comunitat-uji-handle:10234/9
comunitat-uji-handle2:10234/36080
comunitat-uji-handle3:10234/36082
comunitat-uji-handle4:
INVESTIGACION
Resumen
Background:
Idiopathic pulmonary fibrosis (IPF) is the most rapidly progressive and fatal fibrotic disorder, with no
curative therapies. The signal transducer and activator of transcription 3 (STAT3) protein is ... [+]
Background:
Idiopathic pulmonary fibrosis (IPF) is the most rapidly progressive and fatal fibrotic disorder, with no
curative therapies. The signal transducer and activator of transcription 3 (STAT3) protein is activated in lung fibroblasts
and alveolar type II cells (ATII), thereby contributing to lung fibrosis in IPF. Although activation of Janus kinase 2 (JAK2)
has been implicated in proliferative disorders, its role in IPF is unknown. The aim of this study was to analyze JAK2
activation in IPF, and to determine whether JAK2/STAT3 inhibition is a potential therapeutic strategy for this disease.
Methods and results:
JAK2/p-JAK2 and STAT3/pSTAT3 expression was e
valuated using quantitative real time-PCR,
western blotting, and immunohistochemistry. Compared to human healthy lung tissue (
n
= 10) both proteins were
upregulated in the lung tissue of IPF patients (
n
= 12). Stimulating primary ATII and lung fibroblasts with transforming
growth factor beta 1 or interleukin (IL)-6/IL-13 activated JAK2 and STAT3, inducing epithelial to mesenchymal and
fibroblast to myofibroblast transitions. Dual p-JAK2/p-
STAT3 inhibition with JSI-124 or silencing of JAK2 and STAT3
genes suppressed ATII and the fibroblast to myofibroblast transition, with greater effects than the sum of those
obtained using JAK2 or STAT3 inhibitors individually. Dual rather than single inhibition was also more effective for
inhibiting fibroblast migration, preventing increases in fibroblast senescence and Bcl-2 expression, and ameliorating
impaired autophagy. In rats administ
ered JSI-124, a dual inhibitor of p-JAK2/p-STAT3, at a dose of 1 mg/kg/day,
bleomycin-induced lung fibrosis was
reduced and collagen deposition in the lung was inhibited, as were JAK2
and STAT3 activation and several markers of fibrosi
s, autophagy, senescence, and anti-apoptosis.
Conclusions:
JAK2 and STAT3 are activated in IPF, and their dual inhibition may be an attractive strategy for
treating this disease [-]
Derechos de acceso
info:eu-repo/semantics/openAccess