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Metalloelastase (MMP-12) induced inflammatory response in mice airways: effects of dexamethasone, rolipram and marimastat.

Abstract：

:Direct instillation of a recombinant human form of MMP-12 (rhMMP-12) in mice airways elicited an early inflammatory response characterized by neutrophil influx, cytokine release and gelatinase activation followed by a delayed response, mainly characterized by macrophage recruitment. As this experimental model of lung inflammation partially mimics some features of chronic obstructive pulmonary disease (COPD), we have investigated the effects of treatment by anti-inflammatory compounds, dexamethasone and rolipram and a non-specific matrix metalloproteinase (MMP) inhibitor, marimastat. The compounds were administrated orally, 1 h before rhMMP-12 instillation (8 x 10(-3) U/mouse). Total and differential cell counts were evaluated in the bronchoalveolar lavage fluids. Cytokines and MMP-9 were quantified in bronchoalveolar lavage fluids and in lung homogenate supernatants. Marimastat (100 mg/kg), dexamethasone (10 mg/kg) and rolipram (0.1 and 0.3 mg/kg) were able to decrease significantly neutrophil recruitment at 4 and 24 h after rhMMP-12 instillation, but only marimastat (30 and 100 mg/kg) was effective at decreasing the macrophage recruitment occurring at day 7. Marimastat (100 mg/kg), dexamethasone (10 mg/kg) and rolipram (0.3 mg/kg) reduced significantly IL-6, KC/CXCL1, MIP-1alpha/CCL3 and MMP-9 levels in bronchoalveolar lavage fluid. Similar results were obtained in lung homogenates except with rolipram. Dexamethasone and rolipram were able to inhibit the early inflammatory response but were ineffective to limit the macrophage influx. In contrast, marimastat was able to reduce early and late response. These data indicate that MMP-12 instillation in mice could highlight some of the inflammatory response seen in COPD and could be used for the pharmacological evaluation of new anti-inflammatory mechanisms of action.

journal_name

Eur J Pharmacol

journal_title

European journal of pharmacology

authors

Nénan S,Lagente V,Planquois JM,Hitier S,Berna P,Bertrand CP,Boichot E

doi

10.1016/j.ejphar.2006.11.070

subject

Has Abstract

pub_date

2007-03-15 00:00:00

pages

75-81

issue

eissn

0014-2999

issn

1879-0712

pii

S0014-2999(06)01390-2

journal_volume

559

pub_type

杂志文章

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Metalloelastase (MMP-12) induced inflammatory response in mice airways: effects of dexamethasone, rolipram and marimastat.