Colchicine suppresses the release of fibroblast growth factors from alveolar macrophages in vitro. The basis of a possible therapeutic approach ot the fibrotic disorders.
Fibrosis is the accumulation of fibroblasts and the connective tissue products secreted by these cells, usually subsequent to tissue injury. While fibrosis can be useful in preserving the general structural integrity of a tissue, it often alters cell-cell and cell-connective tissue interactions, which leads to loss of tissue function. On the basis of the concept that mononuclear phagocytes can direct the development of fibrosis through the release of specific mediators that stimulate fibroblast proliferation, we propose a therapeutic strategy to prevent fibrosis by preventing the release of these specific mediators. The present study demonstrated that colchicine, a widely used and well-tolerated drug, can block alveolar macrophage release of 2 mediators associated with the development of fibrosis in interstitial lung diseases, fibronectin, and the alveolar-macrophage-derived growth factor (AMDGF). Colchicine blocked the spontaneous release of fibronectin by alveolar macrophages obtained from patients with fibrotic lung disease by 23 +/- 4% after 24 h and by greater than 90% after 72 h. AMDGF release was blocked by 68 +/- 10% after 4 h (p less than 0.01, all comparisons). The effect of colchicine was not due to nonspecific toxicity since [14C]proline tracer studies demonstrated that macrophages treated with colchicine were capable of de novo protein synthesis and the secretion of several protein products, despite the fact that fibronectin and AMDGF release were suppressed. The effect of colchicine on the spontaneous release of both fibronectin and AMDGF could be observed at concentrations less than 10 ng/ml, levels that can be achieved in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)
Rennard
S I
SI
Pulmonary Branch, National Heart, Lung and Blood Institute, Bethesda, MD 20892.
Bitterman
P B
PB
Ozaki
T
T
Rom
W N
WN
Crystal
R G
RG
D003078:Colchicine / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D006133:Growth Substances / Q000378:metabolism*; D066298:In Vitro Techniques; D036341:Intercellular Signaling Peptides and Proteins; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D010455:Peptides; D011650:Pulmonary Alveoli / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000188:drug therapy / Q000378:metabolism*
D005353:Fibronectins; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; C042586:alveolar macrophage growth factor; D003078:Colchicine