PDF(Pubmed)
Abstract：
UNASSIGNED: Traumatic and thermal injuries result in a state of systemic immune suppression, yet the mechanisms that underlie its development are poorly understood. Released from injured muscle and lysed red blood cells, heme is a damage associated molecular pattern with potent immune modulatory properties. Here, we measured plasma concentrations of total heme in over 200 traumatic and thermally-injured patients in order to examine its relationship with clinical outcomes and post-injury immune suppression.
UNASSIGNED: Blood samples were collected from 98 burns (≥15% total body surface area) and 147 traumatically-injured (injury severity score ≥8) patients across the ultra-early (≤1 hour) and acute (4-72 hours) post-injury settings. Pro-inflammatory cytokine production by lipopolysaccharide (LPS) challenged whole blood leukocytes was studied, and plasma concentrations of total heme, and its scavengers haptoglobin, hemopexin and albumin measured, alongside the expression of heme-oxygenase-1 (HO-1) in peripheral blood mononuclear cells (PBMCs). LPS-induced tumour necrosis factor-alpha (TNF-α) production by THP-1 cells and monocytes following in vitro heme treatment was also examined.
UNASSIGNED: Burns and traumatic injury resulted in significantly elevated plasma concentrations of heme, which coincided with reduced levels of hemopexin and albumin, and correlated positively with circulating levels of pro and anti-inflammatory cytokines. PBMCs isolated from trauma patients 4-12 and 48-72 hours post-injury exhibited increased HO-1 gene expression. Non-survivors of burn injury and patients who developed sepsis, presented on day 1 with significantly elevated heme levels, with a difference of 6.5 µM in heme concentrations corresponding to a relative 52% increase in the odds of post-burn mortality. On day 1 post-burn, heme levels were negatively associated with ex vivo LPS-induced TNF-α and interleukin-6 production by whole blood leukocytes. THP-1 cells and monocytes pre-treated with heme exhibited significantly reduced TNF-α production following LPS stimulation. This impairment was associated with decreased gene transcription, reduced activation of extracellular signal-regulated kinase 1/2 and an impaired glycolytic response.
UNASSIGNED: Major injury results in elevated plasma concentrations of total heme that may contribute to the development of endotoxin tolerance and increase the risk of poor clinical outcomes. Restoration of the heme scavenging system could be a therapeutic approach by which to improve immune function post-injury.
UNASSIGNED: Blood samples were collected from 98 burns (≥15% total body surface area) and 147 traumatically-injured (injury severity score ≥8) patients across the ultra-early (≤1 hour) and acute (4-72 hours) post-injury settings. Pro-inflammatory cytokine production by lipopolysaccharide (LPS) challenged whole blood leukocytes was studied, and plasma concentrations of total heme, and its scavengers haptoglobin, hemopexin and albumin measured, alongside the expression of heme-oxygenase-1 (HO-1) in peripheral blood mononuclear cells (PBMCs). LPS-induced tumour necrosis factor-alpha (TNF-α) production by THP-1 cells and monocytes following in vitro heme treatment was also examined.
UNASSIGNED: Burns and traumatic injury resulted in significantly elevated plasma concentrations of heme, which coincided with reduced levels of hemopexin and albumin, and correlated positively with circulating levels of pro and anti-inflammatory cytokines. PBMCs isolated from trauma patients 4-12 and 48-72 hours post-injury exhibited increased HO-1 gene expression. Non-survivors of burn injury and patients who developed sepsis, presented on day 1 with significantly elevated heme levels, with a difference of 6.5 µM in heme concentrations corresponding to a relative 52% increase in the odds of post-burn mortality. On day 1 post-burn, heme levels were negatively associated with ex vivo LPS-induced TNF-α and interleukin-6 production by whole blood leukocytes. THP-1 cells and monocytes pre-treated with heme exhibited significantly reduced TNF-α production following LPS stimulation. This impairment was associated with decreased gene transcription, reduced activation of extracellular signal-regulated kinase 1/2 and an impaired glycolytic response.
