Publication: Targeting thrombin with hirudin alleviates paraquat-induced pulmonary fibrosis via the PAR-1-mediated TGF-β1 pathway
Authors
Weijuan Liu ; Guowen Zheng ; Zhaojun Song ; Zike Zhang ; Xiao Hu
item.page.secondaryauthor
item.page.director
Publisher
publication.page.editor
Universidad de Murcia, Departamento de Biologia Celular e Histiologia
publication.page.department
DOI
https://doi.org/10.14670/HH-25-003
item.page.type
info:eu-repo/semantics/article
Description
Abstract
Background. Paraquat (PQ)-induced
pulmonary fibrosis (PF) is a serious disease without
specific antidotes. Thrombin is important for promoting
fibrosis development. We aimed to explore whether
thrombin promotes PQ-induced PF by activating the
protease-activated receptor-1 (PAR-1)-mediated
transforming growth factor-β1 (TGF-β1) pathway.
Methods. Male Sprague Dawley rats received PQ
treatment, either alone or with thrombin or hirudin (a
thrombin inhibitor) (n=9 in the control, model, thrombin,
and hirudin groups). After 7 or 14 days of treatment,
oxidative stress (OS) indicators and histopathological
damage in the lungs were detected. PF degree was
evaluated using Masson staining and hydroxyproline
levels in lung tissues and collagen levels in
bronchoalveolar lavage fluid. Furthermore, type I
collagen (Col-1), TGF-β1, and PAR-1 expression, as
well as extracellular signal-regulated kinase 1/2
(ERK1/2) and mothers against decapentaplegic homolog
3 (Smad3) phosphorylation in the lungs, were assessed.
To investigate the mechanism of thrombin on PQ
induced PF, rats treated with PQ and thrombin further
received SCH79797 (a PAR-1 inhibitor) alone or
combined with SRI-011381 (a TGF-β agonist) (n=9 in
the thrombin+SCH79797 and thrombin+SCH79797+
SRI-011381 groups). In addition to Masson staining and
detection of the above-mentioned genes and proteins,
alpha-smooth muscle actin (α-SMA), TGFβ receptor
type I (TβRI), and type II (TβRII) expression in the
lungs were also detected.
Results. Both 7 and 14 days of thrombin treatment
triggered OS, exacerbated lung histopathological damage, and promoted PF in PQ-stimulated rats.
Furthermore, thrombin upregulated Col-1, TGF-β1, and
PAR-1 expression as well as ERK1/2 and Smad3
phosphorylation in PQ-stimulated rats. However, hirudin
produced the opposite results. Additionally, the role of
thrombin in promoting PF, increasing Col-1, TGF-β1, α
SMA, PAR-1, TβRI, and TβRII expression and ERK1/2
and Smad3 phosphorylation in PQ-stimulated rats was
reversed by SCH79797, while the inhibitory effects of
SCH79797 were counteracted by SRI-011381.
Conclusions. Thrombin may promote PQ-induced
PF by activating PAR-1-mediated TGF-β1, suggesting
that PAR-1-mediated TGF-β1 is a potential target for
preventing PQ-induced PF.
publication.page.subject
Citation
item.page.embargo
Ir a Estadísticas
Este ítem está sujeto a una licencia Creative Commons. http://creativecommons.org/licenses/by-nc-nd/4.0/