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Role of Protein Kinase C-delta in regulating platelet activation and platelet-leukocyte interaction during sepsis

Liverani, Elisabetta ; Mondrinos, Mark J ; Sun, Shuang ; Kunapuli, Satya P ; Kilpatrick, Laurie E Zhao, You-Yang

PloS one, 2018-04, Vol.13 (4), p.e0195379 [Periódico revisado por pares]

United States: Public Library of Science

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Título:
Role of Protein Kinase C-delta in regulating platelet activation and platelet-leukocyte interaction during sepsis
Autor: Liverani, Elisabetta ; Mondrinos, Mark J ; Sun, Shuang ; Kunapuli, Satya P ; Kilpatrick, Laurie E
Zhao, You-Yang
Assuntos: Adult respiratory distress syndrome ; Amino acids ; Animals ; Binding sites ; Biology and Life Sciences ; Blood circulation ; Blood platelets ; Blood Platelets - drug effects ; Blood Platelets - enzymology ; Causes of ; Cecum ; Cell activation ; Chemokines ; Cloning ; Complications and side effects ; Damage detection ; Development and progression ; Disease Models, Animal ; Endothelium ; Health aspects ; Immune response ; Inflammation ; Inflammatory response ; Inhibition ; Inhibitors ; Kinases ; Laboratory animals ; Leukocyte migration ; Leukocytes ; Leukocytes (neutrophilic) ; Leukocytes - drug effects ; Leukocytes - enzymology ; Lung - drug effects ; Lung - enzymology ; Lung - pathology ; Lungs ; Male ; Medicine ; Medicine and Health Sciences ; Microvasculature ; Neutrophil Infiltration - drug effects ; Neutrophil Infiltration - physiology ; Neutrophils ; P-selectin ; Peptides ; Permeability ; Physiological aspects ; Physiology ; Platelet activation ; Platelet Activation - drug effects ; Platelet Activation - physiology ; Platelet Aggregation - drug effects ; Platelet Aggregation - physiology ; Platelets ; Protein kinase C ; Protein Kinase C-delta - antagonists & inhibitors ; Protein Kinase C-delta - metabolism ; Protein Kinase Inhibitors - pharmacology ; Protein kinases ; Proteins ; Rats, Sprague-Dawley ; Rodents ; Secretion ; Sepsis ; Sepsis - enzymology ; Sepsis - pathology ; Surgery ; Thrombocytopenia ; Thrombocytopenia - enzymology ; Thrombocytopenia - pathology ; Thrombosis ; White blood cells
É parte de: PloS one, 2018-04, Vol.13 (4), p.e0195379
Notas: Competing Interests: L.E.K. is listed as an inventor on U.S. patent 8,470,766 entitled “Novel Protein Kinase C Therapy for the Treatment of Acute Lung Injury,". This does not alter our adherence to PLOS ONE policies on sharing data and materials.
Descrição: 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.
Editor: United States: Public Library of Science
Idioma: Inglês

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Role of Protein Kinase C-delta in regulating platelet activation and platelet-leukocyte interaction during sepsis

Liverani, Elisabetta ; Mondrinos, Mark J ; Sun, Shuang ; Kunapuli, Satya P ; Kilpatrick, Laurie E Zhao, You-Yang

United States: Public Library of Science

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