PMID- 24373231
OWN - NLM
STAT- MEDLINE
DCOM- 20150514
LR  - 20211021
IS  - 1466-609X (Electronic)
IS  - 1364-8535 (Print)
IS  - 1364-8535 (Linking)
VI  - 17
IP  - 6
DP  - 2013 Dec 27
TI  - Inhibition of the inflammatory cytokine tumor necrosis factor-alpha with 
      etanercept provides protection against lethal H1N1 influenza infection in mice.
PG  - R301
LID - 10.1186/cc13171 [doi]
AB  - INTRODUCTION: Factors implicated in influenza-mediated morbidity and mortality 
      include robust cytokine production (cytokine storm), excessive inflammatory 
      infiltrates, and virus-induced tissue destruction. Tumor necrosis factor-alpha 
      (TNF-alpha) is an important pro-inflammatory cytokine present during influenza 
      infection, but it is unclear whether direct inhibition of TNF-alpha can elicit 
      protection against influenza infection. METHODS: In this study, the commercially 
      available TNF-alpha inhibitor etanercept was used to inhibit TNF-alpha induced by lethal 
      A/FM/1/47 (H1N1) influenza virus infection of mice. The effects of TNF-alpha 
      inhibition on mouse survival, pathologic changes, immune cell infiltration, 
      inflammatory cytokine secretion, Toll-like receptor expression, and activation of 
      the NF-kappaB (nuclear factor kappa B) signaling pathway were evaluated. RESULTS: The 
      intranasal delivery of etanercept provided significant protection against 
      mortality (30% of mice survived up to 14 days after infection) in mice treated 
      with etanercept. In contrast, no survivors were found beyond 6 days in mice 
      treated with saline after lethal challenge with H1N1 influenza virus. It was 
      observed that etanercept significantly reduced inflammatory cell infiltration 
      (for example, macrophages and neutrophils), inflammatory cytokine secretion (for 
      example, interleukin-6, TNF-alpha, and interferon gamma), and expression of Toll-like 
      receptors (TLR-3, TLR-4, and TLR-7). Etanercept also downregulated and inhibited 
      the cascade proteins of the NF-kappaB signaling pathway (for example, MyD88, TRIF, 
      NF-kappaB, and p65), as well as enhanced host control of virus replication. 
      CONCLUSIONS: These findings indicate that etanercept, by blocking TNF-alpha, can 
      significantly downregulate excessive inflammatory immune responses and provide 
      protection against lethal influenza infection, making its use a novel strategy 
      for controlling severe influenza-induced viral pneumonia.
FAU - Shi, Xunlong
AU  - Shi X
FAU - Zhou, Wei
AU  - Zhou W
FAU - Huang, Hai
AU  - Huang H
FAU - Zhu, Hongguang
AU  - Zhu H
FAU - Zhou, Pei
AU  - Zhou P
FAU - Zhu, Haiyan
AU  - Zhu H
FAU - Ju, Dianwen
AU  - Ju D
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20131227
PL  - England
TA  - Crit Care
JT  - Critical care (London, England)
JID - 9801902
RN  - 0 (Antiviral Agents)
RN  - 0 (Cytokines)
RN  - 0 (Immunoglobulin G)
RN  - 0 (NF-kappa B)
RN  - 0 (RNA, Messenger)
RN  - 0 (Receptors, Tumor Necrosis Factor)
RN  - 0 (Toll-Like Receptors)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - OP401G7OJC (Etanercept)
SB  - IM
MH  - Animals
MH  - Antiviral Agents/*therapeutic use
MH  - Cytokines/metabolism
MH  - Down-Regulation
MH  - Etanercept
MH  - Immunity, Innate
MH  - Immunoglobulin G/*therapeutic use
MH  - *Influenza A Virus, H1N1 Subtype
MH  - Male
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - NF-kappa B/metabolism
MH  - Orthomyxoviridae Infections/*drug therapy/immunology/pathology
MH  - Pneumonia, Viral/*drug therapy/immunology/pathology
MH  - RNA, Messenger/metabolism
MH  - Receptors, Tumor Necrosis Factor/*therapeutic use
MH  - Signal Transduction
MH  - Toll-Like Receptors/metabolism
MH  - Tumor Necrosis Factor-alpha/*antagonists & inhibitors
MH  - Virus Replication
PMC - PMC4057515
EDAT- 2014/01/01 06:00
MHDA- 2015/05/15 06:00
PMCR- 2013/12/27
CRDT- 2013/12/31 06:00
PHST- 2013/08/20 00:00 [received]
PHST- 2013/12/10 00:00 [accepted]
PHST- 2013/12/31 06:00 [entrez]
PHST- 2014/01/01 06:00 [pubmed]
PHST- 2015/05/15 06:00 [medline]
PHST- 2013/12/27 00:00 [pmc-release]
AID - cc13171 [pii]
AID - 10.1186/cc13171 [doi]
PST - epublish
SO  - Crit Care. 2013 Dec 27;17(6):R301. doi: 10.1186/cc13171.