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CARDIOPULMONARY BYPASS-DERIVED PLASMA EXOSOMAL HMGB1 CONTRIBUTES TO ALVEOLAR EPITHELIAL CELL NECROPTOSIS VIA
Yupeng Zhao1, Jinyuan Zhang1, Huihong Lu1
1Department of Anesthesiology and Critical Care Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
Shock (Augusta, Ga.)
|December 14, 2022
Summary
Cardiopulmonary bypass (CPB) increases exosomal high-mobility group box 1 (HMGB1), inducing lung cell necroptosis via mitochondrial DNA and the cGAS/STING pathway, contributing to acute lung injury (ALI).
Area of Science:
- Cardiovascular Surgery
- Pulmonary Medicine
- Cellular Biology
Background:
- Cardiopulmonary bypass (CPB) is known to cause acute lung injury (ALI).
- High-mobility group box 1 (HMGB1) release and exosome transport are implicated in CPB-induced pulmonary damage.
- Alveolar epithelial cell (AEC) necroptosis is a key factor in ALI pathogenesis.
Purpose of the Study:
- To investigate if exosomal HMGB1 from CPB patients induces AEC necroptosis.
- To elucidate the underlying molecular mechanisms involving mitochondrial DNA and inflammatory pathways.
Main Methods:
- Prospective cohort study of 21 CPB patients with plasma sample collection at four time points.
- Isolation of plasma exosomes and co-culture with A549 cells.
- Treatment with HMGB1 antagonist (Box A) and mitochondrial DNA inhibitor (EtBr) to assess pathway involvement.
Main Results:
- Plasma exosomal HMGB1 levels increased significantly post-CPB, peaking at 24 hours.
- CPB-derived exosomes induced AEC necroptosis, mitochondrial fission, and elevated cytoplasmic mitochondrial DNA (mtDNA).
- Inhibition of HMGB1 or mtDNA blocked necroptosis and the downstream cGAS/STING signaling pathway.
Conclusions:
- CPB-derived exosomal HMGB1 promotes AEC necroptosis.
- The mechanism involves mtDNA release and activation of the cGAS/STING pathway.
- Targeting exosomal HMGB1 or mtDNA may offer therapeutic strategies for CPB-associated ALI.
