FIBRONECTIN-α4β1 INTERACTIONS IN HEPATIC COLD ISCHEMIA REPERFUSION INJURY: REGULATION OF MMP-9 AND MT1-MMP VIA THE p38 MAPK PATHWAY

摘要

Liver ischemia-reperfusion injury (IRI) remains a challenging problem in clinical settings. The expression of fibronectin (FN) by endothelial cells is a prominent feature of the hepatic response to injury. Here we investigate the effects of the connecting segment-1 (CS-1) peptide therapy, which blocks fibronectin (FN)-α4β1 integrin leukocyte interactions, in a well-established model of 24-hour cold liver IRI. CS-1 peptides significantly inhibited leukocyte recruitment and local release of proinflammatory mediators (COX-2, iNOS, and TNF-α), ameliorating liver IRI and improving recipient survival rate. CS1 therapy inhibited the phosphorylation of p38 MAPK, a kinase linked to inflammatory processes. Moreover, in addition to downregulating the expression of matrix metalloproteinase-9 (MMP-9) in hepatic IRI, CS-1 peptide therapy depressed the expression of membrane type 1-matrix metalloproteinase (MT1-MMP/MMP-14) by macrophages, a membrane-tethered MMP important for focal matrix proteolysis. Inhibition of p38 MAPK activity, with its pharmacological antagonist SB203580, downregulated MMP-9 and MT1-MMP/MMP-14 expressions by fibronectin-stimulated macrophages, suggesting that p38 MAPK kinase pathway controls fibronectin mediated inductions of MMP-9 and MT1-MMP/MMP-14. Hence, this study provides new insights on the role of fibronectin in liver injury, which can potentially be applied to the development of new pharmacological strategies for the successful protection against hepatic IRI.