Document Detail


Nuclear factor κB inhibition reduces lung vascular lumen obliteration in severe pulmonary hypertension in rats.
MedLine Citation:
PMID:  24684441     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
NF-κB and IL-6, a NF-κB downstream mediator, play a central role in the inflammatory response of tissues. We aimed to determine the role of the classical NF-κB pathway in severe pulmonary arterial hypertension (PAH) induced by SU5416 and chronic hypoxia (SuHx) in rats. Tissue samples from patients with idiopathic PAH (iPAH) and control subjects were investigated. SuHx rats were treated from Days 1 to 3, 1 to 21, and 29 to 42 with the NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC) and/or from Days 1 to 21 with anti-IL-6 antibody. Nuclear staining for NF-κB, an indicator of the activation of the classical NF-κB pathway, was detected in pulmonary arterial lesions of patients with iPAH and SuHx rats. NF-κB inhibition with PDTC prevented and reduced pulmonary arterial obliteration without reducing muscularization. However, the elevated lung levels of IL-6 were not reduced in PDTC-treated SuHx animals. PDTC treatment prevented or reduced apoptosis of pulmonary artery wall cells and pulmonary arterial obliteration. IL-6 inhibition had only a partial effect on apoptosis and obliteration. Pulmonary arterial media wall thickness was not affected by any of these treatments. Preventive and therapeutic PDTC treatment promoted immune regulation by increasing the number of perivascular CD4(+) T cells, in particular regulatory T cells (early treatment), and by reducing the number of perivascular CD8(+) T lymphocytes and CD45RA(+) B lymphocytes. Therapeutic PDTC treatment further preserved right ventricular function in SuHx animals. Inhibition of NF-κB may represent a therapeutic option for pulmonary arterial obliteration via reduced vessel wall cell apoptosis and improved regulation of the immune system.
Authors:
Daniela Farkas; Aysar A Alhussaini; Donatas Kraskauskas; Vita Kraskauskiene; Carlyne D Cool; Mark R Nicolls; Ramesh Natarajan; Laszlo Farkas
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  American journal of respiratory cell and molecular biology     Volume:  51     ISSN:  1535-4989     ISO Abbreviation:  Am. J. Respir. Cell Mol. Biol.     Publication Date:  2014 Sep 
Date Detail:
Created Date:  2014-08-30     Completed Date:  2014-10-22     Revised Date:  2014-11-05    
Medline Journal Info:
Nlm Unique ID:  8917225     Medline TA:  Am J Respir Cell Mol Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  413-25     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Anoxia / metabolism
Antigens, CD45 / metabolism
Apoptosis
CD4-Positive T-Lymphocytes / metabolism
Humans
Hypertension, Pulmonary / metabolism*,  pathology
Indoles / chemistry
Inflammation
Interleukin-6 / metabolism
Lung / pathology
NF-kappa B / antagonists & inhibitors*,  metabolism*
Pulmonary Artery / pathology
Pyrroles / chemistry
Pyrrolidines / chemistry
Rats
Signal Transduction
Thiocarbamates / chemistry
Time Factors
Grant Support
ID/Acronym/Agency:
5P30NS047463/NS/NINDS NIH HHS; HL114816/HL/NHLBI NIH HHS; P01 HL108797/HL/NHLBI NIH HHS; P30 CA016059/CA/NCI NIH HHS; R01 HL095686/HL/NHLBI NIH HHS; UL1RR031990/RR/NCRR NIH HHS
Chemical
Reg. No./Substance:
0/Indoles; 0/Interleukin-6; 0/NF-kappa B; 0/Pyrroles; 0/Pyrrolidines; 0/Thiocarbamates; 25769-03-3/pyrrolidine dithiocarbamic acid; 71IA9S35AJ/Semaxinib; EC 3.1.3.48/Antigens, CD45

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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