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

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 mu M, whereas it exerts weak activity against cathepsin G and protease-3 (IC50 > 100 mu M), 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 mu M) 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.