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Distinct Blood and Lung Proteins Drive Pulmonary Capillary Leak in Children With Severe Hypoxemic Respiratory Failure
Angeliki Gkaifyllia1, Steven Bruzek2, Vera Ignjatovic2,3
1Department of Pediatrics, Stony Brook University, Stony Brook, NY.
Insights
Blood and lung fluids impact critically ill children's pulmonary barrier function differently. Tracheobronchial lavage fluid showed improved barrier function over time, unlike plasma, suggesting compartment-specific therapeutic potential.
Area of Science:
- Critical care medicine
- Pediatric respiratory failure
- Pulmonary endothelial biology
Background:
- Acute hypoxemic respiratory failure is a major cause of death in critically ill children.
- Pulmonary capillary barrier dysfunction significantly contributes to disease severity.
- Understanding factors affecting barrier integrity is crucial for improving outcomes.
Purpose of the Study:
- To determine how blood and tracheobronchial lavage (TBAL) fluid differentially influence pulmonary capillary barrier function.
- To identify protein mediators involved in these effects.
- To explore compartment-specific and disease-specific impacts on endothelial cells.
Main Methods:
- Secondary analysis of stored blood and TBAL samples from 65 mechanically ventilated children.
- Quantification of inflammatory proteins using Olink Target 48 Cytokine multiplex.
- Assessment of human pulmonary microvascular endothelial cell (HPMEC) barrier function via transendothelial electrical resistance (TEER).
Main Results:
- Plasma enhanced HPMEC barrier function with lower proinflammatory cytokines compared to TBAL.
- TBAL samples improved HPMEC barrier function over time, with reduced proinflammatory cytokines.
- TBAL from children with severe lung injury had a greater augmenting effect on HPMEC barriers.
Conclusions:
- Blood and lung compartments contain distinct proteins influencing pulmonary endothelial integrity.
- These proteins exert differential and evolving effects on barrier function.
- Findings may guide compartment-specific biomarker assessment and therapy delivery in pediatric critical illness.
Objectives:
Acute hypoxemic respiratory failure is a leading cause of death and disability in critically ill children. Pulmonary capillary barrier dysfunction, in large part, drives severity. We aimed to define how blood and tracheobronchial lavage (TBAL) fluid differentially affect pulmonary capillary barrier function and, as a second exploratory aim, identify protein mediators.
Design:
We performed a secondary analysis in April and May of 2024 of blood and TBAL samples from a previously completed observational cohort study of mechanically ventilated children collected from October 2018 to February 2020.
Setting:
Single PICU.
Subjects:
Stored blood and TBAL samples from 65 children requiring mechanical ventilation collected at 24 and 48-72 hours after intubation.
Interventions:
None.
Measurements And Main Results:
We quantified inflammatory proteins in plasma and TBAL using Olink Target 48 Cytokine multiplex. We assessed changes in barrier function of cultured human pulmonary microvascular endothelial cells (HPMECs) using electrical cell-substrate impedance to measure transendothelial electrical resistance. Plasma samples from critically ill children significantly enhanced HPMEC barrier function and contained lower concentrations of proinflammatory cytokines compared with TBAL. Over time, the effects of plasma on barrier integrity diminished, while TBAL samples significantly improved barrier function and had reduced abundance of several proinflammatory cytokines. Notably, TBAL samples from children with severe lung injury augmented HPMEC barriers more than those from children without lung injury, highlighting distinct compartmental and disease-specific influences on HPMEC barriers.
Conclusions:
These unexpected findings reveal that blood and lung compartments contain differentially abundant proteins that exert distinct and evolving influences on pulmonary endothelial integrity in critically ill children. These results may inform on the timing and compartment-specific assessment of biomarkers, and eventually, delivery of therapies.
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