Shock-induced neutrophil mediated priming for acute lung injury in mice - Divergent effects of TLR-4 and TLR-4/FasL deficiency
Shock-induced neutrophil mediated priming for acute lung injury in mice - Divergent effects of TLR-4 and TLR-4/FasL deficiency
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DOI：
10.1016/s0002-9440(10)64504-x
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发表时间：
2002-12-01
影响因子：
6
通讯作者：
Grutkoski, PS
中科院分区：
文献类型：
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作者：
Ayala, A;Chung, CS;Grutkoski, PS
急性肺损伤（ALI）导致呼吸窘迫是休克/创伤的常见后遗症，然而，在单次休克或脓毒性事件的小鼠中模拟这一过程是不一致的。一种解释是，出血通常只是一种“启动损伤”，因此，可能需要二次刺激来“触发”ALI。为了验证这一点，我们进行了研究，评估了单独出血或出血后脓毒性刺激（CLP）诱导ALI的能力。肺水肿、支气管肺泡灌洗液白细胞间素(IL)-6、肺泡充血以及肺IL-6、巨噬细胞炎症蛋白(MIP)-2和髓过氧化物酶（MPO）活性均在出血后24小时而非72小时升高。这与这些小鼠对感染性死亡的易感性显著增加有关。出血后24小时提取的外周血中性粒细胞，而非假手术动物，表现出体外凋亡频率降低和呼吸爆发能力增加，与体内“启动”一致。随后，我们观察到，从出血动物而非假出血动物的中性粒细胞过继性转移到中性粒细胞减少的受体，在随后的败血症攻击中复制ALI，这意味着这种启动是由中性粒细胞介导的。我们还发现，在toll样受体（TLR-4）缺乏或TIR-4/FasL联合缺乏的小鼠中，肺IL-6、MIP-2和MPO普遍显著增加。然而，TLR-4缺陷显著减少中性粒细胞流入肺，而不改变局部细胞因子/趋化因子表达的变化。另外，FasL和TLR-4的联合缺失并没有抑制MPO的增加，反而进一步加剧了肺IL-6/MIP-2水平。
Acute lung injury (ALI) leading to respiratory distress is a common sequela of shock/trauma, however, modeling this process in mice with a single shock or septic event is inconsistent. One explanation is that hemorrhage is often just a "priming insult," thus, secondary stimuli may be required to "trigger" ALI. To test this we carried out studies in which we assessed the capacity of hemorrhage alone or hemorrhage followed by septic challenge (CLP) to induce ALI. Lung edema, bronchoalveolar lavage interleukin (IL)-6, alveolar congestion, as well as lung IL-6, macrophage inflammatory protein (MIP)-2, and myeloperoxidase (MPO) activity were all increased in mice subjected to CLP at 24 but not 72 hours following hemorrhage. This was associated with a marked increase in the susceptibility of these mice to septic mortality. Peripheral blood neutrophils derived from 24 hours post-hemorrhage, but not Sham animals, exhibited an ex vivo decrease in apoptotic frequency and an increase in respiratory burst capacity, consistent with in vivo "priming." Subsequently, we observed that adoptive transfer of neutrophils from hemorrhaged but not sham-hemorrhage animals to neutropenic recipients reproduce ALI when subsequently septically challenged, implying that this priming was mediated by neutrophils. We also found marked general increases in lung IL-6, MIP-2, and MPO in mice deficient for toll-like receptor (TLR-4) or the combined lack of TIR-4/FasL. However, the TLR-4 defect markedly attenuated neutrophil influx into the lung while not altering the change in local ctyokine/chemokine,expression. Alternatively, the combined loss of FasL and TLR-4 did not inhibit the increase in MPO and exacerbated lung IL-6/MIP-2 levels even further.