Abstract
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-α, interleukin-1β, and interferon-γ), 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). α1-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.
Original language | English (US) |
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Pages (from-to) | L868-L878 |
Journal | American Journal of Physiology - Lung Cellular and Molecular Physiology |
Volume | 281 |
Issue number | 4 25-4 |
DOIs | |
State | Published - 2001 |
Keywords
- Collagen
- Fibroblasts
- Interleukin-1
- Matrix metalloproteinases
- Tumor necrosis factor
ASJC Scopus subject areas
- Physiology
- Pulmonary and Respiratory Medicine
- Physiology (medical)
- Cell Biology