Division of HIV, Infectious Diseases, and Global Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, United States.
Early Vaccines and Immune Therapies, AstraZeneca, Gaithersburg, MD, United States.
Front Immunol. 2023 Sep 15;14:1260627. doi: 10.3389/fimmu.2023.1260627. eCollection 2023.
Patients with septic shock caused by have mortality rates exceeding 50%, despite appropriate antibiotic therapy. Our objectives were to establish a rabbit model of septic shock and to determine whether a novel immunotherapy can prevent or halt its natural disease progression.
Anesthetized rabbits were ventilated with lung-protective low-tidal volume, instrumented for advanced hemodynamic monitoring, and characterized for longitudinal changes in acute myocardial dysfunction by echocardiography and sepsis-associated biomarkers after intravenous challenge. To demonstrate the potential utility of this hyperdynamic septic shock model for preclinical drug development, rabbits were randomized for prophylaxis with anti-Hla/Luk/ClfA monoclonal antibody combination that neutralizes alpha-hemolysin (Hla), the bicomponent pore-forming leukocidins (Luk) including Panton-Valentine leukocidin, leukocidin ED, and gamma-hemolysin, and clumping factor A (ClfA), or an irrelevant isotype-matched control IgG (c-IgG), and then challenged with .
Rabbits challenged with , but not those with saline, developed a hyperdynamic state of septic shock characterized by elevated cardiac output (CO), increased stroke volume (SV) and reduced systemic vascular resistance (SVR), which was followed by a lethal hypodynamic state characterized by rapid decline in mean arterial pressure (MAP), increased central venous pressure, reduced CO, reduced SV, elevated SVR, and reduced left-ventricular ejection fraction, thereby reproducing the hallmark clinical features of human staphylococcal septic shock. In this model, rabbits pretreated with anti-Hla/Luk/ClfA mAb combination had 69% reduction in mortality when compared to those pretreated with c-IgG (<0.001). USA300-induced acute circulatory failure-defined as >70% decreased in MAP from pre-infection baseline-occurred in only 20% (2/10) of rabbits pretreated with anti-Hla/Luk/ClfA mAb combination compared to 100% (9/9) of those pretreated with c-IgG. Prophylaxis with anti-Hla/Luk/ClfA mAb combination halted progression to lethal hypodynamic shock, as evidenced by significant protection against the development of hyperlactatemia, hypocapnia, hyperkalemia, leukopenia, neutropenia, monocytopenia, lymphopenia, as well as biomarkers associated with acute myocardial injury.
These results demonstrate the potential utility of a mechanically ventilated rabbit model that reproduced hallmark clinical features of hyperdynamic septic shock and the translational potential of immunotherapy targeting virulence factors for the prevention of staphylococcal septic shock.
由 引起的感染性休克患者的死亡率超过 50%，尽管采用了适当的抗生素治疗。我们的目标是建立一种兔感染性休克模型，并确定一种新型免疫疗法是否可以预防或阻止其自然疾病进展。
麻醉兔进行保护性低潮气量通气，进行先进的血流动力学监测，并通过超声心动图和与脓毒症相关的生物标志物对急性心肌功能障碍进行纵向评估，然后静脉内给予 。为了证明这种高动力性感染性休克模型在临床前药物开发中的潜在应用价值，兔子被随机分为预防组，用抗 Hla/Luk/ClfA 单克隆抗体联合治疗，该联合治疗可中和α-溶血素（Hla）、双组分孔形成白细胞毒素（Luk），包括 Panton-Valentine 白细胞毒素、白细胞毒素 ED 和 γ-溶血素，以及凝聚因子 A（ClfA），或用无关的同种型匹配对照 IgG（c-IgG），然后用 进行挑战。
用 而不是生理盐水挑战的兔子会发生高动力性感染性休克，表现为心输出量（CO）升高、每搏量（SV）增加和全身血管阻力（SVR）降低，随后发生致命性低动力状态，表现为平均动脉压（MAP）迅速下降，中心静脉压升高，CO 降低，SV 降低，SVR 升高，左心室射血分数降低，从而再现了人类葡萄球菌感染性休克的标志性临床特征。在该模型中，与用 c-IgG 预处理的兔子相比，用抗 Hla/Luk/ClfA mAb 联合治疗的兔子的死亡率降低了 69%（<0.001）。USA300 引起的急性循环衰竭定义为 MAP 从感染前基线下降超过 70%，仅在用抗 Hla/Luk/ClfA mAb 联合治疗的兔子中发生 20%（10/50），而在用 c-IgG 预处理的兔子中发生 100%（9/9）。用抗 Hla/Luk/ClfA mAb 联合治疗进行预防可阻止向致命性低动力休克进展，这表现在显著保护免受高乳酸血症、低碳酸血症、高钾血症、白细胞减少、中性粒细胞减少、单核细胞减少、淋巴细胞减少以及与急性心肌损伤相关的生物标志物的发展。
这些结果表明，机械通气兔模型具有潜在的应用价值，该模型再现了高动力性感染性休克的标志性临床特征，并且针对 毒力因子的免疫疗法具有预防葡萄球菌感染性休克的转化潜力。
