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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 J+Biol+Chem
2015 ; 290
(15
): 9428-41
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Plasminogen activator inhibitor-1 suppresses profibrotic responses in fibroblasts
from fibrotic lungs
#MMPMID25648892
Marudamuthu AS
; Shetty SK
; Bhandary YP
; Karandashova S
; Thompson M
; Sathish V
; Florova G
; Hogan TB
; Pabelick CM
; Prakash YS
; Tsukasaki Y
; Fu J
; Ikebe M
; Idell S
; Shetty S
J Biol Chem
2015[Apr]; 290
(15
): 9428-41
PMID25648892
show ga
Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by
progressive interstitial scarification. A hallmark morphological lesion is the
accumulation of myofibroblasts or fibrotic lung fibroblasts (FL-fibroblasts) in
areas called fibroblastic foci. We previously demonstrated that the expression of
both urokinase-type plasminogen activator (uPA) and the uPA receptor are elevated
in FL-fibroblasts from the lungs of patients with IPF. FL-fibroblasts isolated
from human IPF lungs and from mice with bleomycin-induced pulmonary fibrosis
showed an increased rate of proliferation compared with normal lung fibroblasts
(NL-fibroblasts) derived from histologically "normal" lung. Basal expression of
plasminogen activator inhibitor-1 (PAI-1) in human and murine FL-fibroblasts was
reduced, whereas collagen-I and ?-smooth muscle actin were markedly elevated.
Conversely, alveolar type II epithelial cells surrounding the fibrotic foci in
situ, as well as those isolated from IPF lungs, showed increased activation of
caspase-3 and PAI-1 with a parallel reduction in uPA expression. Transduction of
an adenovirus PAI-1 cDNA construct (Ad-PAI-1) suppressed expression of uPA and
collagen-I and attenuated proliferation in FL-fibroblasts. On the contrary,
inhibition of basal PAI-1 in NL-fibroblasts increased collagen-I and ?-smooth
muscle actin. Fibroblasts isolated from PAI-1-deficient mice without lung injury
also showed increased collagen-I and uPA. These changes were associated with
increased Akt/phosphatase and tensin homolog proliferation/survival signals in
FL-fibroblasts, which were reversed by transduction with Ad-PAI-1. This study
defines a new role of PAI-1 in the control of fibroblast activation and expansion
and its role in the pathogenesis of fibrosing lung disease and, in particular,
IPF.
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