Document Detail


Blockade of NOX2 and STIM1 signaling limits lipopolysaccharide-induced vascular inflammation.
MedLine Citation:
PMID:  23348743     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
During sepsis, acute lung injury (ALI) results from activation of innate immune cells and endothelial cells by endotoxins, leading to systemic inflammation through proinflammatory cytokine overproduction, oxidative stress, and intracellular Ca2+ overload. Despite considerable investigation, the underlying molecular mechanism(s) leading to LPS-induced ALI remain elusive. To determine whether stromal interaction molecule 1-dependent (STIM1-dependent) signaling drives endothelial dysfunction in response to LPS, we investigated oxidative and STIM1 signaling of EC-specific Stim1-knockout mice. Here we report that LPS-mediated Ca2+ oscillations are ablated in ECs deficient in Nox2, Stim1, and type II inositol triphosphate receptor (Itpr2). LPS-induced nuclear factor of activated T cells (NFAT) nuclear accumulation was abrogated by either antioxidant supplementation or Ca2+ chelation. Moreover, ECs lacking either Nox2 or Stim1 failed to trigger store-operated Ca2+ entry (SOCe) and NFAT nuclear accumulation. LPS-induced vascular permeability changes were reduced in EC-specific Stim1-/- mice, despite elevation of systemic cytokine levels. Additionally, inhibition of STIM1 signaling prevented receptor-interacting protein 3-dependent (RIP3-dependent) EC death. Remarkably, BTP2, a small-molecule calcium release-activated calcium (CRAC) channel blocker administered after insult, halted LPS-induced vascular leakage and pulmonary edema. These results indicate that ROS-driven Ca2+ signaling promotes vascular barrier dysfunction and that the SOCe machinery may provide crucial therapeutic targets to limit sepsis-induced ALI.
Authors:
Rajesh Kumar Gandhirajan; Shu Meng; Harish C Chandramoorthy; Karthik Mallilankaraman; Salvatore Mancarella; Hui Gao; Roshanak Razmpour; Xiao-Feng Yang; Steven R Houser; Ju Chen; Walter J Koch; Hong Wang; Jonathan Soboloff; Donald L Gill; Muniswamy Madesh
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2013-01-25
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  123     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-04-19     Completed Date:  2013-05-13     Revised Date:  2014-05-19    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  887-902     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
Acute Lung Injury / etiology,  metabolism,  pathology,  prevention & control*
Anilides / pharmacology
Animals
Calcium Signaling
Cells, Cultured
Endothelium, Vascular / metabolism,  pathology
Female
Gene Knockdown Techniques
Inositol 1,4,5-Trisphosphate Receptors / deficiency,  genetics
Lipopolysaccharides / toxicity
Male
Membrane Glycoproteins / antagonists & inhibitors*,  deficiency,  genetics,  metabolism
Mice
Mice, Knockout
Models, Biological
NADPH Oxidase / antagonists & inhibitors*,  deficiency,  genetics,  metabolism
NFATC Transcription Factors / metabolism
Reactive Oxygen Species / metabolism
Sepsis / complications
Signal Transduction
Thiadiazoles / pharmacology
Grant Support
ID/Acronym/Agency:
1S10RR027327-01/RR/NCRR NIH HHS; HL086699/HL/NHLBI NIH HHS; P01 HL080101/HL/NHLBI NIH HHS; R01 AI058173/AI/NIAID NIH HHS; R01 HL077288/HL/NHLBI NIH HHS; R01 HL108910/HL/NHLBI NIH HHS; R01 HL110764/HL/NHLBI NIH HHS; R21 HL109920/HL/NHLBI NIH HHS; R21HL109920-01/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/4-methyl-4'-(3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)-1,2,3-thiadiazole-5-carboxanilide; 0/Anilides; 0/Inositol 1,4,5-Trisphosphate Receptors; 0/Lipopolysaccharides; 0/Membrane Glycoproteins; 0/NFATC Transcription Factors; 0/Reactive Oxygen Species; 0/Stim1 protein, mouse; 0/Thiadiazoles; EC 1.6.3.1/Cybb protein, mouse; EC 1.6.3.1/NADPH Oxidase
Comments/Corrections
Comment In:
J Clin Invest. 2013 Mar 1;123(3):1015-8   [PMID:  23434597 ]

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