Abstract
Neutrophils are recruited to the airways of patients with acute respiratory distress syndrome (ARDS) where they acquire an activated pro-survival phenotype with an enhanced respiratory burst thought to contribute to ARDS pathophysiology. Our in vitro model enables blood neutrophil transepithelial migration into cell-free tracheal aspirate fluid from patients to recapitulate the primary airway neutrophil phenotype observed in vivo. Neutrophils transmigrated through our model toward airway fluid from children with lower respiratory viral infections coinfected with bacteria had elevated levels of neutrophil activation markers but paradoxically exhibited an inability to kill bacteria and a defective respiratory burst compared with children without bacterial coinfection. The airway fluid from children with bacterial coinfections had higher levels of neutrophil elastase activity, as well as myeloperoxidase levels compared to children without bacterial coinfection. Neutrophils transmigrated into the aspirate fluid from children with bacterial coinfection showed decreased respiratory burst and killing activity against H. influenzae and S. aureus compared to those transmigrated into the aspirate fluid from children without bacterial coinfection. Use of a novel transmigration model recapitulates this pathological phenotype in vitro that would otherwise be impossible in a patient, opening avenues for future mechanistic and therapeutic research.
Highlights
Clinical information obtainable at the bedside is often used to prognosticate yet is insufficient for determining the pathobiology of the lung injury
We hypothesized that neutrophils recruited to the cell-free airway fluid of children with bacterial coinfections would have a defective respiratory burst and ability to kill bacteria compared to children with no bacterial coinfection
Blood neutrophils recruited to the lungs of children at risk of or with PARDS due to lower airway viral infections are generally believed to rapidly die therein, leading to the passive release of Human neutrophil elastase (HNE) and other toxic by-products that promote lung injury[31,32,33]
Summary
Clinical information obtainable at the bedside is often used to prognosticate yet is insufficient for determining the pathobiology of the lung injury. Understanding the biology of neutrophils recruited to the lung during PARDS is crucial for advancing prognostication, risk stratification, and development of novel therapeutic strategies for children who progress to severe PARDS. We hypothesized that markers of degranulation on the surface of airway neutrophils and in the cell-free airway fluid within 24-hours of intubation would be associated with bacterial respiratory co-infection. We used an in vitro model based on blood neutrophil transepithelial migration into the airway fluid of endotracheally intubated children with suspected or confirmed lower airway viral infections at risk for progressing to or with PARDS16. We hypothesized that neutrophils recruited to the cell-free airway fluid of children with bacterial coinfections would have a defective respiratory burst and ability to kill bacteria compared to children with no bacterial coinfection
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