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Blockade of TGF-?/Smad signaling by the small compound HPH-15 ameliorates
experimental skin fibrosis
#MMPMID29544542
Luong VH
; Chino T
; Oyama N
; Matsushita T
; Sasaki Y
; Ogura D
; Niwa SI
; Biswas T
; Hamasaki A
; Fujita M
; Okamoto Y
; Otsuka M
; Ihn H
; Hasegawa M
Arthritis Res Ther
2018[Mar]; 20
(1
): 46
PMID29544542
show ga
BACKGROUND: Transforming growth factor-? (TGF-?)/Smad signaling is well known to
play a critical role in the pathogenesis of systemic sclerosis (SSc). We
previously developed an artificial molecule, the histidine-pyridine-histidine
ligand derivative HPH-15, which may have an antifibrotic effect. The purpose of
the present study was to clarify the effects of this drug in human skin
fibroblasts and in a preclinical model of SSc. METHODS: The effects of HPH-15 on
expression of extracellular matrix components and TGF-? signaling in human dermal
fibroblasts were analyzed. The antifibrotic properties of HPH-15 and its
mechanisms were also examined in a bleomycin-induced skin fibrosis mouse model.
RESULTS: HPH-15 suppressed the TGF-?-induced phosphorylation of Smad3 and
inhibited the expression of collagen I, fibronectin 1, connective tissue growth
factor, and ?-smooth muscle actin induced by TGF-? in cultured human skin
fibroblasts. In the bleomycin-induced skin fibrosis model, oral administration of
HPH-15 protected against the development of skin fibrosis and ameliorated
established skin fibrosis. Additionally, HPH-15 suppressed the phosphorylation of
Smad3 in various cells, including macrophages in the bleomycin-injected skin.
Further, in the treated mice, dermal infiltration of proinflammatory macrophages
(CD11b(+)Ly6C(hi)) and M2 profibrotic macrophages (CD11b(+)CD204(+) or
CD11b(+)CD206(+)) was significantly decreased during the early and late stages,
respectively. HPH-15 treatment resulted in decreased messenger RNA (mRNA)
expression of the M2 macrophage markers arginase 1 and Ym-1 in the skin, whereas
it inversely augmented expression of Friend leukemia integration 1 and
Krüppel-like factor 5 mRNAs, the transcription factors that repress collagen
synthesis. No apparent adverse effects of HPH-15 were found during the treatment.
CONCLUSIONS: HPH-15 may inhibit skin fibrosis by inhibiting the phosphorylation
of Smad3 in dermal fibroblasts and possibly in macrophages. Our results
demonstrate several positive qualities of HPH-15, including oral bioavailability,
a good safety profile, and therapeutic effectiveness. Thus, this TGF-?/Smad
inhibitor is a potential candidate therapeutic for SSc clinical trials.
|Animals
[MESH]
|Cells, Cultured
[MESH]
|Fibroblasts/drug effects/pathology
[MESH]
|Fibrosis/drug therapy/pathology
[MESH]
|Histidine/chemistry/*pharmacology/therapeutic use
[MESH]
|Humans
[MESH]
|Infant, Newborn
[MESH]
|Ligands
[MESH]
|Male
[MESH]
|Mice
[MESH]
|Mice, Inbred C57BL
[MESH]
|Pyridines/chemistry/*pharmacology/therapeutic use
[MESH]
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