Xuanfei Baidu decoction ameliorates bleomycin-elicited idiopathic pulmonary fibrosis in mice by regulating the lung-gut crosstalk via IFNγ/STAT1/STAT3 axis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial pneumonia, the available treatment option is limited because the etiology and pathological process are not well understood. Although gut-lung axis reported with an emerging area of host-associated microbiota exist in many chronic lung diseases, the connection between gut-lung microbiota composition with in-site inflammation in IPF development is not yet established. PURPOSE: We aimed to address the microbiota and immunity connection, and make it clear how a listed drug, Xuanfei Baidu Decoction (XFBD) affect the lung-gut crosstalk for IPF amelioration, which was previously reported for restoring disrupted lung in IPF and protecting intestinal injury. METHODS: Firstly, Micro-CT (µCT) and histopathology were used to check for pathological changes in the lungs and intestines of bleomycin (BLM)-induced IPF mice. Then, Reverse Transcription and Quantitative Real-time PCR (RT-qPCR) and Western blot (WB) assays were employed to detect the integrity of the barrier of lungs and intestines in IPF mice. Subsequently, flow cytometry and 16S rRNA sequencing were used to evaluate the immune and microbial microenvironment of the lungs and intestines. We analyzed the lung-gut microbiota crosstalk for further mechanism exploration. RESULTS: Firstly, we revealed that XFBD protected the integrity of the lung and intestinal barriers in the IPF mice, as evidenced by the up-regulation of ZO-1, Claudin-1, Occludin, and VE Cadherin protein expression. Then, we analyzed the changing microbiota and T cell in the gut-lung axis in IPF, and with XFBD, six highly relevant microenvironments were demonstrated that crossing damaged lung-gut barriers and XFBD could reverse these chaotic bacterial and immunity micro-environment, among them Akkermansia was an essential bacteria affecting the expression of systemic IFN-γ downstream STAT1/STAT3 axis was also studied. XFBD prominently up-regulated the production of IFN-γ and p-STAT1 and down-regulated p-STAT3, consequently exerting effects on the lung barrier and gut barrier. Taken together, XFBD ameliorated BLM-induced IPF mice by regulating IFNγ/STAT1/STAT3 axis. CONCLUSION: Altogether, our results revealed that XFBD improved the BLM-elicited IPF mice by regulating gut-lung crosstalk via IFN-γ/STAT1/STAT3 axis and provided a new insight of gut-lung crosstalk in IPF, especially the dynamic changes of microorganisms in the damaged lungs needed to pay more attention during IPF therapy.

Xuanfei Baidu decoction in the treatment of coronavirus disease 2019 (COVID-19): Efficacy and potential mechanisms.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread worldwide and become a major global public health concern. Although novel investigational COVID-19 antiviral candidates such as the Pfizer agent PAXLOVID™, molnupiravir, baricitinib, remdesivir, and favipiravir are currently used to treat patients with COVID-19, there is still a critical need for the development of additional treatments, as the recommended therapeutic options are frequently ineffective against SARS-CoV-2. The efficacy and safety of vaccines remain uncertain, particularly with the emergence of several variants. All 10 versions of the National Health Commission's diagnosis and treatment guidelines for COVID-19 recommend using traditional Chinese medicine. Xuanfei Baidu Decoction (XFBD) is one of the "three Chinese medicines and three Chinese prescriptions" recommended for COVID-19. This review summarizes the clinical evidence and potential mechanisms of action of XFBD for COVID-19 treatment. With XFBD, patients with COVID-19 experience improved clinical symptoms, shorter hospital stay, prevention of the progression of their symptoms from mild to moderate and severe symptoms, and reduced mortality in critically ill patients. The mechanisms of action may be associated with its direct antiviral, anti-inflammatory, immunomodulatory, antioxidative, and antimicrobial properties. High-quality clinical and experimental studies are needed to further explore the clinical efficacy and underlying mechanisms of XFBD in COVID-19 treatment.

Xuanfei Baidu Decoction regulates NETs formation via CXCL2/CXCR2 signaling pathway that is involved in acute lung injury.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening symptoms in Coronavirus Disease 2019 (COVID-19) patients. Xuanfei Baidu Decoction (XFBD) is a recommend first-line traditional Chinese medicine (TCM) formula therapeutic strategy for COVID-19 patients. Prior studies demonstrated the pharmacological roles and mechanisms of XFBD and its derived effective components against inflammation and infections through multiple model systems, which provided the biological explanations for its clinical use. Our previous work revealed that XFBD inhibited macrophages and neutrophils infiltration via PD-1/IL17A signaling pathway. However, the subsequent biological processes are not well elucidated. Here, we proposed a hypothesis that XFBD can regulate the neutrophils-mediated immune responses, including neutrophil extracellular traps (NETs) formation and the generation of platelet-neutrophil aggregates (PNAs) after XFBD administration in lipopolysaccharide (LPS)-induced ALI mice. The mechanism behind it was also firstly explained, that is XFBD regulated NETs formation via CXCL2/CXCR2 axis. Altogether, our findings demonstrated the sequential immune responses of XFBD after inhibiting neutrophils infiltration, as well as shedding light on exploiting the therapy of XFBD targeting neutrophils to ameliorate ALI during the clinical course.

