Ward Peter A, Grailer Jamison J
Department of Pathology, University of Michigan Medical School, 1301 Catherine Rd, Box 5602, Ann Arbor, MI 48109 USA.
Transl Respir Med. 2014 Jan 3;2:1. doi: 10.1186/2213-0802-2-1. eCollection 2014.
Acute respiratory distress syndrome (ARDS) in humans involves ≥ 200,000 individuals in the United States, and has a mortality rate (40%) for which no specific drug has been approved for use in humans. We have studied experimental acute lung injury (ALI) in mice following airway deposition of bacterial lipopolysaccharide (LPS) or the recombinant mouse complement anaphylatoxin, C5a. As ALI developed over 6 hr, extracellular histones appeared in bronchoalveolar lavage fluids (BALF). Extracellular histone appearance required both C5a receptors (C5aR, C5L2) as well as neutrophils (PMNs) and lung macrophages, as genetic loss of either C5a receptor or depletion of PMNs or macrophages reduced histone levels found in BALF during ALI. It is possible that extracellular histones were derived from formation of neutrophil extracellular traps (NETs) in lung after PMN contact with C5a. When purified histones were delivered to lung via the airways, intense inflammatory injury ensued and type II cells developed large blebs indicating cellular damage and apoptosis. Detailed physiological measurements revealed severe disruption of blood/alveolar gas exchange. These data suggest a key role for histones in development of experimental ALI.
在美国，急性呼吸窘迫综合征（ARDS）累及≥20万人，其死亡率为40%，尚无获批用于人类的特效药物。我们研究了小鼠气道内注入细菌脂多糖（LPS）或重组小鼠补体过敏毒素C5a后发生的实验性急性肺损伤（ALI）。随着ALI在6小时内发展，细胞外组蛋白出现在支气管肺泡灌洗液（BALF）中。细胞外组蛋白的出现需要C5a受体（C5aR、C5L2）以及中性粒细胞（PMN）和肺巨噬细胞，因为C5a受体的基因缺失或PMN或巨噬细胞的耗竭都会降低ALI期间BALF中发现的组蛋白水平。细胞外组蛋白可能源自PMN与C5a接触后在肺中形成的中性粒细胞胞外陷阱（NETs）。当通过气道将纯化的组蛋白递送至肺时，会引发强烈的炎性损伤，II型细胞会出现大泡，表明细胞损伤和凋亡。详细的生理学测量显示血液/肺泡气体交换严重受损。这些数据表明组蛋白在实验性ALI的发展中起关键作用。
