Protein kinase C-delta inhibition is organ-protective, enhances pathogen clearance, and improves survival in sepsis.
cecal ligation and puncture
inflammation
macrophages
organ injury
phagocytosis
Journal
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
ISSN: 1530-6860
Titre abrégé: FASEB J
Pays: United States
ID NLM: 8804484
Informations de publication
Date de publication:
02 2020
02 2020
Historique:
received:
10
04
2019
revised:
30
11
2019
accepted:
03
12
2019
pubmed:
8
1
2020
medline:
29
9
2020
entrez:
8
1
2020
Statut:
ppublish
Résumé
Sepsis is a leading cause of morbidity and mortality in intensive care units. Previously, we identified Protein Kinase C-delta (PKCδ) as an important regulator of the inflammatory response in sepsis. An important issue in development of anti-inflammatory therapeutics is the risk of immunosuppression and inability to effectively clear pathogens. In this study, we investigated whether PKCδ inhibition prevented organ dysfunction and improved survival without compromising pathogen clearance. Sprague Dawley rats underwent sham surgery or cecal ligation and puncture (CLP) to induce sepsis. Post-surgery, PBS or a PKCδ inhibitor (200µg/kg) was administered intra-tracheally (IT). At 24 hours post-CLP, there was evidence of lung and kidney dysfunction. PKCδ inhibition decreased leukocyte influx in these organs, decreased endothelial permeability, improved gas exchange, and reduced blood urea nitrogen/creatinine ratios indicating organ protection. PKCδ inhibition significantly decreased bacterial levels in the peritoneal cavity, spleen and blood but did not exhibit direct bactericidal properties. Peritoneal chemokine levels, neutrophil numbers, or macrophage phenotypes were not altered by PKCδ inhibition. Peritoneal macrophages isolated from PKCδ inhibitor-treated septic rats demonstrated increased bacterial phagocytosis. Importantly, PKCδ inhibition increased survival. Thus, PKCδ inhibition improved survival and improved survival was associated with increased phagocytic activity, enhanced pathogen clearance, and decreased organ injury.
Identifiants
pubmed: 31908004
doi: 10.1096/fj.201900897R
pmc: PMC7568544
mid: NIHMS1062952
doi:
Substances chimiques
Chemokines
0
Enzyme Inhibitors
0
Prkcd protein, rat
EC 2.7.1.-
Protein Kinase C-delta
EC 2.7.11.13
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
2497-2510Subventions
Organisme : NIAID NIH HHS
ID : R21 AI132996
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM134701
Pays : United States
Organisme : NIAID NIH HHS
ID : R56 AI125429
Pays : United States
Organisme : Blood Institute of the National Institutes of Health (NIH)
ID : GM114359
Pays : International
Organisme : NHLBI NIH HHS
ID : R01 HL111552
Pays : United States
Organisme : NIDA NIH HHS
ID : P30 DA013429
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM114359
Pays : United States
Organisme : Blood Institute of the National Institutes of Health (NIH)
ID : DA040619
Pays : International
Organisme : Blood Institute of the National Institutes of Health (NIH)
ID : GM134701
Pays : International
Organisme : NIDA NIH HHS
ID : R01 DA040619
Pays : United States
Organisme : Blood Institute of the National Institutes of Health (NIH)
ID : HL111552
Pays : International
Organisme : Blood Institute of the National Institutes of Health (NIH)
ID : P30DA13429
Pays : International
Informations de copyright
© 2019 Federation of American Societies for Experimental Biology.