[Clinical observation of Xuanfei Baidu Decoction in treatment of severe coronavirus disease 2019 (COVID-19)].

The present study evaluated the effectiveness and safety of Xuanfei Baidu Decoction(XFBD) for severe cases with coronavirus disease 2019(COVID-19).Forty-one patients(diagnosed as severe or critical type) admitted to Hubei Provincial Hospital of Integrated Chinese and Western Medicine and Wuhan Hospital of Traditional Chinese Medicine from February 1 to March 1, 2020, were included.All patients were treated with XFBD based on conventional therapies.Clinical outcomes, length of hospital stay, and lung CT images of patients were observed.Laboratory indicators were compared between admission and the 14 th day of treatment.Traditional Chinese medicine(TCM) symptoms and signs on the 7 th and 14 th days of treatment were also compared with baseline.The differences in clinical characteristics and clinical outcomes between XFBD and western medicine or conventional therapies were analyzed with the published trials on severe COVID-19 cases during the same period as external controls.According to the results, among the 41 cases, 40 were cured and discharged, and 1 died; the median length of hospital stay was 22 days, and the improvement rate of lung CT was 87.2%(34/39).Compared with the conditions on admission, the levels of white blood cells(WBC), C-reactive protein(CRP), fibrinogen(FIB), and lactate dehydrogenase(LDH) were reduced(P<0.05, P<0.01), and levels of procalcitonin(PCT), prothrombin time(PT), creatine kinase(CK), alanine aminotransferase(AST), total bilirubin(TBiL), and other indicators showed a downward trend.Moreover, symptoms like fever, cough, chest tightness/shortness of breath, dyspnea, head and body pain, anorexia, and greasy tongue coating were significantly improved on the 7 th and 14 th days of treatment(P<0.05, P<0.01), and fatigue was improved on the 14 th day of treatment(P<0.01).The mortality, adverse reactions, and major events of the XFBD group were significantly lower than those of the western medicine and conventional treatment groups in the same period, and the usage of antibiotics, hormones, vasopressin, and invasive mechanical ventilation during treatment were generally less than other groups.In conclusion, XFBD has good efficacy and safety in the treatment of severe COVID-19 cases by improving inflammation and clinical symptoms, promoting the absorption of lung inflammation, and reducing mortality.

Xuanfei Baidu decoction attenuates intestinal disorders by modulating NF-κB pathway, regulating T cell immunity and improving intestinal flora.

BACKGROUND: A number of studies have shown that gastrointestinal manifestations co-exist with respiratory symptoms in coronavirus disease 2019 (COVID-19) patients. Xuanfei Baidu decoction (XFBD) was recommended by the National Health Commission to treat mild and moderate COVID-19 patients and proved to effectively alleviate intestinal symptoms. However, the exact mechanisms remain elusive. PURPOSE: This study aimed at exploring potential mechanisms of XFBD by utilizing a mouse model of dextran sulfate sodium (DSS)-induced acute experimental colitis, mimicking the disease conditions of intestinal microecological disorders. METHODS: The network pharmacology approach was employed to identify the potential targets and pathways of XFBD on the intestinal disorders. Mice with DSS-induced intestinal disorders were utilized to evaluate the protective effect of XFBD in vivo, including body weight, disease activity index (DAI) score, colon length, spleen weight, and serum tumor necrosis factor-α (TNF-α) level. Colon tissues were used to perform hematoxylin-eosin (H&E) staining, western blot analysis, and transcriptome sequencing. Macrophages, neutrophils and the proportions of T helper cell (Th) 1 and Th2 cells were measured by flow cytometry. Intestinal contents were collected for 16S rRNA gene sequencing. RESULTS: Network pharmacology analysis indicated that XFBD inhibited the progression of COVID-19-related intestinal diseases by repressing inflammation. In mice with DSS-induced intestinal inflammation, XFBD treatment significantly reduced weight loss, the spleen index, the disease activity index, TNF-α levels, and colonic tissue damage, and prevented colon shortening. Transcriptomics and flow cytometry results suggested that XFBD remodeled intestinal immunity by downregulating the Th1/Th2 ratio. Western blot analysis showed that XFBD exerted its anti-inflammatory effects by blocking the nuclear factor-κB (NF-κB) signaling pathway. Indicator analysis of microbiota showed that 75 operational taxonomic units (OTUs) were affected after XFBD administration. Among them, Akkermansia, Muribaculaceae, Lachnospiraceae, and Enterorhabdus were simultaneously negatively correlated with intestinal disorders' parameters, and Bacteroides, Escherichia-Shigella, Eubacterium nodatum,Turicibacter, and Clostridium sensu stricto 1, showed positive correlations with intestinal disorders' parameters. CONCLUSIONS: Our data indicate that XFBD treatment attenuated intestinal disorders associated with inhibiting inflammation, remodeling of intestinal immunity, and improving intestinal flora. These findings provide a scientific basis for the clinical use of XFBD and offer a potential therapeutic approach for the treatment of COVID-19 patients with intestinal symptoms.

