Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland.
Department of Biomedical Engineering, Tufts University, Medford, Massachusetts.
Am J Physiol Heart Circ Physiol. 2021 Jun 1;320(6):H2385-H2400. doi: 10.1152/ajpheart.00092.2021. Epub 2021 May 14.
Cell-free hemoglobin (CFH) levels are elevated in septic shock and are higher in nonsurvivors. Whether CFH is only a marker of sepsis severity or is involved in pathogenesis is unknown. This study aimed to investigate whether CFH worsens sepsis-associated injuries and to determine potential mechanisms of harm. Fifty-one, 10-12 kg purpose-bred beagles were randomized to receive intrapulmonary challenges or saline followed by CFH infusions (oxyhemoglobin >80%) or placebo. Animals received antibiotics and intensive care support for 96 h. CFH significantly increased mean pulmonary arterial pressures and right ventricular afterload in both septic and nonseptic animals, effects that were significantly greater in nonsurvivors. These findings are consistent with CFH-associated nitric oxide (NO) scavenging and were associated with significantly depressed cardiac function, and worsened shock, lactate levels, metabolic acidosis, and multiorgan failure. In septic animals only, CFH administration significantly increased mean alveolar-arterial oxygenation gradients, also to a significantly greater degree in nonsurvivors. CFH-associated iron levels were significantly suppressed in infected animals, suggesting that bacterial iron uptake worsened pneumonia. Notably, cytokine levels were similar in survivors and nonsurvivors and were not predictive of outcome. In the absence and presence of infection, CFH infusions resulted in pulmonary hypertension, cardiogenic shock, and multiorgan failure, likely through NO scavenging. In the presence of infection alone, CFH infusions worsened oxygen exchange and lung injury, presumably by supplying iron that promoted bacterial growth. CFH elevation, a known consequence of clinical septic shock, adversely impacts sepsis outcomes through more than one mechanism, and is a biologically plausible, nonantibiotic, noncytokine target for therapeutic intervention. Cell-free hemoglobin (CFH) elevations are a known consequence of clinical sepsis. Using a two-by-two factorial design and extensive physiological and biochemical evidence, we found a direct mechanism of injury related to nitric oxide scavenging leading to pulmonary hypertension increasing right heart afterload, depressed cardiac function, worsening circulatory failure, and death, as well as an indirect mechanism related to iron toxicity. These discoveries alter conventional thinking about septic shock pathogenesis and provide novel therapeutic approaches.
无细胞血红蛋白 (CFH) 在感染性休克中升高，且在非幸存者中更高。CFH 是否仅为感染严重程度的标志物，还是参与发病机制尚不清楚。本研究旨在探究 CFH 是否会加重与感染相关的损伤，并确定潜在的损伤机制。51 只 10-12kg 的经专门饲养的比格犬被随机分配接受肺内挑战或生理盐水，然后接受 CFH 输注（氧合血红蛋白>80%）或安慰剂。动物接受抗生素和 96 小时的重症监护支持。CFH 显著增加了感染和非感染动物的平均肺动脉压和右心室后负荷，而非幸存者的这些作用更为显著。这些发现与 CFH 相关的一氧化氮 (NO) 清除作用一致，并与心脏功能显著降低以及休克恶化、乳酸水平升高、代谢性酸中毒和多器官衰竭有关。仅在感染动物中，CFH 给药还显著增加了平均肺泡-动脉氧差，而非幸存者的增加程度也更为显著。感染动物的 CFH 相关铁水平显著降低，表明细菌铁摄取会加重肺炎。值得注意的是，幸存者和非幸存者的细胞因子水平相似，且不能预测结局。在无感染和有感染的情况下，CFH 输注会导致肺动脉高压、心源性休克和多器官衰竭，这可能是通过清除 NO 引起的。仅在感染的情况下，CFH 输注会恶化氧合和肺损伤，可能是通过提供促进细菌生长的铁。CFH 升高是临床感染性休克的已知后果，通过不止一种机制对感染性休克结局产生不利影响，并且是一种具有生物学意义的、非抗生素、非细胞因子的治疗干预靶点。无细胞血红蛋白 (CFH) 升高是临床感染的已知后果。使用二乘二析因设计和广泛的生理和生化证据，我们发现了一种与一氧化氮清除相关的直接损伤机制，导致肺动脉高压增加右心后负荷、心脏功能降低、循环衰竭恶化和死亡，以及一种与铁毒性相关的间接机制。这些发现改变了对感染性休克发病机制的传统认识，并提供了新的治疗方法。