Références
Shock. 2013 Jun;39(6):467-79
pubmed: 23572089
J Immunol. 2003 Jun 1;170(11):5681-9
pubmed: 12759450
Immunity. 2013 Nov 14;39(5):799-800
pubmed: 24238335
Shock. 2018 Jun;49(6):682-689
pubmed: 29589840
J Pharmacol Exp Ther. 2015 Oct;355(1):86-98
pubmed: 26243739
Mol Immunol. 2007 Mar;44(9):2257-64
pubmed: 17161867
J Leukoc Biol. 2011 Jan;89(1):3-10
pubmed: 20724665
Crit Care Med. 2014 Mar;42(3):625-31
pubmed: 24201173
J Neuroinflammation. 2018 Nov 6;15(1):309
pubmed: 30400800
Am J Physiol Lung Cell Mol Physiol. 2014 Feb;306(3):L217-30
pubmed: 24318116
Thorax. 2009 Jun;64(6):532-4
pubmed: 19318347
J Appl Physiol (1985). 2006 Apr;100(4):1224-9
pubmed: 16239606
Proc Natl Acad Sci U S A. 2001 Sep 25;98(20):11114-9
pubmed: 11553773
Lancet Infect Dis. 2013 Mar;13(3):260-8
pubmed: 23427891
Physiol Rev. 2013 Jul;93(3):1247-88
pubmed: 23899564
BMJ. 2019 Jan 9;364:k4891
pubmed: 30626586
Am J Physiol Cell Physiol. 2004 Sep;287(3):C633-42
pubmed: 15115707
JAMA. 2016 Feb 23;315(8):801-10
pubmed: 26903338
Toxicol Lett. 2012 Sep 3;213(2):228-34
pubmed: 22728133
J Infect Dis. 2017 Jan 15;215(2):321-332
pubmed: 27815380
J Infect Dis. 2002 Apr 15;185(8):1115-20
pubmed: 11930321
Shock. 2014 Feb;41(2):97-103
pubmed: 24300829
PLoS One. 2013 Nov 12;8(11):e79037
pubmed: 24265742
Immunity. 2013 Nov 14;39(5):874-84
pubmed: 24184056
J Immunol. 2012 Mar 1;188(5):2328-37
pubmed: 22271653
J Immunol. 2008 May 1;180(9):5771-7
pubmed: 18424693
J Leukoc Biol. 2016 Nov;100(5):1027-1035
pubmed: 27190303
PLoS One. 2012;7(5):e37584
pubmed: 22655058
Am J Respir Crit Care Med. 2010 Oct 15;182(8):1047-57
pubmed: 20558630
Shock. 2019 May;51(5):538-547
pubmed: 30095599
J Clin Invest. 2002 Sep;110(6):801-6
pubmed: 12235111
J Leukoc Biol. 2010 Jan;87(1):153-64
pubmed: 19801500
Am J Physiol Cell Physiol. 2002 Jul;283(1):C48-57
pubmed: 12055072
Immunity. 2014 Apr 17;40(4):463-75
pubmed: 24745331
Sci Transl Med. 2010 Sep 29;2(51):51ra71
pubmed: 20881280
PLoS One. 2018 Apr 4;13(4):e0195379
pubmed: 29617417
J Biol Chem. 2001 Jun 8;276(23):19746-52
pubmed: 11274209
Eur J Surg. 2002;168(4):204-14
pubmed: 12440757
J Leukoc Biol. 2011 Mar;89(3):423-32
pubmed: 21106642
N Engl J Med. 2013 Aug 29;369(9):840-51
pubmed: 23984731
J Clin Invest. 2004 Jul;114(1):49-56
pubmed: 15232611
J Immunol. 2007 Aug 1;179(3):1855-63
pubmed: 17641052
Int Immunol. 1999 Feb;11(2):217-27
pubmed: 10069420
Am J Pathol. 2007 Jan;170(1):140-51
pubmed: 17200189
Am J Pathol. 2014 Jan;184(1):200-13
pubmed: 24211111
J Mol Med (Berl). 2010 Oct;88(10):1055-63
pubmed: 20582580
Biochem Biophys Res Commun. 2004 Jun 11;318(4):949-54
pubmed: 15147964
J Leukoc Biol. 2006 Dec;80(6):1512-21
pubmed: 17138860
J Clin Invest. 2002 Sep;110(6):737-9
pubmed: 12235101
Crit Care Med. 2010 Apr;38(4):1179-86
pubmed: 20154604
J Neurosci. 2004 Aug 4;24(31):6880-8
pubmed: 15295022
J Immunol. 2011 Oct 15;187(8):4256-67
pubmed: 21918191
Circulation. 2003 Aug 19;108(7):869-75
pubmed: 12860903
Am J Physiol Lung Cell Mol Physiol. 2012 Nov 15;303(10):L880-8
pubmed: 22983354
Lancet. 2006 Jul 8;368(9530):157-69
pubmed: 16829300
J Biochem. 2009 Jan;145(1):87-94
pubmed: 18974158