QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.105.096248v1 316/2/539    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Dell'Aica, I. Articles by Garbisa, S. Search for Related Content PubMed PubMed Citation Articles by Dell'Aica, I. Articles by Garbisa, S.

INFLAMMATION AND IMMUNOPHARMACOLOGY

Inhibition of Leukocyte Elastase, Polymorphonuclear Chemoinvasion, and Inflammation-Triggered Pulmonary Fibrosis by a 4-Alkyliden--lactam with a Galloyl Moiety

Department of Experimental Biomedical Sciences, Medical School of Padova, Padova, Italy (I.D.A., L.S., S.G.); Department of Chemistry `G. Ciamician', University of Bologna, Bologna, Italy (P.G., D.G., A.Q.); Department of Pathology, Medical School of Padova, Padova, Italy (F.C., C.G.); and Department of Clinical Medicine I, Medical School of Padova, Padova, Italy (E.B., F.P., C.A.)

-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 -lactam with an N-linked galloyl moiety, the latter identified as strategic in conferring anti-LE properties to some flavonols. This N-galloyl-derivative -lactam inhibits the LE activity with a K_i 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 -lactam is a potent anti-inflammatory compound with therapeutic potential.

Address correspondence to: Dr. Spiridione Garbisa, Department of Experimental Biomedical Sciences, Viale G. Colombo 3, 35121 Padova, Italy. E-mail: garbisa{at}unipd.it