Critical Care Medicine Department, Clinical Center, NIH, Bethesda, Maryland, USA.
Department of Pediatrics, Division of Critical Care, Washington University in St. Louis, St. Louis, Missouri, USA.
JCI Insight. 2018 Sep 20;3(18). doi: 10.1172/jci.insight.123013.
During the last half-century, numerous antiinflammatory agents were tested in dozens of clinical trials and have proven ineffective for treating septic shock. The observation in multiple studies that cell-free hemoglobin (CFH) levels are elevated during clinical sepsis and that the degree of increase correlates with higher mortality suggests an alternative approach. Human haptoglobin binds CFH with high affinity and, therefore, can potentially reduce iron availability and oxidative activity. CFH levels are elevated over approximately 24-48 hours in our antibiotic-treated canine model of S. aureus pneumonia that simulates the cardiovascular abnormalities of human septic shock. In this 96-hour model, resuscitative treatments, mechanical ventilation, sedation, and continuous care are translatable to management in human intensive care units. We found, in this S. aureus pneumonia model inducing septic shock, that commercial human haptoglobin concentrate infusions over 48-hours bind canine CFH, increase CFH clearance, and lower circulating iron. Over the 96-hour study, this treatment was associated with an improved metabolic profile (pH, lactate), less lung injury, reversal of shock, and increased survival. Haptoglobin binding compartmentalized CFH to the intravascular space. This observation, in combination with increasing CFHs clearance, reduced available iron as a potential source of bacterial nutrition while decreasing the ability for CFH and iron to cause extravascular oxidative tissue injury. In contrast, haptoglobin therapy had no measurable antiinflammatory effect on elevations in proinflammatory C-reactive protein and cytokine levels. Haptoglobin therapy enhances normal host defense mechanisms in contrast to previously studied antiinflammatory sepsis therapies, making it a biologically plausible novel approach to treat septic shock.
在过去的半个世纪中，已经有许多抗炎药物在数十项临床试验中进行了测试，但均被证明对治疗感染性休克无效。多项研究观察到，细胞游离血红蛋白（CFH）水平在临床败血症期间升高，并且增加的程度与更高的死亡率相关，这提示了一种替代方法。人触珠蛋白与 CFH 具有高亲和力结合，因此可能会降低铁的可用性和氧化活性。在我们的抗生素治疗的金黄色葡萄球菌肺炎犬模型中，CFH 水平在大约 24-48 小时内升高，该模型模拟了人类感染性休克的心血管异常。在这个 96 小时的模型中，复苏治疗、机械通气、镇静和持续护理可以转化为人类重症监护病房的管理。我们发现，在这种金黄色葡萄球菌肺炎诱导感染性休克的模型中，48 小时内输注商业人触珠蛋白浓缩物可结合犬 CFH，增加 CFH 清除率并降低循环铁。在 96 小时的研究中，这种治疗与改善的代谢特征（pH 值、乳酸）、更少的肺损伤、休克逆转和存活率提高相关。触珠蛋白将 CFH 结合到血管腔内。这一观察结果，加上 CFHs 清除率的增加，减少了可用铁作为细菌营养的潜在来源，同时降低了 CFH 和铁引起血管外氧化组织损伤的能力。相比之下，触珠蛋白治疗对升高的促炎 C 反应蛋白和细胞因子水平没有可测量的抗炎作用。触珠蛋白治疗增强了正常的宿主防御机制，与之前研究的抗炎性败血症治疗方法相反，使其成为一种治疗感染性休克的有生物学意义的新方法。
