Verbenalin alleviates acute lung injury induced by sepsis and IgG immune complex through GPR18 receptor. 2023

Lei Yang, and Tianyu Liu, and Yuzhen Zhuo, and Dongmei Li, and Dihua Li, and Junhong Liu, and Hejun Gao, and Lanqiu Zhang, and Jianping Lin, and Ximo Wang
Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Tianjin Nankai Hospital, Tianjin, China.

Acute lung injury is significantly associated with the aberrant activation and pyroptosis of alveolar macrophages. Targeting the GPR18 receptor presents a potential therapeutic approach to mitigate inflammation. Verbenalin, a prominent component of Verbena in Xuanfeibaidu (XFBD) granules, is recommended for treating COVID-19. In this study, we demonstrate the therapeutic effect of verbenalin on lung injury through direct binding to the GPR18 receptor. Verbenalin inhibits the activation of inflammatory signaling pathways induced by lipopolysaccharide (LPS) and IgG immune complex (IgG IC) via GPR18 receptor activation. The structural basis for verbenalin's effect on GPR18 activation is elucidated through molecular docking and molecular dynamics simulations. Furthermore, we establish that IgG IC induces macrophage pyroptosis by upregulating the expression of GSDME and GSDMD through CEBP-δ activation, while verbenalin inhibits this process. Additionally, we provide the first evidence that IgG IC promotes the formation of neutrophil extracellular traps (NETs), and verbenalin suppresses NETs formation. Collectively, our findings indicate that verbenalin functions as a "phytoresolvin" to promote inflammation regression and suggests that targeting the C/EBP-δ/GSDMD/GSDME axis to inhibit macrophage pyroptosis may represent a novel strategy for treating acute lung injury and sepsis.

UI MeSH Term Description Entries
D007074 Immunoglobulin G The major immunoglobulin isotype class in normal human serum. There are several isotype subclasses of IgG, for example, IgG1, IgG2A, and IgG2B. Gamma Globulin, 7S,IgG,IgG Antibody,Allerglobuline,IgG(T),IgG1,IgG2,IgG2A,IgG2B,IgG3,IgG4,Immunoglobulin GT,Polyglobin,7S Gamma Globulin,Antibody, IgG,GT, Immunoglobulin
D007249 Inflammation A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function. Innate Inflammatory Response,Inflammations,Inflammatory Response, Innate,Innate Inflammatory Responses
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000086382 COVID-19 A viral disorder generally characterized by high FEVER; COUGH; DYSPNEA; CHILLS; PERSISTENT TREMOR; MUSCLE PAIN; HEADACHE; SORE THROAT; a new loss of taste and/or smell (see AGEUSIA and ANOSMIA) and other symptoms of a VIRAL PNEUMONIA. In severe cases, a myriad of coagulopathy associated symptoms often correlating with COVID-19 severity is seen (e.g., BLOOD COAGULATION; THROMBOSIS; ACUTE RESPIRATORY DISTRESS SYNDROME; SEIZURES; HEART ATTACK; STROKE; multiple CEREBRAL INFARCTIONS; KIDNEY FAILURE; catastrophic ANTIPHOSPHOLIPID ANTIBODY SYNDROME and/or DISSEMINATED INTRAVASCULAR COAGULATION). In younger patients, rare inflammatory syndromes are sometimes associated with COVID-19 (e.g., atypical KAWASAKI SYNDROME; TOXIC SHOCK SYNDROME; pediatric multisystem inflammatory disease; and CYTOKINE STORM SYNDROME). A coronavirus, SARS-CoV-2, in the genus BETACORONAVIRUS is the causative agent. 2019 Novel Coronavirus Disease,2019 Novel Coronavirus Infection,2019-nCoV Disease,2019-nCoV Infection,COVID-19 Pandemic,COVID-19 Pandemics,COVID-19 Virus Disease,COVID-19 Virus Infection,Coronavirus Disease 2019,Coronavirus Disease-19,SARS Coronavirus 2 Infection,SARS-CoV-2 Infection,Severe Acute Respiratory Syndrome Coronavirus 2 Infection,COVID19,2019 nCoV Disease,2019 nCoV Infection,2019-nCoV Diseases,2019-nCoV Infections,COVID 19,COVID 19 Pandemic,COVID 19 Virus Disease,COVID 19 Virus Infection,COVID-19 Virus Diseases,COVID-19 Virus Infections,Coronavirus Disease 19,Disease 2019, Coronavirus,Disease, 2019-nCoV,Disease, COVID-19 Virus,Infection, 2019-nCoV,Infection, COVID-19 Virus,Infection, SARS-CoV-2,Pandemic, COVID-19,SARS CoV 2 Infection,SARS-CoV-2 Infections,Virus Disease, COVID-19,Virus Infection, COVID-19
D000936 Antigen-Antibody Complex The complex formed by the binding of antigen and antibody molecules. The deposition of large antigen-antibody complexes leading to tissue damage causes IMMUNE COMPLEX DISEASES. Immune Complex,Antigen-Antibody Complexes,Immune Complexes,Antigen Antibody Complex,Antigen Antibody Complexes,Complex, Antigen-Antibody,Complex, Immune,Complexes, Antigen-Antibody,Complexes, Immune
D043562 Receptors, G-Protein-Coupled The largest family of cell surface receptors involved in SIGNAL TRANSDUCTION. They share a common structure and signal through HETEROTRIMERIC G-PROTEINS. G Protein Coupled Receptor,G-Protein-Coupled Receptor,G-Protein-Coupled Receptors,G Protein Coupled Receptors,Receptor, G-Protein-Coupled,Receptors, G Protein Coupled
D055371 Acute Lung Injury A condition of lung damage that is characterized by bilateral pulmonary infiltrates (PULMONARY EDEMA) rich in NEUTROPHILS, and in the absence of clinical HEART FAILURE. This can represent a spectrum of pulmonary lesions, endothelial and epithelial, due to numerous factors (physical, chemical, or biological). Lung Injury, Acute,Acute Lung Injuries,Lung Injuries, Acute
D062105 Molecular Docking Simulation A computer simulation technique that is used to model the interaction between two molecules. Typically the docking simulation measures the interactions of a small molecule or ligand with a part of a larger molecule such as a protein. Molecular Docking,Molecular Docking Simulations,Molecular Docking Analysis,Analysis, Molecular Docking,Docking Analysis, Molecular,Docking Simulation, Molecular,Docking, Molecular,Molecular Docking Analyses,Molecular Dockings,Simulation, Molecular Docking
D018805 Sepsis Systemic inflammatory response syndrome with a proven or suspected infectious etiology. When sepsis is associated with organ dysfunction distant from the site of infection, it is called severe sepsis. When sepsis is accompanied by HYPOTENSION despite adequate fluid infusion, it is called SEPTIC SHOCK. Bloodstream Infection,Pyaemia,Pyemia,Pyohemia,Blood Poisoning,Poisoning, Blood,Septicemia,Severe Sepsis,Blood Poisonings,Bloodstream Infections,Infection, Bloodstream,Poisonings, Blood,Pyaemias,Pyemias,Pyohemias,Sepsis, Severe,Septicemias

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