Takahara Miki, Aoyama-Ishikawa Michiko, Shuno Katsuhito, Yamauhi Chisato, Miyoshi Makoto, Maeshige Noriaki, Usami Makoto, Yamada Taihei, Osako Takaaki, Nakao Atsunori, Kotani Joji
Department of Biophysics Kobe University Graduate School of Health Sciences Kobe Japan.
Department of Emergency, Disaster and Critical Care Medicine Hyogo College of Medicine Nishinomiya Japan.
Acute Med Surg. 2013 Nov 10;1(1):23-30. doi: 10.1002/ams2.6. eCollection 2014 Jan.
Overactivated neutrophils are causes of acute lung injury, which is a major clinical problem with significant morbidity and mortality in sepsis. Serum interleukin (IL)-18 levels correspond to severity of systemic inflammation.
To elucidate the roles of endogenous IL-18 in lung injury during endotoxin-induced systemic inflammation.
Wild-type (WT) and IL-18 gene knockout (KO) mice were injected with lipopolysaccharide (40 mg/kg) intraperitoneally and killed. Lungs were collected at 0 and 12 h to assess mRNA for intercellular adhesion molecule (ICAM)-1, inducible nitric oxide synthase, myeloperoxidase, immunohistochemistry (cleaved caspase-3, 8-hydroxy-2-deoxyguanosine), and wet/dry ratio. Blood was collected at 0, 1, 12, 18, and 24 h to assess plasma cytokine levels.
The survival rates at 24 h were approximately 43% and 76% in the WT and KO mice, respectively. Plasma IL-18 levels were induced time-dependently only in the WT mice. Plasma interferon-γ levels were significantly higher in the WT than in the KO mice at 12 h, but IL-6 and tumor necrosis factor-α levels did not differ between the WT and KO mice. At 12 h, the WT mice showed higher myeloperoxidase activity (P < 0.05), ICAM-1, and wet/dry ratios than KO mice. Cleaved caspase-3 positive neutrophils, which migrated in the lung interstitium, were lower in WT mice than in KO mice.
Endogenous IL-18 induced neutrophil accumulation, accompanied by induction of ICAM-1 expression, inhibition of neutrophil apoptosis, and increased inducible nitric oxide synthase-induced oxidative tissue injury in the lung, leading to lung edema and poor outcome during endotoxemia.
中性粒细胞过度活化是急性肺损伤的病因，急性肺损伤是脓毒症中一个具有显著发病率和死亡率的主要临床问题。血清白细胞介素（IL）-18水平与全身炎症的严重程度相关。
阐明内源性IL-18在内毒素诱导的全身炎症期间肺损伤中的作用。
野生型（WT）和IL-18基因敲除（KO）小鼠腹腔注射脂多糖（40mg/kg）后处死。在0小时和12小时收集肺组织，以评估细胞间黏附分子（ICAM）-1、诱导型一氧化氮合酶、髓过氧化物酶的mRNA水平，进行免疫组织化学检测（裂解的半胱天冬酶-3、8-羟基-2-脱氧鸟苷），并测定湿/干比。在0、1、12、18和24小时收集血液，以评估血浆细胞因子水平。
WT小鼠和KO小鼠在24小时时的生存率分别约为43%和76%。血浆IL-18水平仅在WT小鼠中呈时间依赖性诱导。在12小时时，WT小鼠的血浆干扰素-γ水平显著高于KO小鼠，但WT小鼠和KO小鼠的IL-6和肿瘤坏死因子-α水平没有差异。在12小时时，WT小鼠的髓过氧化物酶活性（P<0.05）、ICAM-1和湿/干比均高于KO小鼠。WT小鼠肺间质中迁移的裂解的半胱天冬酶-3阳性中性粒细胞低于KO小鼠。
内源性IL-18诱导中性粒细胞聚集，伴有ICAM-1表达的诱导、中性粒细胞凋亡的抑制以及诱导型一氧化氮合酶诱导的肺组织氧化损伤增加，导致内毒素血症期间肺水肿和不良预后。
