Specific upregulation of extracellular miR-6238 in particulate matter-induced acute lung injury and its immunomodulation

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening diseases charac-terized by a severe inflammatory response and the destruction of alveolar epithelium and endothelium. ALI/ ARDS is caused by pathogens and toxic environmental stimuli, such as particulate matter (PM). However, the general symptoms of ALI/ARDS are similar, and determining the cause of lung injury is often challenging. In this study, we investigated whether there is a critical miRNA that characterizes PM-induced ALI. We found that the expression of miR-6238 is specifically upregulated in lung tissue and lung-derived extracellular vesicles (EVs) in response to PM exposure. Notably, bacterial endotoxin (Lipopolysaccharide; LPS or peptidoglycan; PTG) does not induce the expression of miR-6238 in the lung. Instead, the expression of miR-155 is dramatically increased in LPS-induced ALI. We further demonstrated that human lung epithelial cells and macrophages predominantly produce miR-6238 and miR-155, respectively. Mechanistically, EV-miR-6238 is effectively internalized into alveolar macrophages (AMs) and regulates inflammatory responses in vivo. CXCL3 is a main target of miR-6238 in AMs and modulates neutrophil infiltration into the lung alveoli. Collectively, our findings suggest that miR-6238 is a novel regulator of pulmonary inflammation and a putative biomarker that distinguishes PM-induced ALI from endotoxin (LPS/PTG)-mediated ALI.

Automated summary

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are severe inflammatory diseases characterized by the destruction of lung tissue and the upregulation of specific miRNAs, such as miR-6238. This study found that miR-6238 is specifically upregulated in response to particulate matter (PM) exposure but not bacterial endotoxin (LPS/PTG), and it plays a role in regulating inflammatory responses in alveolar macrophages (AMs). These findings suggest that miR-6238 could serve as a biomarker to distinguish PM-induced ALI from endotoxin-mediated ALI.