THE EFFECTS OF STROMELYSIN OR MATRIX METALLOPROTEINASE-3 (MMP-3) ON INTESTINAL SECRETORY FUNCTION

Abstract

33 In inflammatory bowel disease there is extensive damage to the extracellular matrix (ECM) and loss of the transepithelial sodium gradient and hence absorption. Stromelysin (MMP-3) is produced in intestinal inflammatory states and is important in tissue degradation. We have previously used human fetal intestine to explore inflammatory mechanisms and here we study the effect of MMP-3 on its secretory function. 3 cm loops of 15 wk gestation gut or T84 cell monolayers were incubated with MMP-3 50 nM or saline (C) on the apical surface then mounted in Using Chambers. MMP-3 after 1, 2 and 3 hrs caused a rise in short circuit current (Isc) of 105±33, 125±5.8 and 145±99 μA/cm2 (p<0.005). Resistance fell from 22±8 to 9±7 ohms/cm2 and PD rose from 1.4±0.8 to 2.6±0.8 mV at 3 hrs. In Cl- free conditions Isc fell by 83%. In contrast in T84 cells the rise in Isc was insignificant (47 vs 53μA/cm2). Thus MMP-3 induces Cl- dependent secretion in intact intestine but not in T84 monolayers suggesting that this is not due to a direct effect on enterocytes. We speculate that disruption of the ECM by MMP-3 also induces secretion and that MMP inhibitors may have a therapeutic role in diarrhoeal states.