Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, MN 55108, USA.
Early Oncology Clinical Science, Astra Zeneca, One Medimmune Way, Gaithersburg, MD 20878, USA.
Int J Mol Sci. 2020 Sep 12;21(18):6688. doi: 10.3390/ijms21186688.
Sepsis is the culmination of hyperinflammation and immune suppression in response to severe infection. Neutrophils are critical early responders to bacterial infection but can become highly dysfunctional during sepsis and other inflammatory disorders. The transmembrane protease ADAM17 (a disintegrin and metalloproteinase 17) is expressed by leukocytes and most other cells and has many substrates that regulate inflammation. We have reported that conditional knockout mice lacking ADAM17 in all leukocytes had a survival advantage during sepsis, which was associated with improved neutrophil effector functions. These and other findings indicate aberrant ADAM17 activity during sepsis. For this study, we evaluated for the first time the effects of an ADAM17 function blocking monoclonal antibody (mAb) on the pathogenesis of polymicrobial sepsis. Mice treated with the ADAM17 mAb MEDI3622 prior to sepsis induction exhibited significantly decreased mortality. When the ADAM17 mAb was combined with antibiotic administration, sepsis survival was markedly enhanced compared to either intervention alone, which was associated with a significant reduction in plasma levels of various inflammation-related factors. MEDI3622 and antibiotic administration after sepsis induction also significantly improved survival. Our results indicate that the combination of blocking ADAM17 as an immune modulator and appropriate antibiotics may provide a new therapeutic avenue for sepsis treatment.
脓毒症是严重感染时过度炎症反应和免疫抑制的最终结果。中性粒细胞是对细菌感染的早期关键反应者，但在脓毒症和其他炎症性疾病中可能变得高度功能失调。跨膜蛋白酶 ADAM17（解整合素和金属蛋白酶 17）由白细胞和大多数其他细胞表达，其许多底物可调节炎症。我们曾报道，所有白细胞中缺乏 ADAM17 的条件性敲除小鼠在脓毒症期间具有生存优势，这与改善中性粒细胞效应功能有关。这些和其他发现表明，在脓毒症期间 ADAM17 活性异常。在这项研究中，我们首次评估了 ADAM17 功能阻断单克隆抗体（mAb）对多微生物脓毒症发病机制的影响。在脓毒症诱导前用 ADAM17 mAb MEDI3622 治疗的小鼠死亡率显著降低。当 ADAM17 mAb 与抗生素联合使用时，与单独使用任一干预措施相比，脓毒症的存活率显著提高，这与各种炎症相关因子的血浆水平显著降低有关。在脓毒症诱导后使用 MEDI3622 和抗生素治疗也显著提高了存活率。我们的研究结果表明，作为免疫调节剂的 ADAM17 阻断与适当的抗生素联合使用可能为脓毒症治疗提供新的治疗途径。
