PMID- 24614528
OWN - NLM
STAT- MEDLINE
DCOM- 20160331
LR  - 20220321
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 9
IP  - 3
DP  - 2014
TI  - Pharmacological inhibition of cochlear mitochondrial respiratory chain induces 
      secondary inflammation in the lateral wall: a potential therapeutic target for 
      sensorineural hearing loss.
PG  - e90089
LID - 10.1371/journal.pone.0090089 [doi]
LID - e90089
AB  - Cochlear lateral wall has recently been reported as a common site of 
      inflammation, yet precise molecular mechanisms of the inflammatory responses 
      remain elucidated. The present study examined the inflammatory responses in the 
      lateral wall following acute mitochondrial dysfunction induced by a mitochondrial 
      toxin, 3-nitropropionic acid (3-NP). Reverse-transcription (RT)-PCR revealed 
      increases in the expression of the proinflammatory cytokines interleukin (IL)-1beta 
      and IL-6. Immunohistochemistry showed an increase in the number of activated 
      cochlear macrophages in the lateral wall, which were in close proximity to 
      IL-6-expressing cells. A genome-wide DNA microarray analysis of the lateral wall 
      revealed that 35% and 60% of the genes showing >2-fold upregulation at 1 d and 3 
      d post-3-NP administration, respectively, were inflammatory genes, including CC- 
      and CXC-type chemokine genes. High expression of CCL-1, 2, and 3 at 1 d, and of 
      CCL-1, 2, 3, 4, and 5, CCR-2 and 5, and CX3CR1 at 3 d post-3-NP administration, 
      coupled with no change in the level of CX3CL1 expression suggested that 
      macrophages and monocytes may be involved in the inflammatory response to 
      3-NP-mediated injury. Quantitative (q)RT-PCR showed a transient induction of 
      IL-1beta and IL-6 expression within 24 h of 3-NP-mediated injury, followed by 
      sustained expression of the chemoattractants, CCL-2, 4 and 5, up until 7 d after 
      injury. The expression of CCL-2 and IL-6 was higher in animals showing permanent 
      hearing impairment than in those showing temporary hearing impairment, suggesting 
      that these inflammatory responses may be detrimental to hearing recovery. The 
      present findings suggest that acute mitochondrial dysfunction induces secondary 
      inflammatory responses in the lateral wall of the cochlear and that the 
      IL-6/CCL-2 inflammatory pathway is involved in monocyte activation. Therefore, 
      these secondary inflammatory responses may be a potential post-insult therapeutic 
      target for treatments aimed at preventing the damage caused by acute 
      mitochondrial dysfunction in the cochlear lateral wall.
FAU - Fujioka, Masato
AU  - Fujioka M
AD  - Department of Otolaryngology, Head and Neck Surgery, Keio University, School of 
      Medicine, Shinjuku, Tokyo, Japan; Department of Physiology, School of Medicine, 
      Keio University, School of Medicine, Shinjuku, Tokyo, Japan.
FAU - Okamoto, Yasuhide
AU  - Okamoto Y
AD  - Department of Otorhinolaryngology, Inagi Municipal Hospital, Inagi, Tokyo, Japan; 
      The Laboratory of Auditory Disorders and Division of Hearing and Balance 
      Research, National Institute of Sensory Organs, National Tokyo Medical Center, 
      Meguro, Tokyo, Japan.
FAU - Shinden, Seiichi
AU  - Shinden S
AD  - Department of Otolaryngology, Saiseikai Utsunomiya Hospital, Utsunomiya, Tochigi, 
      Japan; The Laboratory of Auditory Disorders and Division of Hearing and Balance 
      Research, National Institute of Sensory Organs, National Tokyo Medical Center, 
      Meguro, Tokyo, Japan.
FAU - Okano, Hirotaka James
AU  - Okano HJ
AD  - Department of Physiology, School of Medicine, Keio University, School of 
      Medicine, Shinjuku, Tokyo, Japan; Division of Regenerative Medicine, Jikei 
      University School of Medicine, Tokyo, Japan.
FAU - Okano, Hideyuki
AU  - Okano H
AD  - Department of Physiology, School of Medicine, Keio University, School of 
      Medicine, Shinjuku, Tokyo, Japan.
FAU - Ogawa, Kaoru
AU  - Ogawa K
AD  - Department of Otolaryngology, Head and Neck Surgery, Keio University, School of 
      Medicine, Shinjuku, Tokyo, Japan.
FAU - Matsunaga, Tatsuo
AU  - Matsunaga T
AD  - The Laboratory of Auditory Disorders and Division of Hearing and Balance 
      Research, National Institute of Sensory Organs, National Tokyo Medical Center, 
      Meguro, Tokyo, Japan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140310
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Chemokines)
RN  - 0 (Inflammation Mediators)
RN  - 0 (Interleukin-6)
RN  - 0 (Nitro Compounds)
RN  - 0 (Propionates)
RN  - QY4L0FOX0D (3-nitropropionic acid)
SB  - IM
MH  - Animals
MH  - Chemokines/genetics/metabolism
MH  - Cochlea/drug effects/injuries/*pathology
MH  - Electron Transport/drug effects
MH  - Female
MH  - Gene Expression Profiling
MH  - Genome
MH  - Hearing Loss, Sensorineural/*drug therapy/pathology
MH  - Inflammation/*pathology
MH  - Inflammation Mediators/metabolism
MH  - Interleukin-6/metabolism
MH  - Macrophages/drug effects/metabolism
MH  - Mitochondria/drug effects/*metabolism
MH  - Nitro Compounds/*pharmacology/*therapeutic use
MH  - Propionates/*pharmacology/*therapeutic use
MH  - Rats, Sprague-Dawley
MH  - Time Factors
MH  - Up-Regulation/drug effects
PMC - PMC3948682
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2014/03/13 06:00
MHDA- 2016/04/01 06:00
PMCR- 2014/03/10
CRDT- 2014/03/12 06:00
PHST- 2013/07/13 00:00 [received]
PHST- 2014/01/28 00:00 [accepted]
PHST- 2014/03/12 06:00 [entrez]
PHST- 2014/03/13 06:00 [pubmed]
PHST- 2016/04/01 06:00 [medline]
PHST- 2014/03/10 00:00 [pmc-release]
AID - PONE-D-13-28879 [pii]
AID - 10.1371/journal.pone.0090089 [doi]
PST - epublish
SO  - PLoS One. 2014 Mar 10;9(3):e90089. doi: 10.1371/journal.pone.0090089. eCollection 
      2014.