The synergistic Reduning and cefmetazole sodium treatment of severe pneumonia is mediated by the AhR-Src-STAT3 pathway

Abstract

Background: Reduning (RDN) is a common Chinese medicine preparation with antibacterial, antiinflammatory, antiviral and immunomodulatory effects in respiratory infectious diseases. Clinically, it is used in combination with antibiotics, but its synergistic effect and mechanism in treating severe pneumonia remain unclear.Methods: A rat model of severe pneumonia and an in vitro coculture model consisting of A549 and THP-1 cells were used to observe the synergistic effect of RDN on severe pneumonia. The inflammatory cytokines were tested by enzyme-linked immunosorbent assay (ELISA). The localization of Aryl hydrocarbon receptor (AhR) in A549 cells was observed by immunofluorescence, and the interaction of AhR and signal transducer and activator of transcription 3 (STAT3) proteins was observed by co-immunoprecipitation.AhR-Src tyrosine kinase (Src)-STAT3 pathway in rats and A549 cells were examined by Western Blot. Histopathological changes were observed by Hematoxylin-eosin (HE) staining, X-ray and survival rates were used to evaluate the effects of paclitaxel on severe pneumonia rats.Results: RDN regulation of Src-STAT3-interleukin 10 (IL-10) signaling pathway activation and macrophage polarization were mediated through the nuclear receptor AhR. The expression of AhR was significantly increased after RDN treatment, and this effect was accompanied by STAT3 expression increasing. Coimmunoprecipitation confirmed an interaction between AhR and STAT3 and upregulated IL-10 expression. Silencing AhR decreased Src, STAT3, and IL-10 expression. RDN activated AhR and increased Src, STAT3, and IL-10 expression. In addition, RDN regulated the polarization of macrophages RDN combined with cefmetazole sodium significantly reduced the pulmonary bacterial load, alleviated lung injury, and reduced o inflammatory factors expression, improving their survival.Conclusions: RDN can synergistically enhance the effect of cefmetazole sodium treatment in severe pneumonia, and the mechanism may involve increasing the expression level of IL-10 mediated through the AhR-Src-STAT3 pathway, driving the polarization of macrophages, and attenuating the cytokine storm to control inflammation in severe pneumonia.

Caffeic acid attenuates tissue damage and inflammatory response in Klebsiella pneumonia by modulating AhR‐Src‐STAT3‐IL‐10 signaling pathway

“…Upon binding to ligands, AhR can enter the nucleus and control the expression levels of various genes, and participate in immune and inflammatory 10 pathway, which is a significant intracellular inflammatory pathway. 14,15,21 The present study also indicated that CA significantly enhanced the levels of IL-10 expression as well as the phosphorylation of STAT3 and Src. STAT3 phosphorylation levels, as well as IL-10 significantly decreased after knockout of AhR, which increased slightly after treatment with CA with no significant difference.…”

“…Multiple investigations have demonstrated that Src and STAT3 are downstream AhR targets. They serve a crucial role in regulating inflammation and immunity and can be phosphorylated by activating AhR to perform their physiological function, especially mediating IL‐10 pathway, which is a significant intracellular inflammatory pathway 14,15,21 . The present study also indicated that CA significantly enhanced the levels of IL‐10 expression as well as the phosphorylation of STAT3 and Src.…”

“…10 The aryl hydrocarbon receptor (AhR) is a classical immunomodulator, and it has been found that activation of AhR prevents Streptococcus pneumoniae-induced mortality and reduces the bacterial load in the lungs, whereas activation of AhR in severe pneumonia leads to elevated levels of STAT3 (Signal Transducer and Activator of Transcription 3) and IL-10, which in turn play a therapeutic role in severe pneumonia. 13,14 In addition, AhR-Src-STAT3-IL-10 has been shown to be a key pathway in the regulation of inflammation by macrophages. 13,15 In conclusion, AhR-Src-STAT3-IL-10 signaling pathway can be used as a potential signaling pathway for lung inflammation and lung infection, but it has not been reported in KP.…”

Sivelestat sodium attenuates acute lung injury by inhibiting JNK/NF-κB and activating Nrf2/HO-1 signaling pathways

“…The rats were anesthetized by the intraperitoneal injection of 3% pentobarbital sodium (prediluted with sterile normal saline) at the dose of 50 mg/kg. Then, the bacterial suspension (0.2 mL) was injected into their trachea [ 26 ].…”

Reduning Attenuates LPS-Induced Human Unmilical Vein Endothelial Cells (HUVECs) Apoptosis Through PI3K-AKT Signaling Pathway

“…RDN injection is a kind of TCM injections, which was composed of Artemisia annua, Honeysuckle and Gardenia gardenia ( Jiang et al, 2019 ). With the effects of clearing heat, dispersing wind and detoxifying, RDN is widely accepted as the treatment of acute infectious disease ( Zhang et al, 2013 ; Luo et al, 2022 ). Prior investigations have implemented that RDN could improve the prognosis in early sepsis though reducing the degree of inflammation and improving prognosis ( Zhou et al, 2016 ; Zheng, 2019a ).…”