摘要
COVID-19 is an immune-mediated inflammatory disease caused by SARS-CoV-2 infection,the combination of anti-inflammatory and antiviral therapy is predicted to provide clinical benefits.We recently demonstrated that mast cells(MCs)are an essential mediator of SARS-CoV-2-initiated hyperinflammation.We also showed that spike protein-induced MC degranulation initiates alveolar epithelial inflammation for barrier disruption and suggested an off-label use of antihistamines as MC stabilizers to block degranulation and consequently suppress inflammation and prevent lung injury.In this study,we emphasized the essential role of MCs in SARS-CoV-2-induced lung lesions in vivo,and demonstrated the benefits of co-administration of antihistamines and antiviral drug remdesivir in SARS-CoV-2-infected mice.Specifically,SARSCoV-2 spike protein-induced MC degranulation resulted in alveolar-capillary injury,while pretreatment of pulmonary microvascular endothelial cells with antihistamines prevented adhesion junction disruption;predictably,the combination of antiviral drug remdesivir with the antihistamine loratadine,a histamine receptor 1(HR1)antagonist,dampened viral replication and inflammation,thereby greatly reducing lung injury.Our findings emphasize the crucial role of MCs in SARS-CoV-2-induced inflammation and lung injury and provide a feasible combination antiviral and anti-inflammatory therapy for COVID-19 treatment.
基金
supported by the National Natural Science Foundation of China(82172242,81873965)
State Key Laboratory of Respiratory Disease,Guangzhou,China(SKLRD-OP-202207)
National Key R&D Program of China(2020YFC0842000)
Natural Science Foundation of Guangdong(2022A1515012053)
Key Project from the Chinese Academy of Sciences(QYZDB-SSWSMC059)。
