Department of Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
Department of Pediatrics, Women & Infants Hospital of Rhode Island, The Warren Alpert Medical School, Brown University, Providence, RI.
Blood Adv. 2018 Aug 14;2(15):1923-1934. doi: 10.1182/bloodadvances.2018018986.
The plasma levels of inter-α inhibitor proteins (IAIPs) are decreased in patients with sepsis and the reduced levels correlate with increased mortality. In the present study, we examined the effects of IAIPs on human neutrophils to better understand the beneficial effects of IAIPs in the treatment of sepsis. We demonstrated that IAIPs induced a spherical shape that was smaller in size with a smooth cellular surface in a concentration-dependent manner. These changes were inhibited by a specific antibody against IAIPs. In contrast, bikunin, light chain of IAIP, had no effect on neutrophil morphology. The neutrophils treated with IAIPs could easily pass through the artificial microcapillaries and were prevented from entrapment inside the capillaries. Coincubation of human blood neutrophils with a confluent human vascular endothelial monolayer showed that adhesion of neutrophils on endothelial cells was suppressed by treatment with IAIPs. IAIPs inhibited the spontaneous release of reactive oxygen species (ROS) in a concentration-dependent fashion. ROS inhibition was associated with reductions in p47 phosphorylation on Ser328. These results suggest that IAIP-induced morphological changes that render neutrophils quiescent, facilitate passage through the microvasculature, and reduce adhesion to vascular endothelial cells and production of ROS. Thus, IAIP plays a key role in controlling neutrophil activation.
血浆中抗胰蛋白酶抑制物（IAIP）的水平在脓毒症患者中降低，并且降低的水平与死亡率的增加相关。在本研究中，我们研究了 IAIP 对人中性粒细胞的影响，以更好地理解 IAIP 在治疗脓毒症中的有益作用。我们证明，IAIP 以浓度依赖的方式诱导小球形，尺寸更小且细胞表面光滑的形状。这些变化被针对 IAIP 的特异性抗体所抑制。相比之下，IAIP 的轻链 bikunin 对中性粒细胞形态没有影响。用 IAIP 处理的中性粒细胞可以轻松穿过人工微血管，并且防止被捕获在血管内。与人血管内皮单层共孵育的人血液中性粒细胞显示，用 IAIP 处理可抑制中性粒细胞在内皮细胞上的粘附。IAIP 以浓度依赖性方式抑制活性氧（ROS）的自发释放。ROS 抑制与 Ser328 上 p47 磷酸化的减少有关。这些结果表明，IAIP 诱导的形态变化使中性粒细胞静止，促进通过微血管，并减少与血管内皮细胞的粘附和 ROS 的产生。因此，IAIP 在控制中性粒细胞激活中起关键作用。
