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.