Nuclear factor (NF)-κB 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-κB activation, in experimental sepsis and multiple organ failure.
Prospective, randomized laboratory investigation that used an established model of cecal ligation and puncture to induce polymicrobial sepsis in rats.
University hospital laboratory.
Male Sprague Dawley rats underwent cecal ligation and puncture followed by the administration of saline solution.
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-α, 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-κB 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-κB activity in the lung.
Our data suggest that pharmacologic inhibition of NF-κB may represent a potential therapeutic approach in sepsis.