Parthenolide improves systemic hemodynamics and decreases tissue leukosequestration in rats with polymicrobial sepsis.

Abstract

OBJECTIVE:

Nuclear factor (NF)-kappaB is a transcriptional factor required for the gene expression of many inflammatory mediators. This study was designed to investigate the biological effects of parthenolide, a specific inhibitor of NF-kappaB activation, in experimental sepsis and multiple organ failure.

DESIGN:

Prospective, randomized laboratory investigation that used an established model of cecal ligation and puncture to induce polymicrobial sepsis in rats.

SETTING:

University hospital laboratory.

SUBJECTS:

Male Sprague Dawley rats underwent cecal ligation and puncture followed by the administration of saline solution.

INTERVENTIONS:

A group of rats received parthenolide (1 mg/kg) intraperitoneally. Mean arterial blood pressure was monitored for 18 hrs, and survival rate was monitored for 4 days. In a separate experiment, rats were killed at 1, 3, 6, and 18 hrs after cecal ligation and puncture.

MEASUREMENTS AND MAIN RESULTS:

In vehicle-treated animals, cecal ligation and puncture resulted in polymicrobial sepsis and was associated with 20% mortality rate, marked hypotension, and lung injury. Immunohistochemistry showed positive staining for nitrotyrosine and poly(adenosine diphosphate [ADP]-ribose) polymerase-1 (PARP-1) in thoracic aortas. There was a significant increase in plasma concentrations of tumor necrosis factor-alpha, interleukin-6, and interleukin-10. Elevated levels of myeloperoxidase activity in lung, colon, and liver were indicative of infiltration of neutrophils. These inflammatory events were associated with activation of NF-kappaB in the lung in a time-dependent fashion. In vivo treatment with parthenolide improved the hemodynamic profile and survival; reduced neutrophil infiltration in lung, colon, and liver; and reduced plasma concentrations of cytokines. Treatment with parthenolide also abolished formation of nitrotyrosine and expression of PARP-1 in thoracic aortas. These beneficial effects of parthenolide were associated with reduction of NF-kappaB activity in the lung.

CONCLUSIONS:

Our data suggest that pharmacologic inhibition of NF-kappaB may represent a potential therapeutic approach in sepsis.

• Authors: Maeve Sheehan, Hector R Wong, Paul W Hake, Basilia Zingarelli
• Journal: Critical care medicine (Crit Care Med) Vol. 31 Issue 9 Pg. 2263-70 (Sep 2003) ISSN: 0090-3493 [Print] United States
• PMID: 14501955 (Publication Type: Comparative Study, Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Inflammation Mediators
• NF-kappa B
• Sesquiterpenes
• parthenolide

Topics

• Animals
• Biopsy, Needle
• Disease Models, Animal
• Hemodynamics (drug effects)
• Immunohistochemistry
• Inflammation Mediators (analysis)
• Injections, Intraperitoneal
• Male
• Multiple Organ Failure (drug therapy, pathology, prevention & control)
• NF-kappa B (drug effects, metabolism)
• Random Allocation
• Rats
• Rats, Sprague-Dawley
• Reference Values
• Sepsis (drug therapy, mortality, pathology)
• Sesquiterpenes (pharmacology)
• Survival Rate
• Treatment Outcome