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Fibroblast Activation Protein (FAP) Accelerates Collagen Degradation and
Clearance from Lungs in Mice
#MMPMID26663085
Fan MH
; Zhu Q
; Li HH
; Ra HJ
; Majumdar S
; Gulick DL
; Jerome JA
; Madsen DH
; Christofidou-Solomidou M
; Speicher DW
; Bachovchin WW
; Feghali-Bostwick C
; Puré E
J Biol Chem
2016[Apr]; 291
(15
): 8070-89
PMID26663085
show ga
Idiopathic pulmonary fibrosis is a disease characterized by progressive,
unrelenting lung scarring, with death from respiratory failure within 2-4 years
unless lung transplantation is performed. New effective therapies are clearly
needed. Fibroblast activation protein (FAP) is a cell surface-associated serine
protease up-regulated in the lungs of patients with idiopathic pulmonary fibrosis
as well as in wound healing and cancer. We postulate that FAP is not only a
marker of disease but influences the development of pulmonary fibrosis after lung
injury. In two different models of pulmonary fibrosis, intratracheal bleomycin
instillation and thoracic irradiation, we find increased mortality and increased
lung fibrosis in FAP-deficient mice compared with wild-type mice. Lung
extracellular matrix analysis reveals accumulation of intermediate-sized collagen
fragments in FAP-deficient mouse lungs, consistent within vitrostudies showing
that FAP mediates ordered proteolytic processing of matrix metalloproteinase
(MMP)-derived collagen cleavage products. FAP-mediated collagen processing leads
to increased collagen internalization without altering expression of the
endocytic collagen receptor, Endo180. Pharmacologic FAP inhibition decreases
collagen internalization as expected. Conversely, restoration of FAP expression
in the lungs of FAP-deficient mice decreases lung hydroxyproline content after
intratracheal bleomycin to levels comparable with that of wild-type controls. Our
findings indicate that FAP participates directly, in concert with MMPs, in
collagen catabolism and clearance and is an important factor in resolving scar
after injury and restoring lung homeostasis. Our study identifies FAP as a novel
endogenous regulator of fibrosis and is the first to show FAP's protective
effects in the lung.
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