ASK1-ER stress pathway-mediated fibrotic-EV release contributes to the interaction of alveolar epithelial cells and lung fibroblasts to promote mechanical ventilation-induced pulmonary fibrosis

Abstract

Recent clinical research has revealed that mechanical ventilation (MV) can initiate pulmonary fibrosis and induce mechanical ventilation-induced pulmonary fibrosis (MVPF). However, the underlying mechanism remains largely uncharacterized. Based on a mouse model of MVPF and an alveolar epithelial cell cyclic strain model, the present study explores the possible mechanism of MVPF. Single-cell RNA-sequencing and EV RNA-sequencing analysis revealed that MV promoted apoptosis signal-regulating kinase 1 (ASK1)-mediated endoplasmic reticulum (ER) stress pathway activation and extracellular vesicle (EV) release from alveolar epithelial cells. Furthermore, the ASK1-ER stress pathway was shown to mediate mechanical stretch (MS)- or MV-induced EV release and lung fibroblast activation in vivo and in vitro. These processes were suppressed by ER stress inhibitors or by silencing ASK1 with ASK1- short hairpin RNA (shRNA). In addition, MVPF was suppressed by inhibiting ASK1 and ER stress in vivo. Therefore, the present study demonstrates that ASK1-ER stress pathway-mediated fibrotic-EV release from alveolar epithelial cells contributes to fibroblast activation and the initiation of pulmonary fibrosis during MV. The inhibited release of EVs targeting the ASK1-ER stress pathway might be a promising treatment strategy for MVPF.

Lung disease: stress response pathway linked to ventilator-induced fibrosis

Cells that line airway sacs in the lungs react to the mechanical strain imposed by ventilators by activating a stress response pathway that may be targetable to prevent or treat ventilator-induced pulmonary fibrosis. A team from Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine in China led by Zhengyu He and Yuan Gao profiled gene expression patterns in mice that developed lung fibrosis following mechanical ventilation and in cultured airway sac cells exposed to deforming tension in the laboratory. The researchers showed that the physical strain on the lung tissue activates a key cellular stress response pathway mediated by a protein called ASK1, which is associated with various stress responses. Lung alveolar cells consequently secrete small vesicles containing signaling molecules that prompt another population of cells, lung fibroblasts, to deposit collagen, a process that drives lung fibrosis.