Hirani N, Antonicelli F, Strieter R M, Wiesener M S, Ratcliffe P J, Haslett C, Donnelly S C
The Respiratory Medicine Unit, Centre for Inflammation Research, University of Edinburgh, UK.
Mol Med. 2001 Oct;7(10):685-97.
The acute respiratory distress syndrome (ARDS) represents a form of severe acute inflammatory lung disease. We have previously demonstrated significantly raised interleukin-8 (IL-8) levels in the lungs of at-risk patients that progress to ARDS, and identified the alveolar macrophage as an important source of this chemokine. We wished to extend this study in a well-defined group of patients with major trauma, and to investigate potential mechanisms for rapid intrapulmonary IL-8 generation.
Patients with major trauma underwent bronchoalveolar lavage (BAL) and IL-8 levels were measured in BAL fluid by ELISA. Human macrophages were derived from peripheral blood monocytes from healthy volunteers. Rabbit alveolar macrophages were obtained from ex-vivo lavage of healthy rabbit lungs. Macrophages were culture under normoxic or hypoxic (PO2 26 mmHg) conditions. IL-8 and other proinflammatory mediator expression was measured by ELISA, northern blotting or multi-probe RNase protection assay.
In patients with major trauma, IL-8 levels were significantly higher in patients that progressed to ARDS compared to those that did not (n = 56, P = 0.0001). High IL-8 levels negatively correlated with PaO2/FiO2 (r = -0.56, P < 0.001). In human monocyte derived macrophages hypoxia rapidly upregulated IL-8 protein (within 2 hours) and mRNA expression (within 30 mins). Acute hypoxia also increased rabbit alveolar macrophage IL-8 expression. Hypoxia increased DNA binding activity of AP-1 and C/EBP but not NF-kappaB. Hypoxia induced HIF-1 expression, but cobaltous ions and desferrioxamine did not mimic hypoxic IL-8 induction. Hypoxia downregulated a range of other proinflammatory mediators, including MCP-1 and TNF-alpha. Both the pattern of cytokine expression and transcription factor activation by hypoxia was different to that seen with endotoxin.
Rapidly raised intrapulmonary IL-8 levels are associated with ARDS progression in patients with major trauma. Acute hypoxia, a clinically relevant stimulus, rapidly and selectively upregulates IL-8 in macrophages associated with a novel pattern of transcription factor activation. Acute hypoxia may represent one of potentially several proinflammatory stimuli responsible for rapid intrapulmonary IL-8 generation in patients at-risk of ARDS.
急性呼吸窘迫综合征（ARDS）是一种严重的急性炎症性肺疾病。我们之前已证实在进展为ARDS的高危患者肺中白细胞介素-8（IL-8）水平显著升高，并确定肺泡巨噬细胞是这种趋化因子的重要来源。我们希望在一组明确的严重创伤患者中扩展这项研究，并探讨肺内IL-8快速产生的潜在机制。
严重创伤患者接受支气管肺泡灌洗（BAL），通过ELISA法检测BAL液中的IL-8水平。人巨噬细胞来源于健康志愿者的外周血单核细胞。兔肺泡巨噬细胞取自健康兔肺的体外灌洗。巨噬细胞在常氧或低氧（PO2 26 mmHg）条件下培养。通过ELISA、Northern印迹或多探针核糖核酸酶保护试验检测IL-8和其他促炎介质的表达。
在严重创伤患者中，进展为ARDS的患者IL-8水平显著高于未进展者（n = 56，P = 0.0001）。高IL-8水平与PaO2/FiO2呈负相关（r = -0.56，P < 0.001）。在人单核细胞衍生的巨噬细胞中，低氧迅速上调IL-8蛋白（2小时内）和mRNA表达（30分钟内）。急性低氧也增加兔肺泡巨噬细胞IL-8表达。低氧增加AP-1和C/EBP的DNA结合活性，但不增加NF-κB的活性。低氧诱导HIF-1表达，但钴离子和去铁胺不能模拟低氧诱导的IL-8产生。低氧下调一系列其他促炎介质，包括MCP-1和TNF-α。低氧诱导的细胞因子表达模式和转录因子激活与内毒素不同。
严重创伤患者肺内IL-8水平迅速升高与ARDS进展相关。急性低氧是一种临床相关刺激，可迅速且选择性地上调巨噬细胞中的IL-8，伴随一种新的转录因子激活模式。急性低氧可能是导致ARDS高危患者肺内IL-8快速产生的几种潜在促炎刺激之一。
