Disease-specific differences in particulate matter handling drive pathogenic responses in human derived nasal...

Particulate matter (PM) exposure is associated with increased risk and exacerbation of chronic rhinosinusitis (CRS), yet underlying mechanisms remain poorly understood.

To define the epithelial mechanisms by which PM exposure promotes and exacerbates CRS, with a focus on epithelial remodeling, inflammation, barrier dysfunction, and cellular uptake of PM.

Human nasal epithelial cells obtained from ethmoid tissue of CRS (n = 5) and control donors (n = 4) were cultured at an air-liquid interface and exposed to PM. Single-cell RNA sequencing was performed to characterize PM-induced cellular and transcriptional changes. Protein expression, epithelial barrier integrity, cell death, and intracellular PM uptake were evaluated using biochemical, imaging, and ultrastructural approaches.

Unsupervised clustering identified seven epithelial cell populations. Gene set analysis revealed baseline enrichment of inflammatory and keratinization pathways and reduced ciliogenesis in CRS compared with controls. Although PM induced inflammation and squamous differentiation in controls, the pathogenic responses were significantly amplified in CRS, including uniquely enhanced IL-1 signaling. Transcriptional changes were validated by ELISA, transepithelial electrical resistance, and immunofluorescence, demonstrating increased inflammation, epithelial barrier disruption, and cell death following PM exposure. Transmission electron microscopy revealed increased intracellular PM within membrane-bound organelles. Pre-treatment with an endocytosis inhibitor rescued PM-induced epithelial barrier dysfunction and inflammation.

CRS epithelium exhibits baseline dysfunction that may predispose it to environmental injury. PM exposure both induces CRS-like epithelial changes in controls and exacerbates disease-associated phenotypes.

Compared to controls, CRS nasal epithelium exhibits baseline inflammatory, keratinization, and ciliogenesis abnormalities.Particulate matter induces inflammation and squamous differentiation, while amplifying epithelial injury that is more robust in CRS epithelium compared to controls.Inhibition of dynamin-dependent endocytosis rescues PM-induced epithelial barrier leakiness and inflammation, implicating intracellular particulate matter uptake in disease pathogenesis.

Particulate matter induces CRS-like epithelial remodeling in controls and exacerbates inflammation and epithelial barrier dysfunction in CRS nasal epithelium, which can be rescued with endocytosis inhibition. This suggests a mechanistic link between baseline CRS vulnerability, intracellular uptake of particulate matter, and disease pathogenesis.