Inhibition of leukocyte elastase, polymorphonuclear chemoinvasion, and inflammation-triggered pulmonary fibrosis by a 4-alkyliden-β-lactam with a galloyl moiety

Isabella Dell'Aica, Luigi Sartor, Paola Galletti, Daria Giacomini, Arianna Quintavalla, Fiorella Calabrese, Cinzia Giacometti, Enrico Brunetta, Francesco Piazza, Carlo Agostini, Spiridione Garbisa

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)539-546
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume316
Issue number2
DOIs
Publication statusPublished - Feb 2006

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Lactams
Leukocyte Elastase
Pulmonary Fibrosis
Inflammation
Inhibitory Concentration 50
Cathepsin G
Flavonols
Matrix Metalloproteinase 2
Matrix Metalloproteinase 9
Protease Inhibitors
Pneumonia
Neutrophils
Fibrosis
Peptide Hydrolases
Anti-Inflammatory Agents
Anti-Bacterial Agents
Injections
Therapeutics

ASJC Scopus subject areas

  • Pharmacology

Cite this

Inhibition of leukocyte elastase, polymorphonuclear chemoinvasion, and inflammation-triggered pulmonary fibrosis by a 4-alkyliden-β-lactam with a galloyl moiety. / Dell'Aica, Isabella; Sartor, Luigi; Galletti, Paola; Giacomini, Daria; Quintavalla, Arianna; Calabrese, Fiorella; Giacometti, Cinzia; Brunetta, Enrico; Piazza, Francesco; Agostini, Carlo; Garbisa, Spiridione.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 316, No. 2, 02.2006, p. 539-546.

Research output: Contribution to journalArticle

Dell'Aica, Isabella ; Sartor, Luigi ; Galletti, Paola ; Giacomini, Daria ; Quintavalla, Arianna ; Calabrese, Fiorella ; Giacometti, Cinzia ; Brunetta, Enrico ; Piazza, Francesco ; Agostini, Carlo ; Garbisa, Spiridione. / Inhibition of leukocyte elastase, polymorphonuclear chemoinvasion, and inflammation-triggered pulmonary fibrosis by a 4-alkyliden-β-lactam with a galloyl moiety. In: Journal of Pharmacology and Experimental Therapeutics. 2006 ; Vol. 316, No. 2. pp. 539-546.
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