Coumarinic derivatives show anti-inflammatory effects on alveolar macrophages, but their anti-elastase activity is essential to reduce lung inflammation in vivo.
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.
Bissonnette
Elyse Y
EY
Centre de recherche de l'Hôpital Laval, Institut Universitaire de Cardiologie et de Pneumologie de l'Université Laval, Québec, QC, Canada. elyse.bissonnette@med.ulaval.ca
Tremblay
Guy M
GM
Turmel
Véronique
V
Pirotte
Bernard
B
Reboud-Ravaux
Michèle
M
D000818:Animals; D000893:Anti-Inflammatory Agents; D002460:Cell Line; D003374:Coumarins / Q000494:pharmacology*; D005260:Female; D015850:Interleukin-6 / Q000494:pharmacology; D019272:Leukocyte Elastase; D008070:Lipopolysaccharides; D008168:Lung / Q000473:pathology; D016676:Macrophages, Alveolar / Q000187:drug effects*; D053508:Matrix Metalloproteinase 12 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008970:Molecular Weight; D011014:Pneumonia / Q000139:chemically induced / Q000473:pathology* / Q000517:prevention & control*; D053491:Proteinase Inhibitory Proteins, Secretory; D051381:Rats; D054390:Receptors, CCR2 / Q000378:metabolism; D012603:Scopoletin / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; D003374:Coumarins; D015850:Interleukin-6; D008070:Lipopolysaccharides; D053491:Proteinase Inhibitory Proteins, Secretory; D054390:Receptors, CCR2; D014409:Tumor Necrosis Factor-alpha; D019272:Leukocyte Elastase; D053508:Matrix Metalloproteinase 12; D012603:Scopoletin