Inhibition of Leukocyte Elastase, Polymorphonuclear Chemoinvasion, and Inflammation-triggered Pulmonary Fibrosis by a 4-alkyliden-beta-lactam with a Galloyl Moiety.
From: Department of Experimental Biomedical Sciences, Medical School of Padova, Italy.
The Journal of pharmacology and experimental therapeutics
- Publish Date: Feb 2006
- ISSN: 0022-3565
- Volume: 316
- Issue: 2
- Pages: 539-46
- Medium: Print
- Language: English
- Citation (JAMA): Dell'Aica Isabella, Sartor Luigi, Galletti Paola, et al. Inhibition of Leukocyte Elastase, Polymorphonuclear Chemoinvasion, and Inflammation-triggered Pulmonary Fibrosis by a 4-alkyliden-beta-lactam with a Galloyl Moiety.. J. Pharmacol. Exp. Ther. Feb 2006;316:539-46
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.
Mesh Headings (Keywords): Animals, Bleomycin, Cell Survival, Cells, Cultured, Chemotaxis, Leukocyte, Enzyme Inhibitors, Gallic Acid, Humans, Leukocyte Elastase, Matrix Metalloproteinase 9, Mice, Mice, Inbred C57BL, Neutrophils, Pulmonary Fibrosis, beta-Lactams
Check for Full Text / PubMed Unique Identifier (PMID): 16249367
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