BMSC-Derived Exosomes Alleviate Sepsis-Associated Acute Respiratory Distress Syndrome by Activating the Nrf2 Pathway to Reverse Mitochondrial Dysfunction

Abstract

Type II alveolar epithelial cell (AECII) apoptosis is one of the most vital causes of sepsis-induced acute respiratory distress syndrome (ARDS). Recent evidence has proved that bone mesenchymal stem cell-derived exosomes (BMSC-exos) can effectively reduce sepsis-induced ARDS. However, the function and molecular mechanism of BMSC-exos in sepsis-induced AECII apoptosis remain to be elucidated. In the present study, a more significant number of AECII apoptosis, high mitochondrial fission p-Drp1 protein levels, and low levels of mitochondrial biogenesis-related PGC1α, Tfam, and Nrf1 proteins accompanied with ATP content depression were confirmed in AECIIs in response to sepsis. Surprisingly, BMSC-exos successfully recovered mitochondrial biogenesis, including the upregulated expression of PGC1α, Tfam, Nrf1 proteins, and ATP contents, and prohibited p-Drp1-mediated mitochondrial fission by promoting Nrf2 expression. However, the aforementioned BMSC-exo reversal of mitochondrial dysfunction in AECIIs can be blocked by Nrf2 inhibitor ML385. Finally, BMSC-exos ameliorated the mortality rate, AECII apoptosis, inflammatory cytokine storm including HMGB1 and IL-6, and pathological lung damage in sepsis mice, which also could be prevented by ML385. These findings reveal a new mechanism of BMSC-exos in reversing mitochondrial dysfunction to alleviate AECII apoptosis, which may provide novel strategies for preventing and treating sepsis-induced ARDS.