PMID- 18840548
OWN - NLM
STAT- MEDLINE
DCOM- 20090324
LR  - 20220310
IS  - 1567-5769 (Print)
IS  - 1567-5769 (Linking)
VI  - 9
IP  - 1
DP  - 2009 Jan
TI  - Coumarinic derivatives show anti-inflammatory effects on alveolar macrophages, 
      but their anti-elastase activity is essential to reduce lung inflammation in 
      vivo.
PG  - 49-54
LID - 10.1016/j.intimp.2008.09.009 [doi]
AB  - 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.
FAU - Bissonnette, Elyse Y
AU  - Bissonnette EY
AD  - Centre de recherche de l'Hopital Laval, Institut Universitaire de Cardiologie et 
      de Pneumologie de l'Universite Laval, Quebec, QC, Canada. 
      elyse.bissonnette@med.ulaval.ca
FAU - Tremblay, Guy M
AU  - Tremblay GM
FAU - Turmel, Veronique
AU  - Turmel V
FAU - Pirotte, Bernard
AU  - Pirotte B
FAU - Reboud-Ravaux, Michele
AU  - Reboud-Ravaux M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20081007
PL  - Netherlands
TA  - Int Immunopharmacol
JT  - International immunopharmacology
JID - 100965259
RN  - 0 (Anti-Inflammatory Agents)
RN  - 0 (Coumarins)
RN  - 0 (Interleukin-6)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Proteinase Inhibitory Proteins, Secretory)
RN  - 0 (Receptors, CCR2)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 3.4.21.37 (Leukocyte Elastase)
RN  - EC 3.4.24.65 (Matrix Metalloproteinase 12)
RN  - KLF1HS0SXJ (Scopoletin)
SB  - IM
MH  - Animals
MH  - *Anti-Inflammatory Agents
MH  - Cell Line
MH  - Coumarins/*pharmacology
MH  - Female
MH  - Interleukin-6/pharmacology
MH  - Leukocyte Elastase
MH  - Lipopolysaccharides
MH  - Lung/pathology
MH  - Macrophages, Alveolar/*drug effects
MH  - Matrix Metalloproteinase 12/metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Molecular Weight
MH  - Pneumonia/chemically induced/*pathology/*prevention & control
MH  - *Proteinase Inhibitory Proteins, Secretory
MH  - Rats
MH  - Receptors, CCR2/metabolism
MH  - Scopoletin/pharmacology
MH  - Tumor Necrosis Factor-alpha/pharmacology
EDAT- 2008/10/09 09:00
MHDA- 2009/03/25 09:00
CRDT- 2008/10/09 09:00
PHST- 2008/07/10 00:00 [received]
PHST- 2008/08/28 00:00 [revised]
PHST- 2008/09/16 00:00 [accepted]
PHST- 2008/10/09 09:00 [pubmed]
PHST- 2009/03/25 09:00 [medline]
PHST- 2008/10/09 09:00 [entrez]
AID - S1567-5769(08)00293-2 [pii]
AID - 10.1016/j.intimp.2008.09.009 [doi]
PST - ppublish
SO  - Int Immunopharmacol. 2009 Jan;9(1):49-54. doi: 10.1016/j.intimp.2008.09.009. Epub 
      2008 Oct 7.