Bu-Shen-Fang-Chuan formula attenuates cigarette smoke-induced inflammation by modulating the PI3K/Akt-Nrf2 and NF-κB signalling pathways.

Chronic obstructive pulmonary disease (COPD) is a respiratory inflammatory disease. Unlike asthma, COPD is insensitive to glucocorticoid treatment; thus, it is of great importance to find alternative medications, including Chinese medicine, to suppress inflammation. Bu-Shen-Fang-Chuan formula (BSFCF) is commonly used for the treatment of COPD in China. However, the mechanisms of BSFCF in COPD treatment are still unclear. To verify the anti-inflammatory efficacy of BSFCF in COPD and to explore the possible mechanisms underlying its anti-inflammatory efficacy based on the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt)-Nuclear factor erythroid 2-related factor 2 (Nrf2) and Nuclear factor (NF)-κB signalling pathways. A rat model of COPD was established by chronic exposure to cigarette smoke (CS) for 6 months. Bronchoalveolar lavage fluid (BALF) and blood were obtained to detect inflammatory cytokines. Lung samples were harvested, and part of each sample was fixed for subsequent H&E staining and immunohistochemical (IHC) analysis. The remaining lung tissues were used for RNA sequencing analysis and western blotting. BSFCF significantly reduced inflammatory infiltration in the lungs of CS-exposed rats and decreased the concentrations of tumor necrosis factor (TNF)-α and interleukin (IL)-6 in both the BALF and serum. Additionally, BSFCF evidently attenuated NF-κB activation and downregulation of glucocorticoid receptor (GR) caused by CS. Furthermore, BSFCF increased the activation of PI3K/Akt-Nrf2 signalling in response to CS. BSFCF attenuated CS-induced inflammation in COPD, which was partially achieved through the PI3K/Akt-Nrf2 and NF-κB signalling pathways.

Li Q ，Wang G ，Xiong SH ，Cao Y ，Liu B ，Sun J ，Li L ，Mohammadtursun N ，Yu H ，Dong J ，Wu J ... -  《-》

Bu-Shen-Fang-Chuan formula attenuates T-lymphocytes recruitment in the lung of rats with COPD through suppressing CXCL9/CXCL10/CXCL11-CXCR3 axis.

Chronic obstructive pulmonary disease (COPD) is a common respiratory disease characterized by irreversible airflow limitation. The current medications show limited effects on the decline of pulmonary function in COPD. Our multicenter clinical trial found that Bu-Shen-Fang-Chuan fomula (BSFCF), a Chinese herbal formula, markedly reduced the frequencies of acute exacerbation of COPD and delayed lung function decline. However, the underlying mechanisms are still unclear. In this study, we established a COPD rat model through a 6-month exposure to cigarette smoke (CS) and found that BSFCF (7.2 g/kg) effectively improved CS-induced reduction in pulmonary function and remarkably decreased the numbers of inflammatory cells in bronchoalveolar lavage fluid (BALF). Importantly, BSFCF treatment notably prevented the accumulation of T-lymphocytes (especially CD8+ T-cells) in the lung of COPD rats. RNA sequencing analysis of lung tissue demonstrated that CXCL9/CXCL10/CXCL11-CXCR3 chemokine axis in the lung of CS-exposed rats was significantly suppressed by BSFCF. Moreover, our Real-time PCR data verified that BSFCF evidently inhibited the mRNA expressions of CXCL9, CXCL10, CXCL11 and CXCR3. Conclusively, BSFCF markedly improved pulmonary function and attenuated CD8+ T-cells recruitment in the lung of CS-exposed rats, which were partially through inhibition of CXCL9/CXCL10/CXCL11-CXCR3 axis.

Li Q ，Sun J ，Cao Y ，Liu B ，Li L ，Mohammadtursun N ，Zhang H ，Dong J ，Wu J ... -  《-》

Baicalin attenuates inflammation by inhibiting NF-kappaB activation in cigarette smoke induced inflammatory models.

Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) is a key player in the inflammatory response. Baicalin is an extract from roots of the plant scutellaria baicalensis. Many studies show that baicalin has anti-inflammatory, anti-bacterial and antiviral activities. Here we investigated the influence of baicalin on COPD inflammation and the mechanism of anti-inflammatory effect in vivo and in vitro. In vivo, COPD rat model was established by cigarette smoke (CS) exposure. Thirty-six Sprague-Dawley (SD) rats were randomly assigned to six experimental groups: control, CS, dexamethasone (DXM), and baicalin (20 mg/kg, 40 mg/kg, 80 mg/kg). The lung pathology was observed and leukocytes in bronchoalveolar lavage fluid (BALF) were counted by Optical microscope. Pulmonary function was measured by using an animal plethysmograph. The production of cytokines was measured by ELISA and the expression levels of NF-kappaB p65 protein were detected by immunohistochemistry. The results in vivo show CS exposure significantly increased the expression of IL-8, IL-6 and TNF-alpha in plasma and BALF and enhanced NF-kappaB p65 expression in the lungs. Baicalin treatment markedly attenuated the inflammatory effects of CS. In vitro, cell model was established by using cigarette smoke extract (CSE) to stimulate type II pneumocytes. Type II pneumocytes were also divided into six groups: control, CSE, pyrrolidine dithiocarbamate (PDTC), and baicalin (5 mumol, 10 mumol, 20 mumol). Cytokines levels were measured by ELISA. Expression of IkappaB and p65 phosphorylation was detected by western blotting. NF-kappaB DNA-binding activity was detected by EMSA. The results show that CSE resulted in increasing IL-8, IL-6 and TNF-alpha expression and activation of NF-kappaB. The proinflammatory effects of CSE were inhibited by treatment of baicalin in a dose-dependent manner. It can be concluded that baicalin has significant anti-inflammatory effects on CS induced COPD rat models and CSE-induced cell models, and the effectiveness increases with increasing baicalin dosage. The anti-inflammatory effect is likely achieved by inhibiting the NF-kappaB pathway.

Lixuan Z ，Jingcheng D ，Wenqin Y ，Jianhua H ，Baojun L ，Xiaotao F ... -  《-》

Salvianolic acid B attenuates lung inflammation induced by cigarette smoke in mice.

Salvianolic acid B (Sal B), a bioactive compound isolated from the Chinese herb Radix Salviae Miltiorrhizae, has been reported to exhibit anti-inflammatory and anti-oxidantive effects. The aim of this study was to investigate the protective effects of Sal B on cigarette smoke (CS)-induced acute lung inflammation. Sal B was given intraperitoneally (i.p.) to mice 1h before CS exposure daily for four consecutive days. Bronchoalveolar lavage fluid (BALF) was collected to assess the levels of inflammatory cytokines and cell counts. Lung tissues were used to analysis pathological changes, total glutathione (GSH), nuclear factor erythroid-2 related factor 2 (Nrf-2), and nuclear factor-kappa B (NF-κB) expression. The results showed that Sal B inhibited CS-induced lung pathological changes, the infiltration of inflammatory cells, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), and monocyte chemoattractant protein 1 (MCP-1) productions. Sal B also up-regulated CS-induced total glutathione (GSH) production. Furthermore, Sal B was found to up-regulate Nrf-2, hemeoxygenase1 (HO1) expression and suppress CS-induced NF-κB activation. In conclusion, the current study demonstrated that Sal B exhibited a protective effect on CS-induced lung injury and the possible mechanism was involved in activating Nrf-2 and inhibiting NF-κB activation.

Zhang DF ，Zhang J ，Li R 《-》

Therapeutic effect of Mahaenggamseok-tang on neutrophilic lung inflammation is associated with NF-κB suppression and Nrf2 activation.

Mahaenggamseok-tang (MHGST), an herbal formula in traditional Asian medicine, has been used to treat patients with various pulmonary diseases including common cold and influenza. However, the potential therapeutic effect of MHGST on acute lung injury (ALI), a leading cause of death worldwide, and the anti-inflammatory mechanisms of MHGST remained less understood. The methanol extract of MHGST was prepared and fingerprinted by HPLC. For the induction of ALI, C57BL/6 mice (n=5/group) received a single intraperitoneal (i.p.) injection of LPS. Referring to the dose for patients, two different amounts of MHGST were delivered in an aerosol to mouse lungs via trachea 2h after the i.p. LPS administration. Lung histology, bronchoalveolar lavage fluid, myeloperoxidase (MPO) activity, and the expression of inflammatory and Nrf2-dependent genes were analyzed to determine the effect of MHGST on lung inflammation. For mechanistic studies, western blotting and semi-quantitative RT-PCR were conducted using RAW 264.7 cells. When administered 2h after the onset of ALI, MHGST relieved lung pathology characteristic to ALI, with decreases of neutrophil infiltration and MPO activity. While suppressing the expression of inflammatory genes, MHGST increased the expression of Nrf2-dependent genes in ALI mouse lungs. Concordantly, MHGST activated Nrf2 activity while suppressing NF-κB in RAW 264.7 cells. MHGST suppressed neutrophilic lung inflammation, a hallmark of ALI, which was associated with the activation of anti-inflammatory Nrf2 and the suppression of pro-inflammatory NF-κB. Our results suggest that MHGST has a therapeutic potential against ALI.

Kim KH ，Lee JY ，Kwun MJ ，Choi JY ，Han CW ，Ha KT ，Jeong SI ，Jeong HS ，Joo M ... -  《-》