Received for publication October 31, 2006.
Revised January 30, 2007.
Accepted for publication February 6, 2007.

Hyperforin blocks neutrophil activation of MMP-9, motility and recruitment,and restrains inflammation-triggered angiogenesis and lung fibrosis

Abstract

Hyperforin (Hyp), a polyphenol-derivative of St. John's Wort, has emerged as key player in the anti-depressant activity of the plant, but also as inhibitor of bacteria lymphocyte and tumor-cell proliferation, and matrix proteinases. We tested whether as well as inhibiting leukocyte elastase (LE) activity, Hyp might be effective in containing both polymorphonuclear (PMN) leukocyte recruitment and unfavorable eventual tissue responses. The results show that, without affecting in vitro human PMN viability and chemokine-receptor expression, Hyp (as stable dicyclohexylammonium salt) was able to inhibit in a dose-dependent manner their chemotaxis and chemoinvasion (IC₅₀ 1 µM, for both); this effect was associated with a reduced expression of the adhesion molecule CD11b by fMLF-stimulated neutrophils, and block of leukocyte elastase (LE)-triggered activation of the gelatinase MMP-9. PMN-triggered angiogenesis is also blocked by both local injection and daily i.p. administration of the Hyp salt in an IL-8-induced murine model. Furthermore, i.p. treatment with Hyp reduces acute PMN recruitment, and enhances resolution in a pulmonary bleomycin-induced inflammation model, significantly reducing consequent fibrosis. These results indicate that Hyp is a powerful anti-inflammatory compound with therapeutic potential, and shed light on mechanistic keys.

Key words: MMP-9, PMNs, angiogenesis, hyperforin, leukocyte elastase, pulmonary fibrosis