Davis Heart and Lung Research Institute, Pulmonary, Allergy, Critical Care and Sleep Medicine Division, Wexner Medical Center, The Ohio State University, Columbus, Ohio, United States of America.
PLoS One. 2014 Mar 18;9(3):e90968. doi: 10.1371/journal.pone.0090968. eCollection 2014.
Immune dysregulation during sepsis is poorly understood, however, lymphocyte apoptosis has been shown to correlate with poor outcomes in septic patients. The inflammasome, a molecular complex which includes caspase-1, is essential to the innate immune response to infection and also important in sepsis induced apoptosis. Our group has recently demonstrated that endotoxin-stimulated monocytes release microvesicles (MVs) containing caspase-1 that are capable of inducing apoptosis. We sought to determine if MVs containing caspase-1 are being released into the blood during human sepsis and induce apoptosis..
Single-center cohort study.
50 critically ill patients were screened within 24 hours of admission to the intensive care unit and classified as either a septic or a critically ill control. Circulatory MVs were isolated and analyzed for the presence of caspase-1 and the ability to induce lymphocyte apoptosis. Patients remaining in the ICU for 48 hours had repeated measurement of caspase-1 activity on ICU day 3.
Septic patients had higher microvesicular caspase-1 activity 0.05 (0.04, 0.07) AFU versus 0.0 AFU (0, 0.02) (p<0.001) on day 1 and this persisted on day 3, 0.12 (0.1, 0.2) versus 0.02 (0, 0.1) (p<0.001). MVs isolated from septic patients on day 1 were able to induce apoptosis in healthy donor lymphocytes compared with critically ill control patients (17.8±9.2% versus 4.3±2.6% apoptotic cells, p<0.001) and depletion of MVs greatly diminished this apoptotic signal. Inhibition of caspase-1 or the disruption of MV integrity abolished the ability to induce apoptosis.
These findings suggest that microvesicular caspase-1 is important in the host response to sepsis, at least in part, via its ability to induce lymphocyte apoptosis. The ability of microvesicles to induce apoptosis requires active caspase-1 and intact microvesicles.
脓毒症期间免疫失调的机制尚不清楚，但是淋巴细胞凋亡与脓毒症患者的不良预后相关。炎症小体是一种包含半胱氨酸蛋白酶-1（caspase-1）的分子复合物，对感染引起的固有免疫反应至关重要，在脓毒症诱导的细胞凋亡中也很重要。我们的研究小组最近发现，内毒素刺激的单核细胞释放含有能够诱导凋亡的 caspase-1 的微泡（MVs）。我们试图确定在人类脓毒症期间是否有含有 caspase-1 的 MVs 释放到血液中并诱导凋亡。
单中心队列研究。
在入住重症监护病房的 24 小时内对 50 名危重症患者进行筛查，并分为脓毒症组或危重症对照组。分离循环 MV 并分析其 caspase-1 的存在及其诱导淋巴细胞凋亡的能力。在 ICU 住院 48 小时的患者在 ICU 第 3 天重复测量 caspase-1 活性。
脓毒症患者在第 1 天的微泡 caspase-1 活性更高（0.05[0.04，0.07] AU 比 0.0 AU[0，0.02]，p<0.001），这一现象在第 3 天仍持续存在（0.12[0.1，0.2] AU 比 0.02[0，0.1]，p<0.001）。与危重症对照组患者相比，第 1 天从脓毒症患者中分离的 MV 能够诱导健康供体淋巴细胞凋亡（17.8±9.2%比 4.3±2.6%凋亡细胞，p<0.001），并且 MV 的耗竭大大降低了这种凋亡信号。caspase-1 的抑制或 MV 完整性的破坏消除了诱导凋亡的能力。
这些发现表明，微泡 caspase-1 通过诱导淋巴细胞凋亡，在宿主对脓毒症的反应中很重要，至少部分是通过这种方式。MV 诱导凋亡的能力需要 caspase-1 的活性和完整的 MV。
