Department of Veterinary Medicine, School of Biological Sciences, University of Cambridge, Cambridge, United Kingdom.
Department of Microbiology and Immunology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
Front Immunol. 2023 May 30;14:1192767. doi: 10.3389/fimmu.2023.1192767. eCollection 2023.
Acute respiratory distress syndrome (ARDS) is a life-threatening disorder with a high rate of mortality. Complement activation in ARDS initiates a robust inflammatory reaction that can cause progressive endothelial injury in the lung. Here, we tested whether inhibition of the lectin pathway of complement could reduce the pathology and improve the outcomes in a murine model of LPS-induced lung injury that closely mimics ARDS in human. , LPS binds to murine and human collectin 11, human MBL and murine MBL-A, but not to C1q, the recognition subcomponent of the classical pathway. This binding initiates deposition of the complement activation products C3b, C4b and C5b-9 on LPS the lectin pathway. HG-4, a monoclonal antibody that targets MASP-2, a key enzyme in the lectin pathway, inhibited lectin pathway functional activity , with an IC of circa 10nM. Administration of HG4 (5mg/kg) in mice led to almost complete inhibition of the lectin pathway activation for 48hrs, and 50% inhibition at 60hrs post administration. Inhibition of the lectin pathway in mice prior to LPS-induced lung injury improved all pathological markers tested. HG4 reduces the protein concentration in bronchoalveolar lavage fluid (p<0.0001) and levels of myeloid peroxide (p<0.0001), LDH (p<0.0001), TNFα and IL6 (both p<0.0001). Lung injury was significantly reduced (p<0.001) and the survival time of the mice increased (p<0.01). From the previous findings we concluded that inhibition of the lectin pathway has the potential to prevent ARDS pathology.
急性呼吸窘迫综合征（ARDS）是一种致命性疾病，死亡率很高。补体在 ARDS 中的激活引发了强烈的炎症反应，可导致肺部的内皮细胞渐进性损伤。在这里，我们测试了补体凝集素途径的抑制是否可以减少脂多糖（LPS）诱导的肺损伤小鼠模型中的病理，并改善其结局，该模型与人 ARDS 非常相似。LPS 与鼠类和人类的甘露聚糖结合凝集素 11（collectin 11）、人类的甘露糖结合凝集素（MBL）和鼠类的 MBL-A 结合，但不与经典途径的识别亚单位 C1q 结合。这种结合启动了补体激活产物 C3b、C4b 和 C5b-9 在 LPS 上的沉积——即凝集素途径。靶向凝集素途径关键酶 MASP-2 的单克隆抗体 HG-4 抑制了凝集素途径的功能活性，其 IC 约为 10nM。在 LPS 诱导的肺损伤前给予 HG4（5mg/kg）可导致凝集素途径激活在 48 小时内几乎完全被抑制，而在给药后 60 小时抑制率为 50%。在 LPS 诱导的肺损伤前抑制凝集素途径可改善所有测试的病理标志物。HG4 降低了支气管肺泡灌洗液中的蛋白浓度（p<0.0001）和髓过氧化物酶（p<0.0001）、LDH（p<0.0001）、TNFα 和 IL6（均 p<0.0001）的水平。肺损伤显著减轻（p<0.001），小鼠的存活时间延长（p<0.01）。根据先前的研究结果，我们得出结论，抑制凝集素途径有可能预防 ARDS 病理。
