target.


Subject(s)
COVID-19/pathology , Phosphoric Diester Hydrolases/metabolism , Pulmonary Fibrosis/pathology , Respiratory Distress Syndrome/pathology , Anti-Inflammatory Agents/therapeutic use , COVID-19/blood , Dexamethasone/therapeutic use , Humans , Lung/pathology , Lysophospholipids/metabolism , Phosphoric Diester Hydrolases/blood , Pulmonary Fibrosis/blood , Respiratory Distress Syndrome/blood , SARS-CoV-2 , Signal Transduction/immunology
2.
Int J Mol Sci ; 22(18)2021 Sep 16.
Article in English | MEDLINE | ID: covidwho-1409704

ABSTRACT

Autotaxin (ATX; ENPP2) is a secreted lysophospholipase D catalyzing the extracellular production of lysophosphatidic acid (LPA), a pleiotropic signaling phospholipid. Genetic and pharmacologic studies have previously established a pathologic role for ATX and LPA signaling in pulmonary injury, inflammation, and fibrosis. Here, increased ENPP2 mRNA levels were detected in immune cells from nasopharyngeal swab samples of COVID-19 patients, and increased ATX serum levels were found in severe COVID-19 patients. ATX serum levels correlated with the corresponding increased serum levels of IL-6 and endothelial damage biomarkers, suggesting an interplay of the ATX/LPA axis with hyperinflammation and the associated vascular dysfunction in COVID-19. Accordingly, dexamethasone (Dex) treatment of mechanically ventilated patients reduced ATX levels, as shown in two independent cohorts, indicating that the therapeutic benefits of Dex include the suppression of ATX. Moreover, large scale analysis of multiple single cell RNA sequencing datasets revealed the expression landscape of ENPP2 in COVID-19 and further suggested a role for ATX in the homeostasis of dendritic cells, which exhibit both numerical and functional deficits in COVID-19. Therefore, ATX has likely a multifunctional role in COVID-19 pathogenesis, suggesting that its pharmacological targeting might represent an additional therapeutic option, both during and after hospitalization.


Subject(s)
COVID-19/diagnosis , Dendritic Cells/immunology , Phosphodiesterase Inhibitors/therapeutic use , Phosphoric Diester Hydrolases/blood , SARS-CoV-2/immunology , Adult , Aged , Aged, 80 and over , Biomarkers/blood , COVID-19/blood , COVID-19/immunology , COVID-19/therapy , Cohort Studies , Datasets as Topic , Dendritic Cells/drug effects , Dexamethasone/pharmacology , Dexamethasone/therapeutic use , Endothelium, Vascular/immunology , Endothelium, Vascular/pathology , Female , Humans , Interleukin-6/blood , Interleukin-6/metabolism , Male , Middle Aged , Phosphodiesterase Inhibitors/pharmacology , Phosphoric Diester Hydrolases/metabolism , RNA-Seq , Respiration, Artificial , SARS-CoV-2/isolation & purification , Severity of Illness Index , Signal Transduction/drug effects , Signal Transduction/immunology , Single-Cell Analysis
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