Immunomodulatory effects of plasminogen activators on hepatic fibrogenesis

A. A. Higazi, M. El-Haj, A. Melhem, A. Horani, O. Pappo, C. E. Alvarez, N. Muhanna, S. L. Friedman, R. Safadi

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


Tissue-type plasminogen activators (tPA) and urokinase-type plasminogen activators (uPA) are involved in liver repair. We examined the potential immunomodulatory actions of uPA, tPA and uPA-receptor (uPAR) in carbon-tetrachloride-induced hepatic fibrosis in wild-type (WT), tPA -/-, uPA-/- and uPAR-/- mice. Carbon-tetrachloride treatment increased fibrosis in four groups but significantly less in three knock-out models. Serum cytokines and intrahepatic T cells elevated significantly following fibrosis process in WT animals but not in the knock-out groups. In culture, uPA increased lymphocyte proliferation significantly in WT and uPA-/- but not uPAR-/- animals. Following uPA exposure in vivo, there was CD8 predominance. To isolate uPA's effect on lymphocytes, WT mice were irradiated sublethally and then reconstituted with WT or uPA-/- lymphocytes. In these animals fibrosis was decreased and T cells were reduced in the uPA-/- recipients. Based on these data we postulate that plasminogen activators affect fibrosis in part by liver-specific activation of CD8 subsets that govern the fibrogenic activity of hepatic stellate cells.

Original languageEnglish
Pages (from-to)163-173
Number of pages11
JournalClinical and Experimental Immunology
Issue number1
StatePublished - Apr 2008


  • CD4
  • CD8
  • Cytokines
  • Hepatic fibrosis
  • Lymphocytes
  • Plasminogen activators
  • tPA
  • uPA
  • uPAR


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