Coumarinic derivatives show anti-inflammatory effects on alveolar macrophages, but their anti-elastase activity is essential to reduce lung inflammation in vivo

• Published in: International immunopharmacology 2009, Vol.9 (1), p.49-54
• Main Authors: Bissonnette, Elyse Y., Tremblay, Guy M., Turmel, Véronique, Pirotte, Bernard, Reboud-Ravaux, Michèle
• Format: Article
• Language: English
• Subjects: Alveolar macrophages; Animals; Anti-elastase; Anti-inflammatory; Anti-Inflammatory Agents; Biological and medical sciences; Cell Line; Coumarins; Coumarins - pharmacology; Female; Interleukin-6 - pharmacology; Leukocyte Elastase; Lipopolysaccharides; Lung; Lung - pathology; Macrophages, Alveolar - drug effects; Matrix Metalloproteinase 12 - metabolism; Medical sciences; Mice; Mice, Inbred C57BL; Molecular Weight; Pharmacology. Drug treatments; Pneumonia - chemically induced; Pneumonia - pathology; Pneumonia - prevention & control; Proteinase Inhibitory Proteins, Secretory; Rats; Receptors, CCR2 - metabolism; Scopoletin - pharmacology; TNF; Tumor Necrosis Factor-alpha - pharmacology
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2008.09.009

We have previously demonstrated the potency of coumarinic derivatives to inhibit human leukocyte elastase. Given the anti-inflammatory activities of some coumarins, we investigated the capacity of our coumarinic derivatives to inhibit inflammation and whether their anti-elastase activity was essential for their anti-inflammatory functions. All compounds studied were coumarinic derivatives displaying differential anti-proteinase activity. Coumarinic derivatives 1, 2, and 3 efficiently inhibited human leukocyte elastase in vitro, whereas the coumarinic derivative 4 did not show inhibitory activity. The anti-inflammatory effect of these compounds and a coumarin control, scopoletin, on interleukin-6 (IL-6), tumor necrosis factor (TNF), and macrophage chemotactic protein-1 (MCP-1) release was studied using lipopolysaccharide (LPS)-stimulated alveolar macrophages. The in vivo effect of compound 2, that inhibits elastase, and compound 4, that does not show proteinase inhibition, was investigated using a mouse model of LPS-induced lung inflammation and elastase-induced acute lung injury. All investigated coumarinic derivatives, regardless of their anti-proteinase activity, significantly inhibited IL-6 and TNF production by LPS-stimulated alveolar macrophages. However, only compounds 2, 3, and 4 significantly reduced MCP-1 release. Compound 2 attenuated LPS-induced leukocyte recruitment in bronchoalveolar lavage, whereas no inhibition was observed with compound 4 devoid of elastase inhibitory capacity. Interestingly, MCP-1 level was reduced in bronchoalveolar lavage of compound 4 treated mice, whereas TNF and IL-6 levels were not modulated by coumarins. Furthermore, compound 2, but not 4, reduced elastase induced lung injury. Our data suggest that although coumarinic derivatives have anti-inflammatory properties, their anti-elastase activity is essential to reduce lung inflammation in vivo.