The
peroxisome proliferator-activated receptor (
PPAR) alpha is a member of the
nuclear receptor superfamily of
ligand-dependent
transcription factors related to
retinoid,
steroid, and
thyroid hormone receptors. The aim of the present study is to evaluate the role of
PPAR-alpha receptor on the development of
multiple-organ dysfunction syndrome (
MODS) induced by
zymosan.
MODS was induced by peritoneal injection of
zymosan (dose, 500 mg/kg i.p. as a
suspension in saline) in
PPAR-alpha wild-type (
PPAR-alphaWT) and
PPAR-alpha knockout (
PPAR-alphaKO) mice, was assessed 18 h after the administration of
zymosan, and was monitored for 12 days (for loss of
body weight and mortality). A severe inflammatory process, induced by
zymosan administration in wild-type mice, coincided with the damage of liver, kidney, pancreas, and small intestine.
Myeloperoxidase activity, indicative of neutrophil infiltration, and lipid peroxidation were significantly increased in
zymosan-treated wild-type mice.
Zymosan in the wild-type mice also induced a significant increase in the plasma levels of
nitrite/
nitrate. Immunohistochemical examination demonstrated a marked increase in the immunoreactivity to
nitrotyrosine and
Fas ligand in the intestine of
zymosan-treated wild-type mice. In contrast, the degree of (1) peritoneal
inflammation and tissue injury, (2)
nitrotyrosine formation and
Fas ligand expression, and (3) neutrophil infiltration were markedly enhanced in intestinal tissue obtained from
zymosan-treated
PPAR-alphaKO mice.
Zymosan-treated
PPAR-alphaKO mice also showed a significantly increased mortality. Taken together, the present study clearly demonstrates that
PPAR-alpha pathway modulates the degree of
MODS associated with
zymosan-induced nonseptic
shock.