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Isolation of Mouse Respiratory Epithelial Cells and Exposure to Experimental Cigarette Smoke at Air Liquid Interface
Published on: February 21, 2011
The selective MMP-12 inhibitor, AS111793 reduces airway inflammation in mice exposed to cigarette smoke
C Le Quément1, I Guénon, J-Y Gillon
11INSERM U620, Université de Rennes 1, France.
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.
Insights
Inhibiting macrophage elastase (MMP-12) with AS111793 reduced lung inflammation caused by cigarette smoke (CS) in mice. This suggests MMP-12 plays a specific role in CS-induced lung inflammation.
Area of Science:
- Pulmonary Medicine
- Inflammation Research
- Pharmacology
Background:
- Macrophage elastase (MMP-12) is implicated in the inflammatory pathways of chronic obstructive pulmonary disease (COPD).
- Investigating MMP-12's role in airway inflammation is crucial for developing targeted COPD therapies.
Purpose of the Study:
- To evaluate the efficacy of MMP-12 inhibition on airway inflammation induced by cigarette smoke (CS) and lipopolysaccharide (LPS) in a murine model.
- To assess the impact of the selective MMP-12 inhibitor AS111793 on inflammatory markers.
Main Methods:
- C57BL/6 mice were administered AS111793 (a selective MMP-12 inhibitor), roflumilast (a PDE-4 inhibitor), or vehicle control.
- Mice were exposed to CS for 3 days or LPS for 30 minutes, followed by bronchoalveolar lavage (BAL) and lung tissue analysis.
Main Results:
- AS111793 administration significantly reduced neutrophil and macrophage influx in BAL fluid following CS exposure.
- The inhibitor decreased key inflammatory markers (e.g., TNF receptors, IL-6, MIP-1gamma, pro-MMP-9) in BAL fluid and lung parenchyma after CS exposure.
- MMP-12 inhibition did not attenuate inflammation in mice exposed to LPS, indicating a specific effect on CS-induced inflammation.
Conclusions:
- MMP-12 inhibition effectively mitigated the inflammatory response associated with cigarette smoke exposure in mice.
- These findings highlight a specific role for MMP-12 in the pathogenesis of lung inflammation induced by CS.
- Targeting MMP-12 may represent a viable therapeutic strategy for managing CS-induced lung inflammation in COPD.
