Protective Role of Adipose-Derived Circulating Exosomal miR-122-5p on the Pulmonary Endothelial Barrier Through Inhibiting EndMT via Downregulation of the TGFβ1/TGFβr1/Smad2 Pathway: A Potential Explanation for the Obesity Paradox in ARDS

Background: The “obesity paradox in acute respiratory distress syndrome (ARDS)” refers to the phenomenon that obesity is associated with a lower mortality in patients with ARDS. Endothelial to mesenchymal transition (EndMT) represents a key link in the interaction between endothelial disruption and mesenchymal fibrosis under inflammatory conditions, which are intersectional pathophysiologies of ARDS. Adipose tissue is reported to constitute the major source of circulating exosomal miRNAs, thereby these miRNAs act as genetic forms of adipokines for cell-cell crosstalk. However, the regulation of adipose-derived exosomal miRNAs in the obesity paradox in ARDS are largely unknown.Methods High-fat induced-obese mice and lean control mice were subjected to ARDS insult to investigate the effects of obesity on ARDS and microarray analysis was performed to screen the different circulating microRNAs. Mice and pulmonary endothelial cells were administered to adipose-derived exosomal miR-122-5p to further investigate the molecular mechanism. Findings: We found that high-fat diet-induced obesity protected against ARDS by reinforcing the endothelial barrier and attenuating fibroproliferation in mice. Circulating exosomes produced in the obese state mediated this protective effect by inhibiting EndMT. Mechanistically, adipose-derived exosomal miR-122-5p promoted the integrity and function of pulmonary endothelial barrier and alleviated fibrogenesis by suppressing EndMT through downregulation of the TGFβ1/TGFβR1/Smad2 pathway in vivo and in vitro. Interpretation Our findings propose a potential explanation for the obesity paradox in ARDS and indicate promising prospects for adipose-derived exosomes in cell-free therapies for ARDS. Funding: This work was supported by the NSFC of China (Grant NO. 81800083) and China Postdoctoral Science Foundation (2019M653832XB). Declaration of Interest: The authors declare no conflict of interest. Ethical Approval: Animal procedures were approved by the ethics committee of Chongqing Medical University and implemented according to the instructions of the National Institutes of Health Guide for the Care and Use of Laboratory Animals.