Xuanfei Baidu Decoction reduces acute lung injury by regulating infiltration of neutrophils and macrophages via PD-1/IL17A pathway.

The pathogenic hyper-inflammatory response has been revealed as the major cause of the severity and death of the Corona Virus Disease 2019 (COVID-19). Xuanfei Baidu Decoction (XFBD) as one of the "three medicines and three prescriptions" for the clinically effective treatment of COVID-19 in China, shows unique advantages in the control of symptomatic transition from moderate to severe disease states. However, the roles of XFBD to against hyper-inflammatory response and its mechanism remain unclear. Here, we established acute lung injury (ALI) model induced by lipopolysaccharide (LPS), presenting a hyperinflammatory process to explore the pharmacodynamic effect and molecular mechanism of XFBD on ALI. The in vitro experiments demonstrated that XFBD inhibited the secretion of IL-6 and TNF-α and iNOS activity in LPS-stimulated RAW264.7 macrophages. In vivo, we confirmed that XFBD improved pulmonary injury via down-regulating the expression of proinflammatory cytokines such as IL-6, TNF-α and IL1-ß as well as macrophages and neutrophils infiltration in LPS-induced ALI mice. Mechanically, we revealed that XFBD treated LPS-induced acute lung injury through PD-1/IL17A pathway which regulates the infiltration of neutrophils and macrophages. Additionally, one major compound from XFBD, i.e. glycyrrhizic acid, shows a high binding affinity with IL17A. In conclusion, we demonstrated the therapeutic effects of XFBD, which provides the immune foundations of XFBD and fatherly support its clinical applications.

Xuanfei Baidu Decoction protects against macrophages induced inflammation and pulmonary fibrosis via inhibiting IL-6/STAT3 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Xuanfei Baidu Decoction (XFBD), one of the "three medicines and three prescriptions" for the clinically effective treatment of COVID-19 in China, plays an important role in the treatment of mild and/or common patients with dampness-toxin obstructing lung syndrome. AIM OF THE STUDY: The present work aims to elucidate the protective effects and the possible mechanism of XFBD against the acute inflammation and pulmonary fibrosis. METHODS: We use TGF-ß1 induced fibroblast activation model and LPS/IL-4 induced macrophage inflammation model as in vitro cell models. The mice model of lung fibrosis was induced by BLM via endotracheal drip, and then XFBD (4.6 g/kg, 9.2 g/kg) were administered orally respectively. The efficacy and molecular mechanisms in the presence or absence of XFBD were investigated. RESULTS: The results proved that XFBD can effectively inhibit fibroblast collagen deposition, down-regulate the level of α-SMA and inhibit the migration of fibroblasts. IL-4 induced macrophage polarization was also inhibited and the secretions of the inflammatory factors including IL6, iNOS were down-regulated. In vivo experiments, the results proved that XFBD improved the weight loss and survival rate of the mice. The XFBD high-dose administration group had a significant effect in inhibiting collagen deposition and the expression of α-SMA in the lungs of mice. XFBD can reduce bleomycin-induced pulmonary fibrosis by inhibiting IL-6/STAT3 activation and related macrophage infiltration. CONCLUSIONS: Xuanfei Baidu Decoction protects against macrophages induced inflammation and pulmonary fibrosis via inhibiting IL-6/STAT3 signaling pathway.

Prevention of Cyclophosphamide-Induced Immunosuppression in Mice With Traditional Chinese Medicine Xuanfei Baidu Decoction.

Background and aims: Xuanfei Baidu decoction (XFBD), a traditional Chinese medicine formulation, was designed and successfully applied for COVID-19 disease treatment in China, while the mechanism is still not clear. Methods: To evaluate the protective effect of XFBD on immunosuppression in cyclophosphamide (CY)-treated mice, XFBD was orally administrated, the body weight was measured, and the immune organ index was calculated. HE staining was performed to analyze the pathological structures of the liver, spleen, and thymus. The levels of cytokines and immunoglobulin in the serum and spleen were evaluated by ELISA and RT-PCR. Splenic lymphocytes were isolated, and LPS-stimulated cell proliferation and the number of CD4+ and CD8+ T lymphocytes were evaluated. Results: XFBD significantly suppressed body weight loss and increased the indices of spleen and thymus. The pathological alteration was much improved after XFBD administration. The reductions of TNF-α, IFN-γ, IgG, and IgM levels in serum and IL-2, IL-4, and IL-6 expressions in the spleen were all significantly alleviated by XFBD. Splenic lymphocyte proliferation in response to LPS was further enhanced after treatment with XFBD. The reduction of CD4+ and CD8+ T lymphocytes in CY-treated mice was also highly increased in XFBD groups. Conclusion: Our findings suggested that XFBD played a crucial role in protection against immunosuppression in CY-treated mice and could be a potential candidate for immune modification and therapy.

Corrigendum: Prevention of Cyclophosphamide-Induced Immunosuppression in Mice With Traditional Chinese Medicine Xuanfei Baidu Decoction.

[This corrects the article DOI: 10.3389/fphar.2021.730567.].