PD98059, a specific MAP kinase inhibitor, attenuates multiple organ dysfunction syndrome/failure (MODS) induced by zymosan in mice.
PD98059 (MEK1 Inhibitor) has been shown to act in vivo as a highly selective inhibitor of MEK1 activation and the MAP kinase cascade. In the present study, we have investigated the effects of PD98059, on the development of non-septic shock caused by zymosan in mice. Mice received either intraperitoneally zymosan (500mg/kg, administered i.p. as a suspension in saline) or vehicle (0.25ml/mouse saline). PD98059 (10mg/kg) was administered 1 and 6h after zymosan administration i.p. Organ failure and systemic inflammation in mice was assessed 18h after administration of zymosan and/or PD98059. Treatment of mice with PD98059 attenuated the peritoneal exudation and the migration of polymorphonuclear cells caused by zymosan. PD98059 also attenuated the lung, liver and pancreatic injury and renal dysfunction caused by zymosan as well as the increase of TNF-alpha and IL-1beta plasma levels caused by zymosan. Immunohistochemical analysis for inducible nitric oxide synthase (iNOS), nitrotyrosine, poly(ADP-ribose) (PAR), ICAM-1, P-selectin, Bax, Bcl-2 and FAS-ligand revealed positive staining in pancreatic and intestinal tissue obtained from zymosan-injected mice. The degree of staining for nitrotyrosine, iNOS, PAR, ICAM-1, P-selectin, Bax, Bcl-2 and FAS-ligand were markedly reduced in tissue sections obtained from zymosan-injected mice, which had received PD98059. Moreover treatment of mice with PD98059 (10mg/kg) attenuated the NF-kappaB activation and mitogen-activated protein kinases (MAPK) expression induced by zymosan injection. In addition, administration of zymosan caused a severe illness in the mice characterized by a systemic toxicity, significant loss of body weight and a 60% of mortality at the end of observation period. Treatment with PD98059 significantly reduced the development of systemic toxicity, the loss in body weight and the mortality (20%) caused by zymosan. This study provides evidence that PD98059 attenuates the degree of zymosan-induced non-septic shock in mice.
Di Paola
Rosanna
R
IRCCS Centro Neurolesi Bonino-Pulejo, Messina, Italy.
Galuppo
Maria
M
Mazzon
Emanuela
E
Paterniti
Irene
I
Bramanti
Placido
P
Cuzzocrea
Salvatore
S
D000208:Acute Disease; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D053222:Fas Ligand Protein / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology*; D020672:I-kappa B Proteins / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009102:Multiple Organ Failure / Q000139:chemically induced / Q000201:enzymology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D000072000:NF-KappaB Inhibitor alpha; D020556:Neutrophil Infiltration / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010538:Peritonitis / Q000201:enzymology / Q000517:prevention & control; D010766:Phosphorylation; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D018746:Systemic Inflammatory Response Syndrome / Q000139:chemically induced / Q000201:enzymology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D013997:Time Factors; D051996:Transcription Factor RelA / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D015054:Zymosan; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C494827:Bax protein, mouse; D015815:Cell Adhesion Molecules; D016207:Cytokines; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D005419:Flavonoids; D020672:I-kappa B Proteins; D018836:Inflammation Mediators; C000606205:Nfkbia protein, mouse; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D051028:bcl-2-Associated X Protein; D000072000:NF-KappaB Inhibitor alpha; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D015054:Zymosan; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D011065:Poly(ADP-ribose) Polymerases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one