Metal-catalyzed oxidation of extracellular matrix components perturbs hepatocyte survival with activation of intracellular signaling pathways

Ranjit K. Giri, Harmeet Malhi, Brigid Joseph, Jithender Kandimalla, Sanjeev Gupta

Research output: Contribution to journalArticle

15 Scopus citations


To investigate whether oxidative manipulation of extracellular matrix components could affect cell survival, we studied primary rat hepatocytes cultured on dishes coated with collagen type 1, which was oxidized with a metal-based system. Culture of hepatocytes on oxidized collagen led to decreased cellular catalase activity along with impaired cell survival. The fraction of polyploid hepatocytes decreased early followed by greater reaccumulation of polyploid cells. Cells cultured on oxidized collagen showed greater susceptibility to additional oxidant stress induced by tert.-butyl-hydroperoxide. The capacity of hepatocytes for growth factor-induced DNA synthesis was unaffected by culture on oxidized collagen. In response to culture on oxidized matrix, AP-1, Egr-1, CREB, and NF-κB transcription factor activity was rapidly increased. This change in transcription factor activity was ameliorated by treatment of collagen with a free radical spin trap, N-tert.-butyl-α-phenylnitrone, prior to oxidation. Moreover, culture of hepatocytes with aminoguanidine, an antioxidant drug, decreased cell injury. These findings established that exposure of primary hepatocytes to oxidized extracellular matrix components rapidly activates cell signaling events with loss of hepatocyte subpopulations. Such cell-extracellular matrix interactions may play roles in organ homeostasis and oncogenetic progression.

Original languageEnglish (US)
Pages (from-to)451-462
Number of pages12
JournalExperimental Cell Research
Issue number2
StatePublished - Dec 1 2003



  • Culture
  • Extracellular matrix
  • Hepatocyte
  • Injury
  • Oxidation

ASJC Scopus subject areas

  • Cell Biology

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