title: Absence of peroxisome proliferators-activated receptors (PPAR)alpha enhanced the multiple organ failure induced by zymosan.
abstract: 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.
authors.affiliation: Dipartimento Clinico Sperimentale di Medicina e Farmacologia, Facoltà di Medicina e Chirurgia, Università di Messina, Via C. Valeria, Gazzi, 98100 Messina, Italy.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Di Paola
authors.forename: Emanuela
authors.initials: E
authors.lastname: Esposito
authors.forename: Emanuela
authors.initials: E
authors.lastname: Mazzon
authors.forename: Tiziana
authors.initials: T
authors.lastname: Genovese
authors.forename: Carmelo
authors.initials: C
authors.lastname: Muià
authors.forename: Concetta
authors.initials: C
authors.lastname: Crisafulli
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Malleo
authors.forename: Edoardo
authors.initials: E
authors.lastname: Sessa
authors.forename: Rosaria
authors.initials: R
authors.lastname: Meli
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cuzzocrea
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D053222:Fas Ligand Protein / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007422:Intestines / Q000473:pathology; D007668:Kidney / Q000503:physiopathology; D015227:Lipid Peroxidation; D051379:Mice; D018345:Mice, Knockout; D009102:Multiple Organ Failure / Q000209:etiology* / Q000401:mortality; D020556:Neutrophil Infiltration; D009569:Nitric Oxide / Q000378:metabolism; D047493:PPAR alpha / Q000235:genetics* / Q000378:metabolism*; D012769:Shock / Q000139:chemically induced / Q000209:etiology / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D015854:Up-Regulation; D015054:Zymosan / Q000633:toxicity
chemical_list: D053222:Fas Ligand Protein; D047493:PPAR alpha; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D015054:Zymosan