Blockade of Poly(ADP-ribose) synthetase inhibits neutrophil recruitment, oxidant generation, and mucosal injury in murine colitis

Gastroenterology. 1999 Feb;116(2):335-45. doi: 10.1016/s0016-5085(99)70130-7.


Background & aims: Inflammatory bowel disease is characterized by oxidative and nitrosative stress, leukocyte infiltration, and up-regulation of intercellular adhesion molecule 1 (ICAM-1) expression in the colon. Recent data show that oxidative and nitrosative stress in isolated enterocytes produces DNA single-strand breaks that activate the nuclear enzyme poly(ADP-ribose) synthetase (PARS), resulting in depletion of intracellular energetics and increased paracellular permeability. The aim of the present study was to examine the in vivo relevance of this injury pathway.

Methods: Colitis was induced by rectal instillation of trinitrobenzenesulfonic acid (TNBS) in mice with a genetic deficiency of PARS (PARS-/-) and in wild-type littermates.

Results: In wild-type mice, TNBS treatment resulted in colonic erosion and ulceration that was maintained up to 7 days. Neutrophil infiltration (indicated by myeloperoxidase activity in the mucosa) was associated with up-regulation of ICAM-1 and high levels of malondialdehyde and nitrotyrosine. TNBS-treated PARS-/- mice experienced a similar colonic injury that was, however, completely resolved by 6 days. Resolution of the damage was associated with absence of ICAM-1 up-regulation, reduction of neutrophil infiltration, lipid peroxidation, and nitrosative damage.

Conclusions: These data show that PARS plays a critical role in colonic inflammation possibly by regulating ICAM-1 expression, neutrophil recruitment, and the subsequent oxidant generation.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Colitis / chemically induced
  • Colitis / enzymology
  • Colitis / metabolism*
  • Colitis / pathology*
  • Disease Models, Animal
  • Immunohistochemistry
  • Intercellular Adhesion Molecule-1 / metabolism
  • Intestinal Mucosa / enzymology
  • Intestinal Mucosa / metabolism*
  • Intestinal Mucosa / pathology*
  • Malondialdehyde / metabolism
  • Mice
  • Neutrophils*
  • Oxidative Stress
  • Permeability
  • Peroxidase / metabolism
  • Poly(ADP-ribose) Polymerase Inhibitors*
  • Severity of Illness Index
  • Time Factors
  • Trinitrobenzenesulfonic Acid
  • Tyrosine / analogs & derivatives
  • Tyrosine / metabolism
  • Up-Regulation


  • Poly(ADP-ribose) Polymerase Inhibitors
  • Intercellular Adhesion Molecule-1
  • 3-nitrotyrosine
  • Tyrosine
  • Malondialdehyde
  • Trinitrobenzenesulfonic Acid
  • Peroxidase