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PD98059, a specific MAP kinase inhibitor, attenuates multiple organ dysfunction syndrome/failure (MODS) induced by
Rosanna Di Paola1, Maria Galuppo, Emanuela Mazzon
1IRCCS Centro Neurolesi Bonino-Pulejo, Messina, Italy.
Abstract:
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.
Insights
PD98059, a MEK1 inhibitor, significantly reduced the severity of zymosan-induced non-septic shock in mice. This compound attenuated organ injury, systemic inflammation, and mortality, highlighting its therapeutic potential.
Area of Science:
- Pharmacology
- Immunology
- Pathophysiology
Background:
- Zymosan administration in mice induces non-septic shock, characterized by systemic inflammation and organ damage.
- The mitogen-activated protein kinase (MAPK) cascade plays a critical role in inflammatory responses.
- PD98059 is a selective inhibitor of MEK1, a key enzyme in the MAPK pathway.
Purpose of the Study:
- To investigate the therapeutic effects of PD98059 on zymosan-induced non-septic shock in a murine model.
- To assess the impact of PD98059 on inflammatory markers, organ injury, and survival rates.
Main Methods:
- Mice were administered zymosan intraperitoneally, followed by treatment with PD98059 at specific time points.
- Organ function, peritoneal exudation, and inflammatory cell migration were assessed.
- Plasma levels of TNF-alpha and IL-1beta were measured.
- Immunohistochemical analysis was performed to evaluate markers of inflammation and cell death.
- NF-kappaB activation and MAPK expression were analyzed.
Main Results:
- PD98059 treatment attenuated peritoneal exudation and polymorphonuclear cell migration.
- It reduced lung, liver, pancreatic, and kidney injury caused by zymosan.
- PD98059 decreased plasma levels of TNF-alpha and IL-1beta.
- Immunohistochemical analysis showed reduced expression of iNOS, nitrotyrosine, ICAM-1, P-selectin, Bax, Bcl-2, and FAS-ligand in tissues from PD98059-treated mice.
- PD98059 inhibited zymosan-induced NF-kappaB activation and MAPK expression.
- Mortality was reduced from 60% to 20% in the PD98059 treatment group.
Conclusions:
- PD98059 effectively mitigates the pathological consequences of zymosan-induced non-septic shock in mice.
- Inhibition of the MEK1/MAPK pathway by PD98059 confers protection against systemic inflammation and organ damage.
- PD98059 demonstrates significant potential as a therapeutic agent for non-septic shock.
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