Background: Cyclooxygenase (COX) is the rate-limiting enzyme that catalyzes the formation of prostaglandins. The inducible isoform of COX (COX-2) is highly expressed in aggressive metastatic breast cancers and may play a critical role in cancer progression (i.e. growth and metastasis). However, the exact mechanism(s) for COX-2-enhanced metastasis has yet to be clearly defined. It is well established that one of the direct results of COX-2 action is increased prostaglandin production, especially prostaglandin E 2 (PGE 2 ). Here, we correlate the inhibition of COX-2 activity with decreased breast cancer cell proliferation, migration, invasion and matrix metalloproteinase (MMP) expression.

The insulin sensitizing thiazolidinedione drugs, rosiglitazone and pioglitazone are specific peroxisome proliferator-activated receptor-gamma (PPARγ) agonists and reduce pro-inflammatory responses in patients with type 2 diabetes and coronary artery disease and may be beneficial in sepsis. Sepsis was induced in 8–10 wk old C57BL/6 mice by cecal ligation and puncture (CLP) with a 22g double puncture technique. Mice received intraperitoneal injection of vehicle (DMSO:PBS) or pioglitazone (20mg/kg) at 1h and 6h after CLP and were sacrificed at various timepoints. In sepsis, vehicle-treated mice had hypoglycemia, increased lung injury and increased lung neutrophil infiltration. Pro-inflammatory plasma cytokines were increased but the plasma adipokine, adiponectin, was decreased in vehicle-treated septic mice. This corresponded with inhibitor κB (IκBα) protein degradation and an increase in NF-κB activity in lung. Pioglitazone treatment improved plasma glucose and adiponectin levels and decreased pro-inflammatory cytokines. Lung IκBα protein expression increased and corresponded with a decrease in nuclear factor kappa-B (NF-κB) activity in the lung from pioglitazone treated mice. Pioglitazone reduces the inflammatory response in polymicrobial sepsis in part through inhibition of NF-κB and may be a novel therapy in sepsis.

The purpose of this study was to examine the effect of short-term high fat feeding on the inflammatory response in polymicrobial sepsis. Male C57BL/6 mice at six-weeks of age were randomized to a high-fat diet (HFD) (60% kcal fat) or control diet (CD) (16% kcal fat) for 3 weeks. After 3 weeks of feeding, sepsis was induced by cecal ligation and puncture (CLP) and animals were monitored for survival. In a separate experiment, after 3 weeks of feeding mice underwent CLP and were sacrificed at various time-points thereafter. Tissue was collected for biochemical studies. Mice fed a HFD gained more weight and had a greater fat mass compared to CD-fed mice. Mice on a HFD had a lower probability of survival and more severe lung injury compared with CD-fed mice following sepsis. Myeloperoxidase activity, an indicator of neutrophil infiltration, was increased in the lung and liver after CLP in HFD-fed mice compared with CD (p<0.05). The plasma cytokines tumor necrosis factor-α (TNFα) and interleukin (IL)-6 were increased in both groups after CLP, however TNFα and IL-6 levels were lower in HFD mice at 3h after CLP compared with CD and consistent with lung, but not liver, mRNA expression. Leptin levels were higher in HFD-fed mice at 18h after sepsis compared to baseline levels (p<0.05). Polymicrobial sepsis increased hepatic nuclear factor-κB (NF-κB) activation in HFD-fed mice after CLP vs. CD-fed mice. Short duration high fat feeding increases mortality and organ injury following polymicrobial sepsis. These effects correspond to changes in NF-κB.