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ERG lacking endothelium identifies IL8-CXCR2 axis as a therapeutic target for resolving neutrophilic lung vascular injury

ABSTRACT: Neutrophilic inflammation and hyperpermeable lung microvasculature are consequential to lethal acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). The vascular endothelium is the first point of entry for neutrophils to breach and cause tissue injury. In this study we demonstrate that conditional deletion of ERG (ETS related gene) in adult endothelium of iEC-ERG-/- mice, spontaneously induces accumulation of neutrophils in the lungs. The infiltrated neutrophils showed altered transcriptome, enriched with genes that induce neutrophil recruitment and activation. These activated neutrophils induced lung vascular inflammatory injury. This study shows that endothelial ERG, instructs EC anti-inflammatory niche and thereby controls neutrophil accumulation and activation in the lungs. As the loss of ERG is observed in chronic lung injury, including ARDS, pulmonary hypertension (PAH) and fibrosis, our findings will have implications for understanding and therapeutically mitigating neutrophil function in inflammatory diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE310680 | GEO | 2025/11/25

REPOSITORIES: GEO

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Project description:Although the accumulation of neutrophils in the lungs and airways is common to many inflammatory lung diseases, including acute lung injury, the alterations that neutrophils undergo as they leave the peripheral circulation and migrate into the lungs have not been well characterized. Human volunteers were exposed to endotoxin by bronchoscopic instillation. The resulting air space neutrophil accumulation and peripheral blood neutrophils were isolated 16 h later, compared with circulating neutrophils isolated before or after to the pulmonary endotoxin exposure, and compared with circulating neutrophils exposed to endotoxin in vitro. Microarray analysis was performed on air space, circulatory, and in vitro endotoxin-stimulated neutrophils. Functional analysis included the determination of neutrophil apoptosis, chemotaxis, release of cytokines and growth factors, and superoxide anion release. Dramatic gene expression differences were apparent between air space and circulating neutrophils: approximately 15% of expressed genes have altered expression levels, including broad increases in inflammatory- and chemotaxis-related genes, as well as antiapoptotic and IKK-activating pathways. Functional analysis of air space compared with circulating neutrophils showed increased superoxide release, diminished apoptosis, decreased IL-8-induced chemotaxis, and a pattern of IL-8, macrophage inflammatory protein-1beta, monocyte chemoattractant protein-1, and tumor necrosis factor-alpha release different from either unstimulated or LPS-stimulated circulating neutrophils. Many of these changes are not elicited by in vitro treatment with endotoxin. Limited differences were detected between circulating neutrophils isolated before and 16 h after pulmonary endotoxin instillation. These results suggest that neutrophils sequestered in the lung become fundamentally different from those resident in the circulation, and this difference is distinct from in vitro activation with endotoxin.

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ERG lacking endothelium identifies IL8-CXCR2 axis as a therapeutic target for resolving neutrophilic lung vascular injury

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