Role of Protein Kinase C-delta in regulating platelet activation and platelet-leukocyte interaction during sepsis.
Role of Protein Kinase C-delta in regulating platelet activation and platelet-leukocyte interaction during sepsis.
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DOI：
10.1371/journal.pone.0195379
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Kilpatrick LE
中科院分区：
文献类型：
--
作者：
Liverani E;Mondrinos MJ;Sun S;Kunapuli SP;Kilpatrick LE
脓毒症的特征在于强烈的全身炎症反应，激活一系列促炎事件，导致白细胞失调和宿主组织损伤。肺特别容易受到全身性炎症的影响，导致急性肺损伤。炎症诱导的肺损伤的关键是中性粒细胞过度迁移穿过血管内皮。脓毒症中调节中性粒细胞活化和迁移的机制尚未明确，但越来越多的证据表明血小板积极参与微血管通透性和嗜中性粒细胞介导的器官损伤并发挥关键作用。我们以前确定PKC-δ（PKCδ）作为脓毒症炎症反应的关键调节因子，并证明PKCδ抑制具有肺保护作用。然而，PKCδ在脓毒症诱导的血小板活化和血小板-白细胞相互作用中的作用尚不清楚。在这项研究中，大鼠进行假手术或盲肠结扎穿孔（CLP）诱导败血症。手术后，气管内给予PKCδ抑制剂（200μg/kg）或溶媒（PBS）。术后24小时，采集肺组织、BAL液和血液样本。虽然脓毒症引起血小板减少症，但与假手术动物相比，剩余的循环血小板被激活，表现为p-选择素表达增加、血浆PF 4升高和血小板-白细胞聚集体形成增强。血小板活化与血小板PKCδ活性增加有关。抑制PKCδ可减弱脓毒症诱导的血小板活化、分泌和聚集体形成。脓毒症诱导的血小板减少症也显著减少，循环血小板数量与假手术动物相似。在肺中，脓毒症诱导血小板和中性粒细胞的显著流入和肺损伤的发展。给予PKCδ抑制剂可减少血小板和中性粒细胞的流入，并具有肺保护作用。因此，PKCδ抑制调节局部和全身血小板活性，减少中性粒细胞流入肺，并具有肺保护作用。我们首次证明PKCδ在脓毒症时血小板活化和血小板-中性粒细胞相互作用中起重要作用。
Sepsis is characterized by an intense systemic inflammatory response activating a cascade of proinflammatory events resulting in leukocyte dysregulation and host tissue damage. The lung is particularly susceptible to systemic inflammation, leading to acute lung injury. Key to inflammation-induced lung damage is the excessive migration of neutrophils across the vascular endothelium. The mechanisms which regulate neutrophil activation and migration in sepsis are not well defined but there is growing evidence that platelets are actively involved and play a key role in microvascular permeability and neutrophil-mediated organ damage. We previously identified PKC-delta (PKCδ) as a critical regulator of the inflammatory response in sepsis and demonstrated PKCδ inhibition was lung protective. However, the role of PKCδ in sepsis-induced platelet activation and platelet-leukocyte interactions is not known. In this study, rats underwent sham surgery or cecal ligation and puncture (CLP) to induce sepsis. Following surgeries, a PKCδ inhibitor (200μg/kg) or vehicle (PBS) was administered intra-tracheally. At 24 hours post-surgeries, lung tissue, BAL fluid, and blood samples were collected. While sepsis caused thrombocytopenia, the remaining circulating platelets were activated as demonstrated by increased p-selectin expression, elevated plasma PF4, and enhanced platelet-leukocyte aggregate formation compared to Sham animals. Platelet activation was associated with increased platelet PKCδ activity. Inhibition of PKCδ attenuated sepsis-induced platelet activation, secretion and aggregate formation. Sepsis-induced thrombocytopenia was also significantly reduced and circulating platelet numbers were similar to sham animals. In the lung, sepsis induced significant influx of platelets and neutrophils and the development of lung injury. Administration of the PKCδ inhibitor decreased platelet and neutrophil influx, and was lung protective. Thus, PKCδ inhibition modulated platelet activity both locally and systemically, decreased neutrophil influx into the lung, and was lung protective. We demonstrate for the first time that PKCδ plays an important role in platelet activation and platelet-neutrophil interaction during sepsis.
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DOI：
10.1111/jth.13302
发表时间：
2016-05
期刊：
Journal of thrombosis and haemostasis : JTH
影响因子：
--
作者：
Bye AP;Unsworth AJ;Gibbins JM
通讯作者：
Gibbins JM
影响因子：
3.1
作者：
Hagiwara, Satoshi;Iwasaka, Hideo;Noguchi, Takayuki
通讯作者：
Noguchi, Takayuki
影响因子：
8.8
作者：
Asaduzzaman, Muhammad;Lavasani, Shahram;Thorlacius, Henrik
通讯作者：
Thorlacius, Henrik
DOI：
10.1073/pnas.191369098
发表时间：
2001-09-25
影响因子：
11.1
作者：
Chen, L;Hahn, H;Mochly-Rosen, D
通讯作者：
Mochly-Rosen, D
影响因子：
4.6
作者：
Cai, SR;Xu, G;McLeod, HL
通讯作者：
McLeod, HL