Dual-Route Administration of Umbilical Cord MSC- Exosomes Mitigates LPS-Induced Acute Respiratory Distress Syndrome in Mice

Abstract Background: Acute Respiratory Distress Syndrome (ARDS) is a complex syndrome characterized by acute diffuse lung injury and progressive respiratory failure, caused by various intra- and extra-pulmonary factors. The COVID-19 pandemic has significantly increased the incidence of ARDS, posing a tremendous threat to human health due to its high mortality rate and lack of effective therapeutic drugs. In recent years, mesenchymal stem cell-derived exosomes (MSC-exo) have been considered a new hope for the treatment of ARDS due to their potent immunomodulatory characteristics. Although multiple studies have demonstrated their efficacy and safety, the differential therapeutic effects of various administration routes and doses remain unclear. This study aimed to investigate the optimal administration route and dosage of MSC-exo for ARDS treatment, with the goal of maximizing therapeutic benefits and providing valuable clinical insights. Methods: In this study, we aim to establish an ARDS disease model in male C57/BL6 mice and administer exosomes of umbilical cord mesenchymal stem cells through inhalation, tail vein injection, and dual route administration (inhalation combined with tail vein injection). After perfusing LPS into the trachea for 24 hours, we monitored respiratory function, pulmonary oxygen saturation, lung tissue pathology, and levels of inflammatory cytokines in bronchoalveolar lavage fluid and peripheral blood. Results: Compared with single route administration via inhalation or tail vein injection, dual-route administration significantly improved the respiratory function of ARDS mice, increased blood oxygen saturation, alleviated LPS-induced lung injury, and lowered inflammatory cytokines levels in bronchoalveolar lavage fluid and peripheral blood. Conclusion: The dual-route administration of umbilical cord MSC-exosomes is more effective in controlling the inflammatory response and alleviating lung injury in LPS-induced ARDS animal models. Inhalation rapidly alleviates pulmonary inflammation with a smaller dose, while intravenous injection better manages the systemic inflammation. This dual-route approach holds promise as a novel ARDS treatment strategy.