Abstract
BackgroundExposure to air particulate matter (PM) is associated with various diseases in the human respiratory system. To date, most in vitro studies showing cellular responses to PM have been performed in cell culture using a single cell type. There are few studies considering how multicellular networks communicate in a tissue microenvironment when responding to the presence of PM. Here, an in vitro three-dimensional (3D) respiratory mucosa-on-a-chip, composed of human nasal epithelial cells, fibroblasts, and endothelial cells, is used to recapitulate and better understand the effects of urban particulate matter (UPM) on human respiratory mucosa.ResultsWe hypothesized that the first cells to contact with UPM, the nasal epithelial cells, would respond similar to the tissue microenvironment, and the 3D respiratory mucosa model would be a suitable platform to capture these events. First, whole transcriptome analysis revealed that UPM induced gene expression alterations in inflammatory and adhesion-related genes in human nasal epithelial cells. Next, we developed an in vitro 3D respiratory mucosa model composed of human nasal epithelial cells, fibroblasts, and endothelial cells and demonstrated that the model is structurally and functionally compatible with the respiratory mucosa. Finally, we used our model to expose human nasal epithelial cells to UPM, which led to a disruption in the integrity of the respiratory mucosa by decreasing the expression of zonula occludens-1 in both the epithelium and endothelium, while also reducing vascular endothelial cadherin expression in the endothelium.ConclusionsWe demonstrate the potential of the 3D respiratory mucosa model as a valuable tool for the simultaneous evaluation of multicellular responses caused by external stimuli in the human respiratory mucosa. We believe that the evaluation strategy proposed in the study will move us toward a better understanding of the detailed molecular mechanisms associated with pathological changes in the human respiratory system.
Highlights
Exposure to air particulate matter (PM) is associated with various diseases in the human respiratory system
Once the epithelial cell was exposed to the urban particulate matter (UPM), epithelial integrity was disrupted because of alterations in the expression of genes related to cell adhesion and inflammation
These results indicate that UPM can affect the nasal epithelium by altering the expression of genes related to inflammation and adhesion, and this may alter the tissue microenvironment
Summary
Exposure to air particulate matter (PM) is associated with various diseases in the human respiratory system. Inhalation of UPM induces cardiovascular diseases, neoplastic disorders, and various respiratory diseases such as lung cancer, chronic obstructive pulmonary disease (COPD), asthma, and rhinitis [4,5,6,7] These diseases develop when UPM penetrates the human respiratory mucosa and accumulates in target tissues [8]. Human respiratory mucosa is the first point of contact for hazardous materials such as inhaled bacteria, viruses, pollen, and air pollutants, and acts as a physical and immune barrier to harmful environmental factors [9] It consists of the superficial epithelium, submucosal glands, subepithelial stromal cells, and endothelial cells. Loss of endothelial integrity may cause an increase in vascular permeability, which leads to a potential increase in extracellular edema [16] This phenomenon occurs following the release of various stromal cytokines from the adjacent cell network [17]
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