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Research ArticleINFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

Hyperforin Blocks Neutrophil Activation of Matrix Metalloproteinase-9, Motility and Recruitment, and Restrains Inflammation-Triggered Angiogenesis and Lung Fibrosis

Isabella Dell'Aica, Raffaele Niero, Francesco Piazza, Anna Cabrelle, Luigi Sartor, Cristiano Colalto, Enrico Brunetta, Girieca Lorusso, Roberto Benelli, Adriana Albini, Fiorella Calabrese, Carlo Agostini and Spiridione Garbisa
Journal of Pharmacology and Experimental Therapeutics May 2007, 321 (2) 492-500; DOI: https://doi.org/10.1124/jpet.106.116459
Isabella Dell'Aica
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Raffaele Niero
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Francesco Piazza
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Anna Cabrelle
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Luigi Sartor
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Cristiano Colalto
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Enrico Brunetta
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Girieca Lorusso
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Roberto Benelli
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Adriana Albini
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Fiorella Calabrese
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Carlo Agostini
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Spiridione Garbisa
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Abstract

Hyperforin (Hyp), a polyphenol-derivative of St. John's wort (Hypericum perforatum), has emerged as key player not only in the antidepressant activity of the plant but also as an 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 neutrophil (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 formyl-Met-Leu-Phe-stimulated neutrophils and block of LE-triggered activation of the gelatinase matrix metalloproteinase-9. PMN-triggered angiogenesis is also blocked by both local injection and daily i.p. administration of the Hyp salt in an interleukin-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 they elucidate mechanistic keys.

Footnotes

  • This work was supported by grants from the Associazione Italiana per la Ricerca sul Cancro, Fondo per gli Investimenti della Ricerca di Base-Ministero dell'Istruzione, dell'Università e della Ricerca, and Programmi di Ricerca di Interesse Nazionale-Ministero dell'Istruzione, dell'Università e della Ricerca Italian Government, University of Padova, and “Compagnia di San Paolo” project 1958StS/fs, Italy. G.L. is in the “Degenerative Disease and Immunopathology” Ph.D. program at the Medical School, University of Insubria, Varese, Italy.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.106.116459.

  • ABBREVIATIONS: Hyp, hyperforin; LE, leukocyte elastase; PMN, polymorphonuclear leukocyte; ECM, extracellular matrix; MMP, matrix metalloproteinase; Hyp-DCHA, dicyclohexylammonium salt of hyperforin; DMSO, dimethyl sulfoxide; fMLF, N-formyl-Met-Leu-Phe; BM, basement membrane; DMEM, Dulbecco's modified Eagle's medium; MFI, mean fluorescence intensity; IL, interleukin; PBS, phosphate-buffered saline; BAL, bronchoalveolar lavage; H&E, hematoxylin and eosin; MP, mean percentage.

    • Received October 31, 2006.
    • Accepted February 6, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 381 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 381, Issue 2
1 May 2022
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Research ArticleINFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

Hyperforin Blocks Neutrophil Activation of Matrix Metalloproteinase-9, Motility and Recruitment, and Restrains Inflammation-Triggered Angiogenesis and Lung Fibrosis

Isabella Dell'Aica, Raffaele Niero, Francesco Piazza, Anna Cabrelle, Luigi Sartor, Cristiano Colalto, Enrico Brunetta, Girieca Lorusso, Roberto Benelli, Adriana Albini, Fiorella Calabrese, Carlo Agostini and Spiridione Garbisa
Journal of Pharmacology and Experimental Therapeutics May 1, 2007, 321 (2) 492-500; DOI: https://doi.org/10.1124/jpet.106.116459

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Research ArticleINFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

Hyperforin Blocks Neutrophil Activation of Matrix Metalloproteinase-9, Motility and Recruitment, and Restrains Inflammation-Triggered Angiogenesis and Lung Fibrosis

Isabella Dell'Aica, Raffaele Niero, Francesco Piazza, Anna Cabrelle, Luigi Sartor, Cristiano Colalto, Enrico Brunetta, Girieca Lorusso, Roberto Benelli, Adriana Albini, Fiorella Calabrese, Carlo Agostini and Spiridione Garbisa
Journal of Pharmacology and Experimental Therapeutics May 1, 2007, 321 (2) 492-500; DOI: https://doi.org/10.1124/jpet.106.116459
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