Taxifolin ameliorates sepsis-induced lung capillary leak through inhibiting the JAK/STAT3 pathway

Abstract

Background: As a systemic inflammatory reaction, sepsis is associated with various organ dysfunctions. The capillary leakage and the imbalance between T helper 17 and regulatory T (Th17/Treg) cells are associated with sepsis-induced lung injury. Taxifolin (TXL) has been found to play a vital role in regulating this diverse disease. However, the detailed functioning and mechanism of TXL in regulating sepsis-induced lung capillary leak remain elusive. Methods: Balb/c mice were used to establish sepsis-induced lung injury model through administration of lipopolysaccharide (LPS). The structure of lung tissues was observed by using hematoxylin & eosin staining. Protein level and total cells in bronchoalveolar lavage fluid (BALF) were measured by bicinchoninic acid (BCA) protein assay kit and hematimetry assay, respectively. Quantitative real-time reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay were employed to detect the level of inflammatory cytokines. The content of Th17 and Treg cells were measured by flow cytometry analysis. Western blot assay was used to determine the protein level of retinoid-related orphan receptor-γt (RORγt), Forkhead box P3 (Foxp3), Janus kinase 2 (JAK2), phospho(p)-JAK2, signal transducer and activator of transcription 3 (STAT3), and phospho(p)-STAT3. Results: Taxifolin effectively prolonged the survival period of sepsis mice and alleviated LPS-induced lung injury in a dose-dependent manner. Moreover, TXL reduced LPS-induced increase in protein levels and T cell content in BALF, and effectively restored the wet:dry ratio of lung tissue and tissue permeability. Treating with TXL notably inhibited the production of pro-inflammatory cytokines induced by sepsis and influenced the balance between Th17 and Treg cells. Furthermore, TXL treatment suppressed the activation of JAK/STAT3 signaling pathway in a dose-dependent manner. Conclusion: Our findings revealed that TXL alleviated sepsis-induced capillary leak in the lungs of mice by regulating JAK/STAT3 signaling pathway.

Fasudil and SR1001 synergistically protect against sepsis-associated pancreatic injury by inhibiting RhoA/ROCK pathway and Th17/IL-17 response

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Combining Runmu fengye tang preparation with hydroxysugar glycolic acid eye drops regulates Th17/Treg balance to treat dry eyes via inhibition of JAK2/STAT3 pathway

“…Janus kinase 2 signal transducer/transcription activator 3 (JAK2/STAT3) signaling pathway regulates inflammatory mediators involved in extracellular signaling pathways and plays an overall regulatory role in inflammatory responses and cell survival [19]. Most importantly, the JAK2/STAT3 signaling pathway is also involved in the regulation of Th17/Treg homeostasis [20]. In T lymphocytes, activated STAT3 mediates its downstream signaling pathway to enhance RORγt expression in initial CD4 + T lymphocytes, thereby contributing to the differentiation of CD4 + T cells to Th17 [21].…”

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