Antiinflammatory and Antifibrotic Properties of Colchicine: Implications for Idiopathic Pulmonary Fibrosis
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© Springer-Verlag New York Inc. 1997
Antiinflammatory and Antifibrotic Properties of Colchicine: Implications for Idiopathic Pulmonary Fibrosis P. Entzian,1 M. Schlaak,1 U. Seitzer,2 A. Bufe,1 Y. Acil,3 and P. Zabel1 1
Medizinische Klinik and 2Institutsbereich Immunologie und Zellbiologie, Forschungszentrum Borstel, Parkallee 35, 23845 Borstel; 3Institut fu¨r Medizinische Molekularbiologie, Medizinische Universita¨t Lu¨beck, Lu¨beck, Germany
Abstract. The ancient drug colchicine has repeatedly been proposed as a novel drug for therapy of pulmonary fibrosis. The present study was undertaken to add to the knowledge on colchicine’s antiinflammatory and antifibrotic properties and thus help determine its actual rank in the treatment of pulmonary fibrosis. In vitro cell culture experiments with stimulated and unstimulated normal donor peripheral blood mononuclear cells (PMNC) and a human lung fibroblast cell line (WI-38) were used to determine the effects of colchicine on PMNC cytokine release (interleukin-6 and tumor necrosis factor-a) as well as on fibroblast proliferation and collagen synthesis rates. Reverse transcriptase polymerase chain amplifications of a1(III) collagen were done to detect collagen messenger ribonucleic acid (mRNA) expression. Colchicine did not significantly modulate tumor necrosis factor-a (TNF-a) and interleukin-6 (IL-6) release of PMNC. Colchicine inhibited fibroblast proliferation and total collagen synthesis significantly at concentrations obtainable in serum in vivo. Transcription of the a1(III) collagen gene into mRNA continued under colchicine. We conclude that colchicine is a potent in vitro inhibitor of fibroblast functions in terms of proliferation and collagen synthesis. The mechanism of collagen inhibition is more likely an inhibition of cellular collagen secretion than a switch off of collagen mRNA transcription. On the other hand, although colchicine is known to inhibit many leukocyte functions, it is a poor inhibitor of cytokines known to be important for fibrogenesis (e.g. IL-6, TNF-a, IL-1, platelet-derived growth factor, and transforming growth factor-b). This makes colchicine, at least from a theoretical standpoint and as concluded from in vitro studies, a preferable candidate for a combined therapeutic strategy.
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Key words: Colchicine—Idiopathic pulmonary fibrosis—Fibroblast growth— Collagen—Cytokines.
Introduction The fibrotic response to lung injury is far from understood. Regardless of the multifactorial origins of fibrosis, chronic inflammation causes mesenchymal cells to migrate to the site of injury, proliferate, and subsequently synthesize extracellular matrix components [7]. Neither the factors that contribute to chronic inflammation nor those that contribute to excess or sustained matrix production in fibrosis are fully characterized. The effectiveness of current therapeutic strategies is still in doubt. Although 40–70% of patients treated with corticosteroids feel subjective improvement, results of obje
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