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Exosomes Isolated from Blood Induce Acute Lung Injury in a Rat Septic Peritonitis Model
Hiroshi Kono1, Shinji Furuya, Hidetake Amemiya
1First Department of Surgery, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan.
Aim:
Acute lung injury (ALI) is a common cause of morbidity in patients with severe sepsis. Exosomes (EXOs) have been reported to induce ALI after severe hemorrhagic shock; therefore, this study aimed to investigate the role of EXOs isolated from the blood of septic rats with ALI.
Materials And Methods:
Blood samples and lung tissues were collected from rats undergoing cecal ligation and puncture (CLP). EXOs were isolated by centrifugation from the blood of rats undergoing CLP and administered intravenously to normal rats, and 12 h after administration, lung tissues were harvested. Pathophysiological changes in the lung, the lung wet/dry weight ratio, and the lung microvascular permeability were assessed. Plasma inflammatory cytokines, namely tumor necrosis factor (TNF)-α, interleukin-6, and high-mobility group box chromosomal protein 1, were measured by enzyme-linked immunosorbent assay. In addition, lung microthrombosis was evaluated by immunohistochemistry. To investigate the effects of EXOs on tissue macrophages (Mϕs), the production of TNF-α by isolated tissue Mϕs was assessed in the presence or absence of EXOs in vitro .
Results:
Interstitial pulmonary edema, inflammatory cell infiltration, microhemorrhage, and microthrombosis were observed in the lung after CLP. Similar pathophysiological changes were observed in normal rats administered EXOs, although the extent of these changes was less severe than that in rats undergoing CLP. After EXO administration, the lung wet/dry ratio, lung microvascular permeability, and plasma inflammatory cytokine levels increased. The production of TNF-α by tissue Mϕs increased during coculture with EXOs, blocked by anti-toll-like receptor 4 antibodies in the media. Furthermore, TNF-α production significantly decreased in EXO-stimulated cells treated with Triton X or proteinase K, suggesting that the surface protein and lipid fraction were most likely primary determinants.
Conclusion:
EXOs isolated from the blood of septic rats trigger ALI by increasing inflammatory mediators.
