RT Journal Article
SR Electronic
T1 Inhibition of Leukocyte Elastase, Polymorphonuclear Chemoinvasion, and Inflammation-Triggered Pulmonary Fibrosis by a 4-Alkyliden-β-lactam with a Galloyl Moiety
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 539
OP 546
DO 10.1124/jpet.105.096248
VO 316
IS 2
A1 Isabella Dell'Aica
A1 Luigi Sartor
A1 Paola Galletti
A1 Daria Giacomini
A1 Arianna Quintavalla
A1 Fiorella Calabrese
A1 Cinzia Giacometti
A1 Enrico Brunetta
A1 Francesco Piazza
A1 Carlo Agostini
A1 Spiridione Garbisa
YR 2006
UL http://jpet.aspetjournals.org/content/316/2/539.abstract
AB β-Lactams, a well known class of antibiotics, have been investigated as inhibitors of the disruptive protease released by inflammatory cells, leukocyte elastase (LE). We have synthesized a new β-lactam with an N-linked galloyl moiety, the latter identified as strategic in conferring anti-LE properties to some flavonols. This N-galloyl-derivative β-lactam inhibits the LE activity with a Ki of 0.7 μM, whereas it exerts weak activity against cathepsin G and protease-3 (IC50 > 100 μM), and matrix metalloproteinase (MMP)-2 and MMP-9. Without affecting chemotactic response and viability of polymorphonuclear (PMN) leukocytes, the compound efficiently restrains their chemoinvasion (IC50 of 1-2 μM) blocking the LE-triggered activation of pro-MMP-9, instrumental to extravasation. Daily i.p. injection of compound enhances resolution in a pulmonary inflammation model, significantly reducing consequent fibrosis. These results indicate that the new β-lactam is a potent anti-inflammatory compound with therapeutic potential. The American Society for Pharmacology and Experimental Therapeutics