title: Inhibition of leukocyte elastase, polymorphonuclear chemoinvasion, and inflammation-triggered pulmonary fibrosis by a 4-alkyliden-beta-lactam with a galloyl moiety.
abstract: beta-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 beta-lactam with an N-linked galloyl moiety, the latter identified as strategic in conferring anti-LE properties to some flavonols. This N-galloyl-derivative beta-lactam inhibits the LE activity with a K(i) of 0.7 microM, whereas it exerts weak activity against cathepsin G and protease-3 (IC(50) > 100 microM), and matrix metalloproteinase (MMP)-2 and MMP-9. Without affecting chemotactic response and viability of polymorphonuclear (PMN) leukocytes, the compound efficiently restrains their chemoinvasion (IC(50) of 1-2 microM) 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 beta-lactam is a potent anti-inflammatory compound with therapeutic potential.
authors.affiliation: Department of Experimental Biomedical Sciences, Medical School of Padova, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Dell'Aica
authors.forename: Luigi
authors.initials: L
authors.lastname: Sartor
authors.forename: Paola
authors.initials: P
authors.lastname: Galletti
authors.forename: Daria
authors.initials: D
authors.lastname: Giacomini
authors.forename: Arianna
authors.initials: A
authors.lastname: Quintavalla
authors.forename: Fiorella
authors.initials: F
authors.lastname: Calabrese
authors.forename: Cinzia
authors.initials: C
authors.lastname: Giacometti
authors.forename: Enrico
authors.initials: E
authors.lastname: Brunetta
authors.forename: Francesco
authors.initials: F
authors.lastname: Piazza
authors.forename: Carlo
authors.initials: C
authors.lastname: Agostini
authors.forename: Spiridione
authors.initials: S
authors.lastname: Garbisa
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000009:adverse effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D005707:Gallic Acid / Q000737:chemistry*; D006801:Humans; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D047090:beta-Lactams / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*
chemical_list: D004791:Enzyme Inhibitors; D047090:beta-Lactams; D001761:Bleomycin; D005707:Gallic Acid; D019272:Leukocyte Elastase; D020780:Matrix Metalloproteinase 9