Aberrant differentiation of epithelial progenitors is accompanied by a hypoxic microenvironment in the paraquat-injured human lung
Paraquat is a toxic herbicide that can cause severe lung injury, leading to alveolar epithelial cell death, subsequent lung fibrosis and respiratory failure. Understanding the repair process following paraquat injury is critical for developing effective therapeutic strategies to treat paraquat-poisoned patients. However, the lung repair program in paraquat-injured lungs is currently unknown. In this study, we analyzed lung parenchyma samples from an 18-year-old female patient who had ingested paraquat and subsequently underwent a double-lung transplantation on the 34th day after poisoning. By the combination of single cell RNA sequencing analysis and immunostaining analysis, we reveal that the airway stem/progenitor cells and AT2 cells in the paraquat-injured lung exhibit a significantly reduced capacity to regenerate alveolar epithelium epithelial in the paraquat-injured lung. The hypoxic microenvironment may contribute to this aberrant repair program by activating the NOTCH signaling pathway, ultimately leading to an irreversible loss of gas-exchange units and an exacerbated lung tissue damage. Overall design: Lung specimens of the paraquat poisoning patient were obtained from the lung removed at the time of lung transplantation. This patient is an 18-year-old female who had ingested paraquat and subsequently underwent a double-lung transplantation on the 34th day after poisoning. Epithelial cells, endothelial cells, immune cells, and stromal cells were harvested by fluorescence-activated cell sorting and then single-cell RNA analysis were performed to analysis the cellular and molecular changes of the paraquat-injured lung.