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

Br J Pharmacol. 2008 Jul;154(6):1206-15. doi: 10.1038/bjp.2008.180. Epub 2008 May 19.


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.

MeSH terms

  • Aminopyridines / pharmacology
  • Aminopyridines / therapeutic use
  • Animals
  • Benzamides / pharmacology
  • Benzamides / therapeutic use
  • Bronchoalveolar Lavage Fluid / cytology
  • Chemokine CXCL1 / biosynthesis
  • Cyclopropanes / pharmacology
  • Cyclopropanes / therapeutic use
  • Inflammation / drug therapy*
  • Inflammation / pathology*
  • Interleukin-6 / biosynthesis
  • Lipopolysaccharides / toxicity
  • Male
  • Matrix Metalloproteinase Inhibitors*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Protease Inhibitors / pharmacology
  • Protease Inhibitors / therapeutic use*
  • Respiratory System / pathology*
  • Smoking / pathology*


  • Aminopyridines
  • Benzamides
  • Chemokine CXCL1
  • Cyclopropanes
  • Interleukin-6
  • Lipopolysaccharides
  • Matrix Metalloproteinase Inhibitors
  • Protease Inhibitors
  • Roflumilast