UNASSIGNED: Major injury results in elevated plasma concentrations of total heme that may contribute to the development of endotoxin tolerance and increase the risk of poor clinical outcomes. Restoration of the heme scavenging system could be a therapeutic approach by which to improve immune function post-injury.
摘要：
■创伤和热损伤导致全身免疫抑制状态，然而，人们对其发展背后的机制知之甚少。从受伤的肌肉和溶解的红细胞中释放出来，血红素是一种与损伤相关的分子模式，具有有效的免疫调节特性。这里,我们测量了200多名创伤和热损伤患者的血浆总血红素浓度,以研究其与临床结局和损伤后免疫抑制的关系.
■在超早期（≤1小时）和急性（4-72小时）损伤后设置中，从98例烧伤（全身表面积≥15％）和147例外伤（损伤严重程度评分≥8）患者中收集了血液样本。研究了由脂多糖（LPS）攻击的全血白细胞产生的促炎细胞因子，和血浆总血红素浓度，和它的清除剂结合珠蛋白，血色素结合蛋白和白蛋白测量，血红素加氧酶-1（HO-1）在外周血单核细胞（PBMC）中的表达。还检查了体外血红素处理后THP-1细胞和单核细胞产生的LPS诱导的肿瘤坏死因子-α（TNF-α）。
■烧伤和外伤导致血浆血红素浓度显著升高，这与血红蛋白和白蛋白水平降低同时发生，并与促炎和抗炎细胞因子的循环水平呈正相关。从创伤患者伤后4-12和48-72小时分离的PBMC表现出增加的HO-1基因表达。烧伤的非幸存者和发生败血症的患者，在第1天呈现显著升高的血红素水平，血红素浓度差异为6.5µM，相当于烧伤后死亡率的相对增加52%。烧伤后第1天,血红素水平与离体LPS诱导的全血白细胞产生TNF-α和白细胞介素-6呈负相关。用血红素预处理的THP-1细胞和单核细胞在LPS刺激后表现出显著降低的TNF-α产生。这种损伤与基因转录降低有关，细胞外信号调节激酶1/2的激活减少和糖酵解反应受损。
■严重损伤导致血浆总血红素浓度升高，这可能有助于内毒素耐受性的发展，并增加不良临床结局的风险。血红素清除系统的恢复可能是改善损伤后免疫功能的治疗方法。
■在超早期（≤1小时）和急性（4-72小时）损伤后设置中，从98例烧伤（全身表面积≥15％）和147例外伤（损伤严重程度评分≥8）患者中收集了血液样本。研究了由脂多糖（LPS）攻击的全血白细胞产生的促炎细胞因子，和血浆总血红素浓度，和它的清除剂结合珠蛋白，血色素结合蛋白和白蛋白测量，血红素加氧酶-1（HO-1）在外周血单核细胞（PBMC）中的表达。还检查了体外血红素处理后THP-1细胞和单核细胞产生的LPS诱导的肿瘤坏死因子-α（TNF-α）。
■烧伤和外伤导致血浆血红素浓度显著升高，这与血红蛋白和白蛋白水平降低同时发生，并与促炎和抗炎细胞因子的循环水平呈正相关。从创伤患者伤后4-12和48-72小时分离的PBMC表现出增加的HO-1基因表达。烧伤的非幸存者和发生败血症的患者，在第1天呈现显著升高的血红素水平，血红素浓度差异为6.5µM，相当于烧伤后死亡率的相对增加52%。烧伤后第1天,血红素水平与离体LPS诱导的全血白细胞产生TNF-α和白细胞介素-6呈负相关。用血红素预处理的THP-1细胞和单核细胞在LPS刺激后表现出显著降低的TNF-α产生。这种损伤与基因转录降低有关，细胞外信号调节激酶1/2的激活减少和糖酵解反应受损。
■严重损伤导致血浆总血红素浓度升高，这可能有助于内毒素耐受性的发展，并增加不良临床结局的风险。血红素清除系统的恢复可能是改善损伤后免疫功能的治疗方法。
