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2018 ; 59
(8
): 3511-3520
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Inhibition of Human Corneal Myofibroblast Formation
#MMPMID30025094
Guo X
; Sriram S
; Tran JA
; Hutcheon AEK
; Zieske JD
Invest Ophthalmol Vis Sci
2018[Jul]; 59
(8
): 3511-3520
PMID30025094
show ga
PURPOSE: Transforming growth factor-beta (TGF-?) isoform 1 (T1) is involved in
corneal fibrotic wound healing by stimulating myofibroblast transformation and
altering fibrotic gene expression. In this study, two specific inhibitors were
used to dissect the relationship between myofibroblast generation and the
TGF-?/Smad- or TGF-?/p38-signaling pathway in human corneal fibroblasts (HCF).
METHODS: In HCF, Trx-SARA (Smad-pathway inhibitor) was used to block the
TGF-?/Smad-signaling pathway, and the p38 inhibitor (p38inh, SB202190) was used
to inhibit p38MAPK, thus blocking the TGF-?/p38-signaling pathway. HCF ± Trx-SARA
or Trx-GA (SARA control) were serum starved overnight in Eagle's minimum
essential medium (EMEM) ± p38inh, grown in EMEM ± T1 ± p38inh for 24 hours, and
then processed for indirect-immunofluorescence, Western blot, or quantitative
real-time polymerase chain reaction to examine ?-smooth muscle actin (?SMA) and
other fibrotic genes, such as fibronectin, thrombospondin1, and type III
collagen. In addition, the morphology and the effect of p38inh on myofibroblast
phenotype after myofibroblast formation were examined. RESULTS: We observed that
Trx-SARA had little effect on ?SMA expression, indicating that blocking the Smad
pathway did not significantly inhibit myofibroblast formation. However, p38inh
did significantly inhibit ?SMA and other fibrotic genes, thus efficiently
preventing the transition of HCFs to myofibroblasts. In addition, morphology
changed and ?SMA decreased in myofibroblasts exposed to p38inh medium, as
compared with controls. CONCLUSIONS: HCF transition to myofibroblasts was mainly
through the p38 pathway. Therefore, blocking the p38 pathway may be a potential
therapeutic tool for human corneal fibrosis prevention/treatment, because it
controls myofibroblast formation in human corneal cells, while leaving other
functions of T1 unaffected.
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