Role of Protein Kinase C-delta in regulating platelet activation and platelet-leukocyte interaction during sepsis.
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 lu...
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doaj-fc9efd8e9e0043b784230d3bf81524b32020-11-25T01:53:42ZengPublic Library of Science (PLoS)PLoS ONE1932-62032018-01-01134e019537910.1371/journal.pone.0195379Role of Protein Kinase C-delta in regulating platelet activation and platelet-leukocyte interaction during sepsis.Elisabetta LiveraniMark J MondrinosShuang SunSatya P KunapuliLaurie E KilpatrickSepsis 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.http://europepmc.org/articles/PMC5884571?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Elisabetta Liverani Mark J Mondrinos Shuang Sun Satya P Kunapuli Laurie E Kilpatrick |
spellingShingle |
Elisabetta Liverani Mark J Mondrinos Shuang Sun Satya P Kunapuli Laurie E Kilpatrick Role of Protein Kinase C-delta in regulating platelet activation and platelet-leukocyte interaction during sepsis. PLoS ONE |
author_facet |
Elisabetta Liverani Mark J Mondrinos Shuang Sun Satya P Kunapuli Laurie E Kilpatrick |
author_sort |
Elisabetta Liverani |
title |
Role of Protein Kinase C-delta in regulating platelet activation and platelet-leukocyte interaction during sepsis. |
title_short |
Role of Protein Kinase C-delta in regulating platelet activation and platelet-leukocyte interaction during sepsis. |
title_full |
Role of Protein Kinase C-delta in regulating platelet activation and platelet-leukocyte interaction during sepsis. |
title_fullStr |
Role of Protein Kinase C-delta in regulating platelet activation and platelet-leukocyte interaction during sepsis. |
title_full_unstemmed |
Role of Protein Kinase C-delta in regulating platelet activation and platelet-leukocyte interaction during sepsis. |
title_sort |
role of protein kinase c-delta in regulating platelet activation and platelet-leukocyte interaction during sepsis. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2018-01-01 |
description |
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. |
url |
http://europepmc.org/articles/PMC5884571?pdf=render |
work_keys_str_mv |
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