PMID- 33359326
OWN - NLM
STAT- MEDLINE
DCOM- 20210423
LR  - 20211204
IS  - 1096-0007 (Electronic)
IS  - 0014-4835 (Linking)
VI  - 203
DP  - 2021 Feb
TI  - Effects of mammalian target of rapamycin inhibitors on fibrosis after 
      trabeculectomy.
PG  - 108421
LID - S0014-4835(20)30679-5 [pii]
LID - 10.1016/j.exer.2020.108421 [doi]
AB  - Glaucoma, the second leading cause of blindness worldwide, is characterized by 
      aberrant elevations of intraocular pressure (IOP), which can damage the optic 
      nerve. IOP reduction is the only effective therapy for prevention of visual 
      impairment and blindness in both hypertensive and normotensive individuals, and 
      in some cases, trabeculectomy is a major surgical procedure that can lower IOP in 
      patients with glaucoma. No matter how surgical technique and postoperative care 
      advances, excessive scarring and tissue fibrosis could result from increased 
      human conjunctival fibroblast (HCF) proliferation and extracellular matrix (ECM) 
      deposition of the subconjunctival tissue and scleral flaps would persist after 
      trabeculectomy. And these issues are major impediments to IOP reduction and 
      filtering of bleb formations, so the modulation of the factors which can induce 
      fibrosis could used as a novel strategy to control scarring after trabeculectomy. 
      In this study, we examined the effects of mammalian target of rapamycin (mTOR) 
      inhibitors (rapamycin or Torin1) on the fibrotic response induced by transforming 
      growth factor-beta 1 (TGF-beta1) in cultured human conjunctival fibroblast (HCF) 
      cells. The study also examined the effects of mTOR inhibitor on fibrosis after 
      trabeculectomy in rabbit eyes. In in vitro studies, we stimulated HCFs with 
      TGF-beta1, and confirmed that the expression levels of fibronectin, collagen type I 
      alpha 1 chain (COL1A1), and alpha-smooth muscle actin (SMA) were significantly 
      upregulated in HCFs with TGF-beta1, by means of quantitative real-time polymerase 
      chain reaction and immunocytochemistry. And those TGF-beta1-induced changes were 
      significantly attenuated with mTOR inhibitors, rapamycin or Torin1. Additionally 
      the migration rate of HCFs was examined under conditions of TGF-beta1 induction, 
      TGF-beta1-induced changes were significantly attenuated with mTOR inhibitors. A 
      rabbit model of trabeculectomy was examined in vivo, and the effects of topical 
      mTOR inhibitor were also examined, and found that topical treatment with mTOR 
      inhibitor significantly suppressed collagen deposition in rabbit eyes after 
      trabeculectomy. These results have demonstrated that mTOR inhibitors may provide 
      a novel treatment modality for reducing the fibrotic response in HCFs and 
      improving bleb scarring after filtration surgery.
CI  - Copyright (c) 2020 Elsevier Ltd. All rights reserved.
FAU - Igarashi, Nozomi
AU  - Igarashi N
AD  - Department of Ophthalmology, Graduate School of Medicine, The University of 
      Tokyo, Tokyo, Japan.
FAU - Honjo, Megumi
AU  - Honjo M
AD  - Department of Ophthalmology, Graduate School of Medicine, The University of 
      Tokyo, Tokyo, Japan. Electronic address: honjomegumi@gmail.com.
FAU - Aihara, Makoto
AU  - Aihara M
AD  - Department of Ophthalmology, Graduate School of Medicine, The University of 
      Tokyo, Tokyo, Japan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20201224
PL  - England
TA  - Exp Eye Res
JT  - Experimental eye research
JID - 0370707
RN  - 0 
      (1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo(h)(1,6)naphthyridin-2(1H)-one)
RN  - 0 (ACTA2 protein, human)
RN  - 0 (Actins)
RN  - 0 (COL1A1 protein, human)
RN  - 0 (Collagen Type I)
RN  - 0 (Collagen Type I, alpha 1 Chain)
RN  - 0 (Fibronectins)
RN  - 0 (Naphthyridines)
RN  - 0 (RNA, Messenger)
RN  - 0 (Transforming Growth Factor beta1)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Actins/genetics/metabolism
MH  - Animals
MH  - Blotting, Western
MH  - Cells, Cultured
MH  - Collagen Type I/genetics/metabolism
MH  - Collagen Type I, alpha 1 Chain
MH  - Conjunctiva/metabolism/*pathology
MH  - Fibroblasts/metabolism/pathology
MH  - Fibronectins/genetics/metabolism
MH  - Fibrosis
MH  - Humans
MH  - Immunohistochemistry
MH  - Male
MH  - Naphthyridines/*pharmacology
MH  - RNA, Messenger/genetics
MH  - Rabbits
MH  - Real-Time Polymerase Chain Reaction
MH  - Sirolimus/*pharmacology
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors
MH  - *Trabeculectomy
MH  - Transforming Growth Factor beta1/pharmacology
OTO - NOTNLM
OT  - Human conjunctival fibroblasts
OT  - Rapamycin
OT  - Torin 1
OT  - Trabeculectomy
OT  - mTOR
EDAT- 2020/12/29 06:00
MHDA- 2021/04/24 06:00
CRDT- 2020/12/28 10:46
PHST- 2020/09/22 00:00 [received]
PHST- 2020/11/19 00:00 [revised]
PHST- 2020/12/21 00:00 [accepted]
PHST- 2020/12/29 06:00 [pubmed]
PHST- 2021/04/24 06:00 [medline]
PHST- 2020/12/28 10:46 [entrez]
AID - S0014-4835(20)30679-5 [pii]
AID - 10.1016/j.exer.2020.108421 [doi]
PST - ppublish
SO  - Exp Eye Res. 2021 Feb;203:108421. doi: 10.1016/j.exer.2020.108421. Epub 2020 Dec 
      24.