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The selective MMP-12 inhibitor, AS111793 reduces airway inflammation in mice exposed to cigarette smoke.

Abstract：

BACKGROUND:Macrophage elastase (MMP-12) is involved in the inflammatory process of chronic obstructive pulmonary disease (COPD). The aim of this study was to investigate in mice the effect of MMP-12 inhibition on the inflammatory process induced by cigarette smoke (CS) or by lipopolysaccharide (LPS) exposure of the airways. EXPERIMENTAL APPROACH:C57BL/6 mice were given, orally, either the selective MMP-12 inhibitor AS111793 (3, 10, 30 and 100 mg kg(-1)), the PDE-4 inhibitor roflumilast (3 mg kg(-1)) or vehicle, then exposed to CS (for 3 days) or to LPS (100 microg mL(-1), 30 min). Subsequent to the last smoke or LPS exposure, bronchoalveolar lavages (BAL) were performed and lungs were removed and homogenized to analyze various markers of inflammation at appropriate times. KEY RESULTS:Inhibition of MMP-12 by AS111793 (10 and 30 mg kg(-1)) was associated with a reduction of the increase in neutrophil number in BAL fluids after 4 days and of macrophages after 11 days. On day 4, AS111793 also significantly reduced all the inflammation markers that had increased after CS exposure, including soluble TNF receptors I and II, MIP-1gamma, IL-6 and pro-MMP-9 activity in BAL fluids, and KC/CXCL1, fractalkine/CX3CL1, TIMP-1 and I-TAC/CXCL11 in lung parenchyma. In contrast, inhibition of MMP-12 did not reduce neutrophil influx, pro-MMP-9 activity or KC/CXCL1 release in BAL fluids of mice exposed to LPS. CONCLUSION:Inhibition of MMP-12 with AS111793, reduced the inflammatory process associated with exposure of mice to CS, strongly suggesting a specific involvement of MMP-12 in lung inflammation following CS exposure.

journal_name

Br J Pharmacol

journal_title

British journal of pharmacology

authors

Le Quément C,Guénon I,Gillon JY,Valença S,Cayron-Elizondo V,Lagente V,Boichot E

doi

10.1038/bjp.2008.180

subject

Has Abstract

pub_date

2008-07-01 00:00:00

pages

1206-15

issue

6

eissn

0007-1188

issn

1476-5381

pii

bjp2008180

journal_volume

154

pub_type

杂志文章

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