The role of matrix metalloproteinases in intestinal epithelial wound healing during normal and inflammatory states.

BACKGROUND

Healing of the epithelium is a key consideration in gastrointestinal surgery. Inflammation is one factor innate to patients with inflammatory bowel disease that poses a risk of delayed healing of the intestinal epithelium postoperatively.

MATERIALS AND METHODS

Epithelial wounding model was performed on rat intestinal epithelial cells grown under control and interferon gamma (IFN-γ)-, interleukin-1beta (IL-1β)-, and tumor necrosis factor-alpha (TNF-α)-stimulated conditions. Wounds were measured and percent healing was calculated at 0, 8 and 24 h. Western blot analysis was performed using matrix metalloproteinase (MMP)-7 primary antibody and semiquantitative densitometry was conducted.

RESULTS

Wounds were 50.0% and 99.7% healed under control conditions at 8 and 24 h, respectively. IL-1β and IFN-γ delayed wound closure. MMP-7 increased by 2.3-fold at 8 h and 1.6-fold at 24 h during wound healing. Activated MMP-7 increased by 3- to 5-fold at 24 h. IL-1β stimulation increased levels of MMP-7 by 17% to 37% above the elevated expression due to healing alone. TNF-α up-regulated MMP-7 in non-wounded and wounded cells, and IFN-γ did not affect its expression. When MMP-7 activity was blocked, wound closure was delayed.

CONCLUSIONS

MMP-7 significantly contributes to intestinal epithelial wound closure evidenced by: (1) presence of increased MMP-7 during healing under control conditions and (2) the delayed rate of closure when MMP-7 activity was blocked. IL-1β increased MMP-7 levels beyond those seen during normal healing. It appears that some increase in MMP-7 is necessary for normal wound closure; however, its overexpression may delay intestinal epithelial wound healing, especially when MMP-7 is up-regulated by cytokines present in the inflammatory environment of inflammatory bowel disease (IBD).