Inhibition of the Lectin Pathway of Complement Activation Reduces Acute Respiratory Distress Syndrome Severity in a Mouse Model of SARS-CoV-2 Infection
Inhibition of the Lectin Pathway of Complement Activation Reduces Acute Respiratory Distress Syndrome Severity in a Mouse Model of SARS-CoV-2 Infection
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DOI：
10.1093/infdis/jiad462
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发表时间：
2023-11-14
影响因子：
6.4
通讯作者：
Schwaeble，Wilhelm
中科院分区：
文献类型：
--
作者：
Ali，Youssif M.;Carnell，George W.;Schwaeble，Wilhelm
重症监护室中的大多数COVID-19患者会出现急性呼吸窘迫综合征，其特征是严重低氧血症、肺顺应性降低和血管通透性高。补体系统的激活是中度和重度COVID-19的标志，在COVID-19期间，补体蛋白在发炎组织和内皮上大量沉积。使用SARS-CoV-2感染的转基因小鼠模型，我们评估了靶向MASP-2（凝集素途径中的关键酶）的抑制性抗体（HG 4）的治疗效用。与接受同种型对照抗体的小鼠相比，用HG 4治疗感染的小鼠降低了疾病严重程度评分并改善了存活率。给予HG 4显著降低肺损伤评分，包括肺泡炎性细胞浸润、肺泡水肿和肺泡出血。HG 4处理小鼠脑小胶质细胞促炎激活的显着减少反映了MASP-2抑制对COVID-19病理严重程度的改善作用。
Most patients with COVID-19 in the intensive care unit develop an acute respiratory distress syndrome characterized by severe hypoxemia, decreased lung compliance, and high vascular permeability. Activation of the complement system is a hallmark of moderate and severe COVID-19, with abundant deposition of complement proteins in inflamed tissue and on the endothelium during COVID-19. Using a transgenic mouse model of SARS-CoV-2 infection, we assessed the therapeutic utility of an inhibitory antibody (HG4) targeting MASP-2, a key enzyme in the lectin pathway. Treatment of infected mice with HG4 reduced the disease severity score and improved survival vs mice that received an isotype control antibody. Administration of HG4 significantly reduced the lung injury score, including alveolar inflammatory cell infiltration, alveolar edema, and alveolar hemorrhage. The ameliorating effect of MASP-2 inhibition on the severity of COVID-19 pathology is reflected by a significant reduction in the proinflammatory activation of brain microglia in HG4-treated mice.