PMID- 19965984
OWN - NLM
STAT- MEDLINE
DCOM- 20100301
LR  - 20211020
IS  - 1522-1504 (Electronic)
IS  - 1040-0605 (Print)
IS  - 1040-0605 (Linking)
VI  - 298
IP  - 2
DP  - 2010 Feb
TI  - Targeted disruption of NF-kappaB1 (p50) augments cigarette smoke-induced lung 
      inflammation and emphysema in mice: a critical role of p50 in chromatin 
      remodeling.
PG  - L197-209
LID - 10.1152/ajplung.00265.2009 [doi]
AB  - NF-kappaB-mediated proinflammatory response to cigarette smoke (CS) plays a 
      pivotal role in the pathogenesis of chronic obstructive pulmonary disease (COPD). 
      The heterodimer of RelA/p65-p50 (subunits of NF-kappaB) is involved in 
      transactivation of NF-kappaB-dependent genes, but interestingly p50 has no 
      transactivation domain. The endogenous role of p50 subunit, particularly in 
      regulation of CS-mediated inflammation in vivo, is not known. We therefore 
      hypothesized that p50 subunit plays a regulatory role on RelA/p65, and genetic 
      ablation of p50 (p50(-/-)) leads to increased lung inflammation and lung 
      destruction in response to CS exposure in mouse. To test this hypothesis, 
      p50-knockout and wild-type (WT) mice were exposed to CS for 3 days to 6 mo, and 
      inflammatory responses as well as air space enlargement were assessed. Lungs of 
      p50-deficient mice showed augmented proinflammatory response to acute and chronic 
      CS exposures as evidenced by increased inflammatory cell influx and 
      proinflammatory mediators release such as monocyte chemoattractant protein-1 
      (MCP-1) and interferon-inducible protein-10 (IP-10) compared with WT mice. IKK2 
      inhibitor (IMD-0354), which reduces the nuclear translocation of RelA/p65, 
      attenuated CS-mediated neutrophil influx in bronchoalveolar lavage fluid and 
      cytokine (MCP-1 and IP-10) levels in lungs of WT but not in p50-deficient mice. 
      Importantly, p50 deficiency resulted in increased phosphorylation (Ser276 and 
      Ser536), acetylation (Lys310), and DNA binding activity of RelA/p65 in mouse 
      lung, associated with increased chromatin remodeling evidenced by specific 
      phosphoacetylation of histone H3 (Ser10/Lys9) and acetylation of H4 (Lys12) in 
      response to CS exposure. Surprisingly, p50-null mice showed spontaneous air space 
      enlargement, which was further increased after CS exposure compared with WT mice. 
      Thus our data showed that p50 endogenously regulates the activity of RelA/p65 by 
      decreasing its phosphoacetylation and DNA binding activity and specific histone 
      modifications and that genetic ablation of p50 leads to air space enlargement in 
      mouse.
FAU - Rajendrasozhan, Saravanan
AU  - Rajendrasozhan S
AD  - Department of Environmental Medicine, Lung Biology and Disease Program, 
      University of Rochester Medical Center, Rochester, New York , USA.
FAU - Chung, Sangwoon
AU  - Chung S
FAU - Sundar, Isaac K
AU  - Sundar IK
FAU - Yao, Hongwei
AU  - Yao H
FAU - Rahman, Irfan
AU  - Rahman I
LA  - eng
GR  - 1-R01-HL-097751-01/HL/NHLBI NIH HHS/United States
GR  - ES-01247/ES/NIEHS NIH HHS/United States
GR  - R01-HL-085613/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20091204
PL  - United States
TA  - Am J Physiol Lung Cell Mol Physiol
JT  - American journal of physiology. Lung cellular and molecular physiology
JID - 100901229
RN  - 0 (I-kappa B Proteins)
RN  - 0 (NF-kappa B p50 Subunit)
RN  - 0 (NFKBIA protein, human)
RN  - 0 (Nfkbia protein, mouse)
RN  - 0 (Rela protein, mouse)
RN  - 0 (Smoke)
RN  - 0 (Transcription Factor RelA)
RN  - 139874-52-5 (NF-KappaB Inhibitor alpha)
RN  - EC 2.7.11.10 (I-kappa B Kinase)
SB  - IM
MH  - Animals
MH  - *Chromatin Assembly and Disassembly
MH  - Gene Targeting
MH  - Humans
MH  - I-kappa B Kinase/antagonists & inhibitors
MH  - I-kappa B Proteins/metabolism
MH  - Lung/cytology/immunology/metabolism/pathology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - NF-KappaB Inhibitor alpha
MH  - NF-kappa B p50 Subunit/genetics/*metabolism
MH  - Neutrophils/cytology/immunology
MH  - *Pneumonia/etiology/immunology/pathology
MH  - *Pulmonary Emphysema/etiology/immunology/pathology
MH  - Smoke/*adverse effects
MH  - Smoking/*adverse effects
MH  - Transcription Factor RelA/genetics/metabolism
PMC - PMC2822556
EDAT- 2009/12/08 06:00
MHDA- 2010/03/02 06:00
PMCR- 2011/02/01
CRDT- 2009/12/08 06:00
PHST- 2009/12/08 06:00 [entrez]
PHST- 2009/12/08 06:00 [pubmed]
PHST- 2010/03/02 06:00 [medline]
PHST- 2011/02/01 00:00 [pmc-release]
AID - 00265.2009 [pii]
AID - L-00265-2009 [pii]
AID - 10.1152/ajplung.00265.2009 [doi]
PST - ppublish
SO  - Am J Physiol Lung Cell Mol Physiol. 2010 Feb;298(2):L197-209. doi: 
      10.1152/ajplung.00265.2009. Epub 2009 Dec 4.