Microvascular hyperpermeability is a leading mechanism responsible for occurrence of edema in remoteorgans and tissues in patients with burn injury. Accumulated evidence has shown that exosomes can betransported into target cells, where they are capable of regulating biological functions and physiology. Ofexosomal proteins contributing to enhanced inflammation and vascular permeability, S100 calcium bindingprotein A9 (S100A9) has received increasing attention. Here we hypothesized that S100A9-containing serumexosomes of patients with burn injury contribute to pathogenesis of hyperpermeability of microvascularstructure in lung by transferring signaling molecules into it and activating downstream signaling pathways,ultimately leading to disruption of the tight junctions (TJs) and endothelial barrier. A use of enzyme-linkedimmunosorbent assay revealed that total serum concentrations of S100A9 were significantly augmented inburn injury patients in comparison to normal controls. With use of human pulmonary microvascularendothelial cells (HPMECs) as an in vitro model, we found that patients’ serum exosomes were effectivelyinternalized by HPMECs. We further found that serum exosomes of stage II/II burn patients inhibited zonulaoccludens (ZO-1) and occludin protein levels, which are essential for TJs integrity and endothelial barrierfunction, but activated p38 MAPK signaling pathway in HPMECs. As expected, such exosomes-mediatedeffects on HPMECs were reversed by a simultaneous treatment of anti-S100A9 neutralizing antibody. Finally,we found that a recombinant human S100A9 treatment led to inhibition of expression of occludin and ZO-1 butan activation of p38 signaling in HPMECs, and that such effects were reversed when p38 activity wasrepressed, implying that S100A9 may stimulate p38 activity to inhibit ZO-1 and occludin in HPMECs.Collectively, these data suggest that S100A9-containing serum exosomes may play a critical role in contributingto pulmonary microvascular hyperpermeability, thus supporting that blocking exosomes’ access toHPMECs could hold a promise strategy for treatment of lung edema resulting from burn injuries.
Volume 46, 2021
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