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Am J Physiol Lung Cell Mol Physiol 281: L868-L878, 2001;
1040-0605/01 $5.00
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Vol. 281, Issue 4, L868-L878, October 2001

Synergistic neutrophil elastase-cytokine interaction degrades collagen in three-dimensional culture

Y. K. Zhu1, X. D. Liu2, C. M. Sköld3, T. Umino2, H. J. Wang2, J. R. Spurzem2, T. Kohyama2, R. F. Ertl2, and S. I. Rennard2

1 Jincheng Hospital, Lanzhou 730050, China; 2 University of Nebraska Medical Center, Omaha, Nebraska 68198-5125; and 3 Karolinska Institute, S-171 76 Stockholm, Sweden

Proteolytic degradation of extracellular matrix is thought to play an important role in many lung disorders. In the current study, human lung fibroblasts were cast into type I collagen gels and floated in medium containing elastase, cytomix (combination of tumor necrosis factor-alpha , interleukin-1beta , and interferon-gamma ), or both. After 5 days, gel collagen content was determined by measuring hydroxyproline. Elastase alone did not result in collagen degradation, but in the presence of fibroblasts, elastase reduced hydroxyproline content to 75.2% (P < 0.01), whereas cytomix alone resulted in reduction of hydroxyproline content to 93% (P < 0.05). The combination of elastase and cytomix reduced hydroxyproline content to 5.2% (P < 0.01). alpha 1-Proteinase inhibitor blocked this synergy. Gelatin zymography and Western blot revealed that matrix metalloproteinase (MMP)-1, -3, and -9 were induced by cytomix and activated in the presence of elastase. Tissue inhibitor of metalloproteinase (TIMP)-1 and -2 were also induced by cytomix but were cleaved by elastase. We conclude that a synergistic interaction between cytomix and elastase, mediated through cytokine induction of MMP production and elastase-induced activation of latent MMPs and degradation of TIMPs, can result in a dramatic augmentation of collagen degradation. These findings support the notion that interaction among inflammatory mediators secreted by mononuclear cells and neutrophils can induce tissue cells to degrade extracellular matrix. Such a mechanism may contribute to the protease-anti-protease imbalance in emphysema.

matrix metalloproteinases; collagen; fibroblasts; interleukin-1; tumor necrosis factor


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