Fibronectin-α4β1 interactions in hepatic cold ischemia and reperfusion injury: Regulation of MMP-9 and MT1-MMP via the p38 MAPK pathway

S. Duarte, X. D. Shen, C. Fondevila, R. W. Busuttil, A. J. Coito

Research output: Contribution to journalArticlepeer-review

36 Scopus citations


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 FN-α4β1 integrin leukocyte interactions, in a well-established model of 24-h 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 FN-stimulated macrophages, suggesting that p38 MAPK kinase pathway controls FN-mediated inductions of MMP-9 and MT1-MMP/MMP-14. Hence, this study provides new insights on the role of FN in liver injury, which can potentially be applied to the development of new pharmacological strategies for the successful protection against hepatic IRI. This study reveals new insights into the role of fibronectin in hepatic cold ischemia and reperfusion injury, and provides evidence that fibronectin induces the expression of both MMP-9 and MT1-MMP/MMP-14 through activation of the p38 MAPK kinase pathway in macrophages.

Original languageEnglish (US)
Pages (from-to)2689-2699
Number of pages11
JournalAmerican Journal of Transplantation
Issue number10
StatePublished - Oct 2012


  • fibronectin
  • leukocyte migration
  • liver cold ischemia and reperfusion injury
  • matrix metalloproteinases

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)


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