Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:3.4.24.17 (
MMP-3
)
3,419
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
S100 calcium-binding protein A9
(
S100A9
), is elevated in plasma and bronchoalveolar lavage fluid (BALF) of COPD patients and aging enhances
S100A9
expression in several tissues. Currently, the direct impact of
S100A9
-mediated signaling on lung function and within the aging lung is unknown. Here, we observed that elevated
S100A9
levels in human BALF correlated with age. Elevated lung levels of
S100A9
were higher in older mice compared to young animals and coincided with pulmonary function changes. Both acute and chronic exposure to cigarette smoke enhanced
S100A9
levels in age-matched mice. To examine the direct role of
S100A9
on the development of COPD, S100a9
-/-
mice or inhibited activity with paquinimod, and exposed the models to chronic cigarette smoke
S100A9
depletion and inhibition attenuated the loss of lung function, pressure-volume loops, airway inflammation, lung compliance, and FEV
0.05
/FVC, compared to age-matched wild type or vehicle administered animals. Loss of S100a9 signaling reduced cigarette smoke-induced airspace enlargement, alveolar remodeling, lung destruction, ERK, and c-RAF phosphorylation,
MMP-3
, MMP-9, MCP-1, IL-6, and KC release into the airways. Paquinimod administered to non-smoked aged animals reduced age-associated loss of lung function. Since fibroblasts play a major role in the production and maintenance of extracellular matrix in emphysema, primary lung fibroblasts were treated with the ERK inhibitor, LY3214996, or the c-RAF inhibitor, GW5074, resulting in less
S100A9
-induced
MMP-3
, MMP-9, MCP-1, IL-6, and IL-8. Silencing TLR4, RAGE or EMMPRIN prevented
S100A9
-induced phosphorylation of ERK and c-RAF. Our data suggest that
S100A9
signaling contributes to the progression of smoke and age-related COPD.
...
PMID:Cigarette smoke induction of S100A9 contributes to chronic obstructive pulmonary disease. 3296 23
