Induction of neutrophil apoptosis and secondary necrosis during endotoxin-induced pulmonary inflammation in mice
Induction of neutrophil apoptosis and secondary necrosis during endotoxin-induced pulmonary inflammation in mice
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DOI：
10.1002/jcp.10105
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发表时间：
2002-06-01
影响因子：
5.6
通讯作者：
Rojanasakul, Y
中科院分区：
文献类型：
--
作者：
Medan, D;Wang, LY;Rojanasakul, Y
本研究探讨了细胞凋亡和坏死细胞死亡的关系及其在内毒素引起的肺部炎症反应中的作用。肺给药脂多糖（LIPS）引起促炎细胞因子tnf - α水平的迅速增加和支气管肺泡灌洗液（BAL）中炎症细胞的内流。对照组小鼠只有常驻肺泡巨噬细胞，无凋亡，而lps处理小鼠BAL细胞明显凋亡，显微镜研究证实存在凋亡中性粒细胞和巨噬细胞摄取凋亡小体。随着中性粒细胞内流的增加，凋亡中性粒细胞的数量增加，在治疗后第1天达到峰值。然而，在早期未发现坏死，但随后增加，并在第3天达到高峰。高剂量LPS使坏死和凋亡水平升高并延长。含有磷脂酰丝氨酸（PS）的脂质体可以抑制巨噬细胞对凋亡细胞的吞噬作用，可增加LPS引起的小鼠凋亡和坏死水平，而对照非磷脂酰丝氨酸脂质体或生理盐水处理则没有影响。我们得出结论，在LPS处理的肺模型中，坏死继发于细胞凋亡，这种发展不是LPS直接损伤的结果。相反，我们的结果和先前的研究表明，巨噬细胞对凋亡细胞的低效清除至少在一定程度上导致了LPS诱导的细胞凋亡和坏死水平。由于坏死与细胞损伤和组织毒性内容物的释放有关，这一发展可能在决定内毒素引起的肺毒性的严重程度和持续时间方面发挥作用。(C) 2002 Wiley-Liss, Inc。
The present study investigated the relationship between apoptotic and necrotic cell death and their role in pulmonary inflammatory response to endotoxin. Pulmonary administration of lipopolysaccharide (LIPS) caused a rapid increase in the levels of pro-inflammatory cytokine TNF-alpha and inflammatory cell influx in the bronchoalveolar lavage (BAL) fluids. Control mice showed only resident alveolar macrophages with no apoptosis, whereas LPS-treated mice showed clear apoptosis of BAL cells, Microscopic studies confirmed the presence of apoptotic neutrophils and macrophages ingesting apoptotic bodies. The number of apoptotic neutrophils increased concomitantly with the increase in neutrophil influx which peaked I day after the treatment. However, necrosis was not detected at this early time, but increased subsequently and peaked at day 3. The levels of necrosis and apoptosis were both elevated and prolonged at high LPS doses. Treatment of mice with phosphatidylserine (PS)-containing liposome, known to inhibit macrophage phagocytosis of apoptotic cells, increased the level of apoptosis and necrosis caused by LPS, whereas control non-PS liposome or saline treatment had no effects. We conclude that necrosis occurs secondary to apoptosis in LPS-treated lung model and that this development is not the result of direct insult by LPS. instead, Our results and previous studies suggest that inefficient clearance of apoptotic cells by macrophages contributes, at least in part, to the levels of apoptosis and necrosis induced by LPS. Because necrosis is associated with cell damage and release of histotoxic contents, this development is likely to play a role in determining the severity and duration of lung toxicity induced by endotoxin. (C) 2002 Wiley-Liss, Inc.