Proteolytic degradation of extracellular matrix is thought to play an important role both in
emphysema and in tissue development and repair.
Retinoic acid has been suggested to modify tissue injury, and in an animal model of
emphysema may induce alveolar repair. Since
cytokines can induce
matrix metalloproteinase (
MMP) production in fibroblasts and
neutrophil elastase (NE) can activate
MMPs, we hypothesized that
retinoic acid could attenuate
collagen degradation by modifying
MMP production and activation. To evaluate this, human lung fibroblasts were cast into native
type I collagen gels and floated in medium containing cytomix (TNF-alpha, IL-1beta, and IFN-gamma) alone or in combination with NE in the presence and absence of
retinoic acid (1 microM). After 5 d, cytomix with
elastase induced significant degradation of the
collagen gels assessed by quantifying total
hydroxyproline (41.6 +/- 1.6 microg versus 3.3 +/- 1.5 microg, P < 0.01).
Retinoic acid significantly inhibited this degradation (23.3 +/- 1.5 microg versus 3.3 +/- 1.5 microg, P < 0.01).
Gelatin zymography and Western blot revealed that MMP-1, MMP-3, and MMP-9 were induced by cytomix and that co-exposure to NE resulted in increased production of activated forms of these
enzymes.
Retinoic acid attenuated the induction and activation of MMP-1 and MMP-3. The current study, therefore, suggests that in addition to stimulating
anabolic effects,
retinoic acid may modulate proteolytic processes thought to contribute to tissue destruction in
emphysema.