PMID- 23530143
OWN - NLM
STAT- MEDLINE
DCOM- 20130729
LR  - 20211021
IS  - 1550-6606 (Electronic)
IS  - 0022-1767 (Print)
IS  - 0022-1767 (Linking)
VI  - 190
IP  - 9
DP  - 2013 May 1
TI  - NADPH oxidase limits lipopolysaccharide-induced lung inflammation and injury in 
      mice through reduction-oxidation regulation of NF-kappaB activity.
PG  - 4786-94
LID - 10.4049/jimmunol.1201809 [doi]
AB  - Although reactive oxygen species (ROS) produced by NADPH oxidase are known to 
      regulate inflammatory responses, the impact of ROS on intracellular signaling 
      pathways is incompletely understood. In these studies, we treated wild-type (WT) 
      and p47(phox)-deficient mice with LPS to investigate mechanisms by which NADPH 
      oxidase regulates signaling through the NF-kappaB pathway. After intratracheal 
      instillation of LPS, ROS generation was impaired in p47(phox)(-/-) mice, whereas 
      these mice had increased neutrophilic alveolitis and greater lung injury compared 
      with WT controls. In mice interbred with transgenic NF-kappaB reporters (HIV-long 
      terminal repeat/luciferase [HLL]), we found exaggerated LPS-induced NF-kappaB 
      activation and increased expression of proinflammatory cytokines in lungs of 
      p47(phox)(-/-)/HLL mice compared with controls. Both lung macrophages and bone 
      marrow-derived macrophages (BMDMs) isolated from p47(phox)(-/-)/HLL mice showed 
      enhanced LPS-stimulated NF-kappaB activity compared with controls. Although nuclear 
      translocation of NF-kappaB proteins was similar between genotypes, EMSAs under 
      nonreducing conditions showed increased DNA binding in p47(phox)(-/-)/HLL BMDMs, 
      suggesting that ROS production reduces NF-kappaB binding to DNA without affecting 
      nuclear translocation. Increased intracellular reduced glutathione/glutathione 
      disulfide ratio and greater nuclear redox factor 1 (Ref-1) levels were present in 
      p47(phox)(-/-)/HLL compared with WT BMDMs, pointing to NADPH oxidase modulating 
      intracellular redox status in macrophages. Treatment with the Ref-1-specific 
      inhibitor E3330 or hydrogen peroxide inhibited LPS-induced NF-kappaB activation in 
      p47(phox)(-/-)/HLL BMDMs but not in WT/HLL cells. Consistent with these findings, 
      small interfering RNA against Ref-1 selectively reduced NF-kappaB activity in 
      LPS-treated p47(phox)(-/-)/HLL BMDMs. Together, these results indicate that NADPH 
      oxidase limits LPS-induced NF-kappaB transcriptional activity through regulation of 
      intracellular redox state.
FAU - Han, Wei
AU  - Han W
AD  - Division of Allergy, Pulmonary and Critical Care Medicine, Department of 
      Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. 
      wei.han@vanderbilt.edu
FAU - Li, Hui
AU  - Li H
FAU - Cai, Jiyang
AU  - Cai J
FAU - Gleaves, Linda A
AU  - Gleaves LA
FAU - Polosukhin, Vasiliy V
AU  - Polosukhin VV
FAU - Segal, Brahm H
AU  - Segal BH
FAU - Yull, Fiona E
AU  - Yull FE
FAU - Blackwell, Timothy S
AU  - Blackwell TS
LA  - eng
GR  - R01 AI079253/AI/NIAID NIH HHS/United States
GR  - R01 HL061419/HL/NHLBI NIH HHS/United States
GR  - HL61419/HL/NHLBI NIH HHS/United States
GR  - AI079253/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20130325
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
RN  - 0 (Lipopolysaccharides)
RN  - 0 (NF-kappa B)
RN  - 0 (Reactive Oxygen Species)
RN  - EC 1.6.3.- (NADPH Oxidases)
RN  - EC 4.2.99.18 (Apex1 protein, mouse)
RN  - EC 4.2.99.18 (DNA-(Apurinic or Apyrimidinic Site) Lyase)
SB  - IM
MH  - Animals
MH  - DNA-(Apurinic or Apyrimidinic Site) Lyase/immunology/metabolism
MH  - Lipopolysaccharides/*immunology/pharmacology
MH  - Lung/drug effects/immunology/metabolism
MH  - Lung Injury/chemically induced/immunology/*metabolism
MH  - Mice
MH  - NADPH Oxidases/immunology/*metabolism
MH  - NF-kappa B/immunology/*metabolism
MH  - Neutrophils/immunology/metabolism
MH  - Oxidation-Reduction
MH  - Pneumonia/chemically induced/immunology/*metabolism
MH  - Reactive Oxygen Species/immunology/metabolism
PMC - PMC3633681
MID - NIHMS450936
EDAT- 2013/03/27 06:00
MHDA- 2013/07/31 06:00
PMCR- 2014/05/01
CRDT- 2013/03/27 06:00
PHST- 2013/03/27 06:00 [entrez]
PHST- 2013/03/27 06:00 [pubmed]
PHST- 2013/07/31 06:00 [medline]
PHST- 2014/05/01 00:00 [pmc-release]
AID - jimmunol.1201809 [pii]
AID - 10.4049/jimmunol.1201809 [doi]
PST - ppublish
SO  - J Immunol. 2013 May 1;190(9):4786-94. doi: 10.4049/jimmunol.1201809. Epub 2013 
      Mar 25.