Baek Jin Hyen, Zhang Xiaoyuan, Williams Matthew C, Schaer Dominik J, Buehler Paul W, D'Agnillo Felice
Laboratory of Biochemistry and Vascular Biology, Division of Hematology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA.
Division of Internal Medicine, University Hospital, CH-8091 Zurich, Switzerland.
Toxins (Basel). 2014 Mar 31;6(4):1244-59. doi: 10.3390/toxins6041244.
Endotoxemia plays a major causative role in the myocardial injury and dysfunction associated with sepsis. Extracellular hemoglobin (Hb) has been shown to enhance the pathophysiology of endotoxemia. In the present study, we examined the myocardial pathophysiology in guinea pigs infused with lipopolysaccharide (LPS), a Gram-negative bacterial endotoxin, and purified Hb. We also examined whether the administration of the Hb scavenger haptoglobin (Hp) could protect against the effects observed. Here, we show that Hb infusion following LPS administration, but not either insult alone, increased myocardial iron deposition, heme oxygenase-1 expression, phagocyte activation and infiltration, as well as oxidative DNA damage and apoptosis assessed by 8-hydroxy-2'-deoxyguanosine (8-OHdG) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) immunostaining, respectively. Co-administration of Hp significantly attenuated the myocardial events induced by the combination of LPS and Hb. These findings may have relevant therapeutic implications for the management of sepsis during concomitant disease or clinical interventions associated with the increased co-exposures to LPS and Hb, such as trauma, surgery or massive blood transfusions.
内毒素血症在与脓毒症相关的心肌损伤和功能障碍中起主要致病作用。细胞外血红蛋白（Hb）已被证明会加剧内毒素血症的病理生理学过程。在本研究中，我们检测了输注脂多糖（LPS，一种革兰氏阴性菌内毒素）和纯化Hb的豚鼠的心肌病理生理学情况。我们还检测了给予Hb清除剂触珠蛋白（Hp）是否能预防所观察到的效应。在此，我们发现，LPS给药后输注Hb，但单独给予任何一种刺激均不会，会增加心肌铁沉积、血红素加氧酶-1表达、吞噬细胞活化和浸润，以及分别通过8-羟基-2'-脱氧鸟苷（8-OHdG）和末端脱氧核苷酸转移酶dUTP缺口末端标记（TUNEL）免疫染色评估的氧化性DNA损伤和细胞凋亡。联合给予Hp可显著减轻LPS和Hb联合诱导的心肌事件。这些发现可能对脓毒症的治疗具有相关意义，脓毒症发生于伴随疾病或临床干预期间，此时与LPS和Hb的共同暴露增加相关，如创伤、手术或大量输血。
