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A High Dimensionality Approach Reveals Immunopathogenic Responses Driving Severe Pediatric Acute Respiratory Distress Syndrome

ABSTRACT: Mechanisms underlying paediatric acute respiratory distress syndrome (PARDS) remain poorly understood, limiting advances in diagnosis and treatment. To address this gap, we adopted a high-dimensional multi-omics approach to better understand immune dysregulation in PARDS, aiming to identify distinct pathogenic pathways. We show that severe PARDS is marked by interferon-driven immune dysregulation, with pulmonary T cells and myeloid cells exhibiting strong interferon responses and suppressed IL-1 pathways, resulting in impaired immune cell function and reduced IL-1α/β levels.

ORGANISM(S): Homo sapiens

PROVIDER: GSE327171 | GEO | 2026/05/12

REPOSITORIES: GEO

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Project description:Importance: Monocytes are plastic cells that assume different polarization states that can either promote inflammation or tissue repair and inflammation resolution. Polarized monocytes are partially defined by their transcriptional profiles that are influenced by environmental stimuli. The airway monocyte response in pediatric acute respiratory distress syndrome (PARDS) is undefined. Objectives: To identify differentially expressed genes and networks using a novel transcriptomic reporter assay with donor monocytes exposed to the airway fluid of intubated children with and at-risk for PARDS. To determine differences in gene expression at two time points using the donor monocyte assay exposed to airway fluid from intubated children with PARDS obtained 48-96 hours following initial tracheal aspirate sampling. Design, Setting and Participants: In vitro pilot study carried out using airway fluid supernatant from 57 children: 44 children with PARDS and 13 children at-risk for PARDS. Main Outcomes and Measures: We performed bulk RNA sequencing using a transcriptomic reporter assay of monocytes exposed to airway fluid from intubated children to discover gene networks differentiating PARDS from at-risk for PARDS. We also report differences in gene expression in children with PARDS 48-96 hours following initial tracheal aspirate sampling. Results: We found that interleukin (IL)-10, -4, and -13, cytokine/chemokine signaling, and the senescence-associated secretory phenotype are upregulated in monocytes exposed to airway fluid from intubated children with PARDS compared to those at-risk for PARDS. Signaling by NOTCH, histone deacetylation/acetylation, DNA methylation, chromatin modifications (B-WICH complex), and RNA polymerase I transcription and its associated regulatory apparatus were upregulation in children with PARDS 48-96 hours following initial tracheal aspirate sampling. Conclusions and Relevance: We identified gene networks important to the PARDS airway immune response using bulk RNA sequencing from a monocyte reporter assay that exposed monocytes to airway fluid from intubated children with and at-risk for PARDS. Mechanistic investigations are needed to validate our findings.

Project description:Acute respiratory distress syndrome (ARDS) is a lung inflammatory condition associated with the accumulation of fluid edema and cell infiltrates into the alveolar space along with the dysregulation in the immune response. Current therapeutics are limited to palliative care, i.e., mechanical ventilators, thus highlighting the need of developing targeted therapeutic for ARDS. Interleukin-27 (IL-27) is a multifunctional cytokine with the capability for immune modulation. Our interest lies in exploring the properties of IL-27, particularly as an anti-inflammatory cytokine that functions as an antagonist of IL-6 signaling, as an inducer of anti-viral genes, as a promoter of tissue repair, and as a regulator of both the innate and adaptive immune responses, possessing promising potential as a therapeutic for ARDS. To overcome the challenge of repeated administration due to the short half-life of cytokines, we utilized a cell-based gene therapy approach. IL-27-expressing plasmid was transfected into adipose mesenchymal stromal cells (ASC) that serve as the gene therapy carriers. For in vitro studies, we treated mono- and co-culture lung lipopolysaccharide (LPS)-induced lung epithelial and monocytes/macrophages cell line with IL-27-expressing ASC (IL-27) conditioned media (CM) to determine the effects on pro-inflammatory gene expression. For in vivo studies, male C57BL/6 mice was intratracheally injected with LPS (5mg/kg) and treated either PBS, ASC, or IL-27 ASC (5 x 105 cells/mouse) after 24h of LPS instillation. Measurements of gene expression, histopathological changes, cell infiltrations, and protein content in the bronchoalveolar lavage fluid and RNA-seq analysis were performed for the in vivo studies. Results indicated that IL-27ASC CM were able to reduce pro-inflammatory gene expression of lung epithelial and macrophages cultured in both mono- and co-culture systems. Additionally, IL-27 ASC were able to reduce pro-inflammatory markers, decrease cell infiltration into the lungs, promote genes and immune cells involved in tissue repair, and rebalance innate and adaptive immunity in an LPS-induced in vivo model. Collectively, our in vitro and in vivo results showed promising potential for IL-27 cell-based gene therapy as a treatment for ARDS.

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A High Dimensionality Approach Reveals Immunopathogenic Responses Driving Severe Pediatric Acute Respiratory Distress Syndrome

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