Epithelial MAPK Signaling Directs Endothelial NRF2 Signaling and IL-8 Secretion in the Alveolar Capillary Region

Particulate matter 2.5 (PM2.5) deposition in the lung's alveolar capillary region (ACR) is significantly associated with respiratory disease development, yet the underlying molecular mechanisms are not completely understood. Adverse responses that promote respiratory disease development involve orchestrated, intercellular signaling between multiple cell types within the ACR. Our goal was to use an organotypic, in vitro model of the ACR to investigate if alveolar epithelial PM2.5 exposure induces exposure responses in alveolar epithelial cells and in underlying microvascular endothelial cells in the ACR. Our findings demonstrate that alveolar epithelial PM2.5 exposure induces robust transcriptional responses in the microvascular endothelial cells within the ACR. We show that the underlying microvascular endothelial cells develop redox dysfunction and increase proinflammatory cytokine secretion, two exposure responses commonly associated with respiratory disease development. Moreover, we identified intercellular signaling mechanisms between the alveolar epithelium and microvascular endothelium that modulate these adverse endothelial exposure responses. Our findings illustrate a new mechanism of intercellular communication between cells of the ACR that significantly improves our understanding of respiratory disease development following pulmonary exposure to inhaled materials. Overall design: Two different human cell lines are used within this study: 1) NCI-H441 cells, an alveolar-like epithelial cell line and 2) HULEC, human lung endothelial cells. These cells were incorporated into the organotypic ACRE model and RNA-seq data was collected for comparative gene expression profiling analysis following a 6 and 24 h VEH or ACRE-DEP exposure. 3 indpendent experiments were run, serving as 3 biological replicates for each cell type, time point, and treatment. Average log2FC values were obtained by averaging the differential gene expression changes of the 3 biological replicates per condition. The average log2FC values per condition are the reported / published data.