Received for publication September 28, 2005.
Revised October 24, 2005.
Accepted for publication October 24, 2005.

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

Abstract

B-lactams - 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 flavanols. This N-galloyl-derivative -lactam inhibits the LE activity with a Ki of 0.7 µM, while exerting week activity against cathepsin G and protease-3 (IC₅₀ > 100 µM), and metallo-proteases MMP-2 and MMP-9. Without affecting chemotactic response and viability of polymorphonuclear (PMN) leukocytes, the compound efficiently restrains their chemoinvasion (IC₅₀ 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.

Key words: MMP-9, N-galloyl-4-alkyliden-beta-lactam, PMNs, inflammation, leukocyte elastase, lung fibrosis