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

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 μg 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‐1γ, 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. British Journal of Pharmacology (2008) 154 , 1206–1215; doi: 10.1038/bjp.2008.180 ; published online 19 May 2008