These results suggest that NADPH-oxidase-derived ROS are essential to the development of pulmonary fibrosis. The absence of collagen deposition in KO mice seems to be associated with an elevated MMP-9/TIMP-1 ratio in the lungs. This finding highlights the importance of metalloproteinases and protease/anti-protease imbalances in pulmonary fibrosis.

The aim of the present study was to characterise a mouse model of airways inflammation induced by cigarette smoke and to compare it with a lipopolysaccharide (LPS) model with regards to the efficacy of a PDE4 inhibitor (cilomilast), a corticosteroid (dexamethasone) and macrophage metalloelastase (MMP)-12 gene deletion.Cigarette smoke exposure for 3 days induced a time-dependent airway neutrophilia associated with an increased level of keratinocyte-derived chemokine (KC), macrophage inflammatory protein (MIP)-2, MIP-1a and MMP-9 in the bronchoalveolar lavage (BAL). LPS exposure also induced an increase in the number of neutrophils in BAL. Studies in MMP-12-/-mice showed that in contrast to the smoking model, MMP-12 did not have a critical role in LPS-induced inflammation. Both cilomilast and dexamethasone blocked LPS-induced neutrophilia in a dosedependent manner. Cilomilast inhibited cigarette smoke-induced neutrophilia and MIP-1a, but only 10 mg?kg -1 of dexamethasone was effective. Both anti-inflammatory treatments had no effect on the levels of KC and MIP-2 in the BAL. Although the inflammatory response was very similar in the smoking model and LPS, the pharmacological modulation and the MMP-12 gene deletion highlighted the differences in the mechanisms involved. Furthermore, the cigarette smoke model seemed to better represent the situation described in chronic obstructive pulmonary disease patients.In conclusion, these differences underline the importance of using an acute smoke-exposure model to investigate potential new treatments for chronic obstructive pulmonary disease.

1. It was proposed previously that oxidative stress is a main component of the inflammatory process in chronic obstructive pulmonary disease (COPD). Thus, in the present study, we investigated the inflammatory response in mice deficient for the p47(phox) subunit of NADPH oxidase (p47 KO) exposed to cigarette smoke (CS). 2. Exposure of mice to CS elicited an increase in the number of macrophages and neutrophils and levels of interleukin (IL)-6, keratinocyte-derived chemokine (KC/CXCL1) and monocyte chemoattractant protein-1 (MCP1/CCL2) in bronchoalveolar lavage fluid (BALF), which were lower in p47 KO mice compared with control mice. In contrast, 24 h after lipopolysaccharide (LPS) exposure, the number of macrophages and neutrophils, as well as KC/CXCL1 levels, in BALF was significantly greater in p47 KO mice compared with control mice. 3. The present study has shown that airway inflammation is decreased in p47 KO mice after exposure to CS, but not LPS, suggesting that oxidative stress is involved in the pathogenesis of airway inflammation associated with COPD.