Is sepsis-induced apoptosis associated with macrophage dysfunction?
Is sepsis-induced apoptosis associated with macrophage dysfunction?
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DOI：
10.1097/00005373-199604000-00008
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发表时间：
1996-04-01
影响因子：
--
通讯作者：
Chaudry, IH
中科院分区：
文献类型：
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作者：
Ayala, A;Urbanich, MA;Chaudry, IH
细胞凋亡(A(O))是细胞经历一种可诱导的非坏死性细胞自杀的病理过程。体外研究表明，巨噬细胞(Mo)A(O)比率的变化可能与促炎细胞因子分泌能力的增加有关，如IL-1β(IL-1β)(通过IL-1转换酶激活)。此外，据报道，钼在实验性败血症早期(0-4小时)被激活，作为促炎细胞因子的来源，如IL-1。然而，随着脓毒症的发展，这些细胞对进一步的刺激变得难以接受(看起来功能失调)。然而，尚不清楚这种获得性免疫抑制(功能障碍)是否与巨噬细胞A(O)的加速有关。为了确定这一点，雄性C3H/HEN小鼠造成脓毒症(盲肠结扎和穿孔，CLP)或假CLP，4或24小时后从腹膜(PMO)和肝脏(KMO)分离Mo，在体外或在LPS刺激前立即(24小时)用脂多糖(LPS)刺激后立即裂解巨噬细胞单层，并保留胞浆细胞部分。用细胞死亡酶联免疫吸附试验测定A(O)的程度，该方法检测细胞质寡核小体的存在和碘化丙啶染色强度的变化。结果表明，CLP后早期(4h)，只有在体外用内毒素刺激的PMO才有A(O)升高的迹象。在脓毒症发病后24小时(晚期)，PMO的A(O)的体外范围增加，而KMO的A(O)的体外范围减少。然而，在体外加入内毒素后，败血症PMO和KMO A(O)均显著增加。这一结果表明，在败血症晚期(24小时)，Mo不能对刺激物(如内毒素)做出反应，这可能是因为在这些Mo人群中诱导了加速的A(O)。
Apoptosis (A(o)) is a pathological process by which cells undergo a form of inducible nonnecrotic cellular suicide. In vitro studies suggest that changes in the rate of macrophage (Mo) A(o) may be associated with elevated proinflammatory cytokine secretory capacity, such as interleukin-1 beta (IL-1 beta) (via IL-1 converting enzyme activation). Furthermore, it has been reported that Mo are activated during early (0-4 hours) experimental septic insult to act as sources of proinflammatory cytokines, such as IL-1. However, with the progression of sepsis, these same cells become refractory to further stimulation (appearing dysfunctional). Nonetheless, it remains unknown if this acquired immunosuppression (dysfunction) is associated with an acceleration in macrophage A(o). To determine this, male C3H/HeN mice were subjected to sepsis (cecal ligation and puncture, CLP) or sham-CLP and 4 or 24 hours thereafter Mo were isolated from the peritoneum (PMo) and liver (KMo), Macrophage monolayers were lysed either after stimulation with lipopolysaccharide (LPS) (10 mu g/mL, 24 hours) in vitro or immediately (ex vivo) before LPS stimulation and the cytoplasmic cell fraction was retained. The extent of A(o) was determined using a cell-death enzyme-linked immunosorbent assay, which detects the presence of cytoplasmic oligonucleosomes and changes in the propidium iodide staining intensity. The results indicate that, early after CLP (4 hours) only PMo stimulated with LPS in vitro showed evidence of increasing A(o). At 24 hours (late) after the onset of sepsis, the ex vivo extent of A(o) in PMo was increased but it was decreased in KMo. However, the addition of LPS in vitro results in a marked increase in both septic PMo and KMo A(o). This latter result suggests that the inability of Mo to release cytokines in response to stimulants, such as LPS during late sepsis (24 hours), may be because of induction of accelerated A(o) in these Mo populations.