Differential type I interferon response and primary airway neutrophil extracellular trap release in children with acute respiratory distress syndrome

Jocelyn R Grunwell,Kaitlin Jones,Carrie Mason,Anne M Fitzpatrick,Susan T Stephenson,Ahmad F Mohammad,Cydney Opolka

doi:10.1038/s41598-020-76122-1

Jocelyn R Grunwell, Kaitlin Jones + Show 5 more

Open Access

https://doi.org/10.1038/s41598-020-76122-1

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Abstract

Acute respiratory distress syndrome (ARDS) is a heterogeneous condition characterized by the recruitment of large numbers of neutrophils into the lungs. Neutrophils isolated from the blood of adults with ARDS have elevated expression of interferon (IFN) stimulated genes (ISGs) associated with decreased capacity of neutrophils to kill Staphylococcus aureus and worse clinical outcomes. Neutrophil extracellular traps (NETs) are elevated in adults with ARDS. Whether pediatric ARDS (PARDS) is similarly associated with altered neutrophil expression of ISGs and neutrophil extracellular trap release is not known. Tracheal aspirate fluid and cells were collected within 72 h from seventy-seven intubated children. Primary airway neutrophils were analyzed for differential ISG expression by PCR, STAT1 phosphorylation and markers of degranulation and activation by flow cytometry. Airway fluid was analyzed for the release of NETs by myeloperoxidase-DNA complexes using an ELISA. Higher STAT1 phosphorylation, markers of neutrophil degranulation, activation and NET release were found in children with versus without PARDS. Higher NETs were detected in the airways of children with ventilator-free days less than 20 days. Increased airway cell IFN signaling, neutrophil activation, and NET production is associated with PARDS. Higher levels of airway NETs are associated with fewer ventilator-free days.

Highlights

Acute respiratory distress syndrome (ARDS) is a heterogeneous condition characterized by the recruitment of large numbers of neutrophils into the lungs
Children with pediatric ARDS (PARDS) were more likely to be supported by extracorporeal life support (ECLS), had a longer duration of mechanical ventilation, and spent more days in the hospital and the Pediatric Intensive Care Unit (PICU) (Table 1)
There were no significant differences in severity of illness (PRISM III) or organ dysfunction (PELOD) scores, the absolute number or percentage of alive neutrophils from children based on PARDS status (Table 1)

Summary

Introduction

Acute respiratory distress syndrome (ARDS) is a heterogeneous condition characterized by the recruitment of large numbers of neutrophils into the lungs. Neutrophils isolated from the blood of adults with ARDS have elevated expression of interferon (IFN) stimulated genes (ISGs) associated with decreased capacity of neutrophils to kill Staphylococcus aureus and worse clinical outcomes. Whether pediatric ARDS (PARDS) is associated with altered neutrophil expression of ISGs and neutrophil extracellular trap release is not known. Abbreviations IFN Interferon MPO Myeloperoxidase NETs Neutrophil extracellular traps PARDS Pediatric acute respiratory distress syndrome PICU Pediatric intensive care unit. In adults with acute respiratory distress syndrome (ARDS), worse clinical outcomes are associated with increased levels of both circulating and airway fluid neutrophil-related products and in dysregulated neutrophil functions[5,6,7]. Since viral lower respiratory tract infections are a primary trigger for PARDS, we questioned whether differential ISG expression was associated with neutrophil responses in intubated children at risk or with PARDS. We hypothesized that children with PARDS would have a greater type I IFN response resulting in more neutrophil extracellular trap (NET) release

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