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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Serum amyloid A opposes lipoxin A_4 to mediate glucocorticoid refractory lung inflammation in chronic obstructive pulmonary disease
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Serum amyloid A opposes lipoxin A_4 to mediate glucocorticoid refractory lung inflammation in chronic obstructive pulmonary disease

机译：在慢性阻塞性肺疾病中，血清淀粉样蛋白A反对脂蛋白A_4介导糖皮质激素难治性肺部炎症

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摘要

Chronic obstructive pulmonary disease (COPD) will soon be the third most common cause of death globally. Despite smoking cessation, neutrophilic mucosal inflammation persistently damages the airways and fails to protect from recurrent infections. This maladaptive and excess inflammation is also refractory to glucocorticosteroids (GC). Here, we identify serum amyloid A (SAA) as a candidate mediator of GC refractory inflammation in COPD. Extrahepatic SAA was detected locally in COPD bronchoal-veolar lavage fluid, which correlated with IL-8 and neutrophil elastase, consistent with neutrophil recruitment and activation. Immunohistochemistry detected SAA was in close proximity to airway epithelium, and in vitro SAA triggered release of IL-8 and other proinflammatory mediators by airway epithelial cells in an ALX/FPR2 (formyl peptide receptor 2) receptor-dependent manner. Lipoxin A_4 (LXA_4) can also interact with ALX/FPR2 receptors and lead to allosteric inhibition of SAA-initiated epithelial responses (pA_2 13 nM). During acute exacerbation, peripheral blood SAA levels increased dramatically and were disproportionately increased relative to LXA4. Human lung macrophages (CD68~+) colocalized with SAA and GCs markedly increased SAA in vitro (THP-1, pEC_(50) 43 nM). To determine its direct actions, SAA was administered into murine lung, leading to induction of CXC chemokine ligand 1/2 and a neutrophilic response that was inhibited by 15-epi-LXA_4 but not dexamethasone. Taken together, these findings identify SAA as a therapeutic target for inhibition and implicate SAA as a mediator of GC-resistant lung inflammation that can overwhelm organ protective signaling by lipoxins at ALX/FPR2 receptors.
机译：慢性阻塞性肺疾病（COPD）很快将成为全球第三大最常见的死亡原因。尽管戒烟，中性粒细胞黏膜炎症仍会持续损害气道，无法预防反复感染。这种适应不良和过度的炎症也对糖皮质激素（GC）难治。在这里，我们确定血清淀粉样蛋白A（SAA）是COPD中GC难治性炎症的候选介质。在COPD支气管肺泡灌洗液中局部检测到肝外SAA，这与IL-8和中性粒细胞弹性蛋白酶相关，与中性粒细胞募集和激活一致。免疫组织化学检测到SAA紧邻气道上皮，并且体外SAA触发了气道上皮细胞以ALX / FPR2（甲酰肽受体2）受体依赖性方式释放IL-8和其他促炎介质。脂蛋白A_4（LXA_4）也可以与ALX / FPR2受体相互作用，并导致SAA引发的上皮反应的变构抑制（pA_2 13 nM）。在急性发作期间，外周血SAA水平相对于LXA4显着增加，并且成比例增加。与SAA和GC共定位的人肺巨噬细胞（CD68〜+）在体外显着增加SAA（THP-1，pEC_（50）43 nM）。为了确定其直接作用，将SAA注入鼠肺，导致CXC趋化因子配体1/2的诱导和中性粒细胞反应，该反应被15-epi-LXA_4抑制但不被地塞米松抑制。综上所述，这些发现确定SAA为抑制的治疗靶标，并暗示SAA为GC抵抗性肺部炎症的介质，该介质可以压倒ALX / FPR2受体上的脂蛋白的器官保护信号。

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    Steven Bozinovski; Mohib Uddin; Ross Vlahos; Michelle Thompson; Jonathan L. McQualter; Anne-Sophie Merritt; Peter A. B. Wark; Anastasia Hutchinson; Louis B. Irving; Bruce D. Levy; Gary P. Anderson;

  • 作者单位

    Department of Pharmacology, and 'Department of Medicine, University of Melbourne, Parkville, Victoria, Australia 3010;

    Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;

    Department of Pharmacology, and 'Department of Medicine, University of Melbourne, Parkville, Victoria, Australia 3010;

    Department of Respiratory Medicine, Royal Melbourne Hospital,Parkville, Victoria, Australia 3010;

    Department of Pharmacology, and 'Department of Medicine, University of Melbourne, Parkville, Victoria, Australia 3010;

    Department of Pharmacology, and 'Department of Medicine, University of Melbourne, Parkville, Victoria, Australia 3010;

    Centre for Asthma and Respiratory Disease, Hunter Medical Research Institute, University of Newcastle, Australia 2305,Department of Respiratory and Sleep Medicine, John Hunter Hospital, Australia 2305;

    Department of Respiratory Medicine, Royal Melbourne Hospital,Parkville, Victoria, Australia 3010;

    Department of Respiratory Medicine, Royal Melbourne Hospital,Parkville, Victoria, Australia 3010;

    Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;

    Department of Pharmacology, and 'Department of Medicine, University of Melbourne, Parkville, Victoria, Australia 3010;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    resolution; leukocyte activation; G protein-coupled receptor; innate immunity;

    机译：解析度;白细胞活化G蛋白偶联受体;先天免疫;

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