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Aminophylline modulates the permeability of endothelial cells via the Slit2-Robo4 pathway in lipopolysaccharide-induced inflammation.

ABSTRACT: Sepsis and septic shock are the main cause of mortality in intensive care units. The prevention and treatment of sepsis remains a significant challenge worldwide. The endothelial cell barrier plays a critical role in the development of sepsis. Aminophylline, a non-selective phosphodiesterase inhibitor, has been demonstrated to reduce endothelial cell permeability. However, little is known regarding the role of aminophylline in regulating vascular permeability during sepsis, as well as the potential underlying mechanisms. In the present study, the Slit2/Robo4 signaling pathway, the downstream protein, vascular endothelial (VE)-cadherin and endothelial cell permeability were investigated in a lipopolysaccharide (LPS)-induced inflammation model. It was indicated that, in human umbilical vein endothelial cells (HUVECs), LPS downregulated Slit2, Robo4 and VE-cadherin protein expression levels and, as expected, increased endothelial cell permeability in vitro during inflammation. After administration of aminophylline, the protein expression levels of Slit2, Robo4 and VE-cadherin were upregulated and endothelial cell permeability was significantly improved. These results suggested that the permeability of endothelial cells could be mediated by VE-cadherin via the Slit2/Robo4 signaling pathway. Aminophylline reduced endothelial permeability in a LPS-induced inflammation model. Therefore, aminophylline may represent a promising candidate for modulating vascular permeability induced by inflammation or sepsis.

SUBMITTER: Chen Q

PROVIDER: S-EPMC8343459 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:SLIT2, a member of neuronal guidance cues, has been reported to regulate inflammation and cancer progression. Periodontitis is an oral inflammatory disease that degenerates periodontal tissue, alveolar bone and tooth. This study aims to explore the expression pattern of SLIT2 in periodontitis and its role in disease progression and bone loss. Gingival tissue of 20 periodontitis patients and 20 healthy-controls was obtained. Ligature-induced periodontitis (LIP) mice-model was developed in Slit2-Tg and wild-type mice. The effect of SLIT2 on inflammation, immune cell infiltration, M1 macrophage polarization, and alveolar bone loss in periodontitis was analyzed extensively. In periodontitis-affected gingival-tissue, SLIT2 expression was 4.4-fold higher compared to healthy-volunteers. LIP enhanced SLIT2 expression in mice periodontitis-affected periodontal tissue (PAPT) and blood circulation of wild-type mice by 4. 6-, and 5.0-fold, respectively. In Slit2-Tg-mice PAPT, SLIT2 expression was 1.8-fold higher compared to wild-type mice. Micro-CT and histomorphometric analysis revealed a 1.3-fold higher cement-enamel-junction to the alveolar-bone-crest (CEJ-ABC) distance and alveolar bone loss in LIP Slit2-Tg-mice compare to LIP wild-type mice. Results from RNA-sequencing, RT-qPCR, and ELISA showed a higher expression of Cxcr2, Il-18, TNF?, IL-6, and IL-1? in Slit2-Tg-mice PAPT compared to wild-type-mice. Slit2-Tg-mice PAPT showed a higher number of osteoclasts, M1 macrophages, and the upregulation of Robo1 expression. Slit2-Tg-mice PAPT showed upregulation of M1 macrophage marker CD16/32 and osteoclastogenic markers Acp5, Ctsk, and Nfatc1, but osteogenic markers (Alp, Bglap) remained unchanged. Immunohistochemistry unveiled the higher vasculature and infiltration of leucocytes and macrophages in Slit2-Tg-mice PAPT. RNA-sequencing, GO-pathway enrichment analysis, and western blot analysis revealed the activation of the MAPK signaling pathway in Slit2-Tg mice PAPT. In conclusion, SLIT2 overexpression in periodontitis intensifies inflammation, immune cells infiltration, M1 macrophage polarization, osteoclastogenesis, and alveolar bone loss, possibly via activation of MAPK signaling, suggesting the role of SLIT2 on exacerbation of periodontitis and alveolar bone loss.

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Aminophylline modulates the permeability of endothelial cells via the Slit2-Robo4 pathway in lipopolysaccharide-induced inflammation.

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