Norepinephrine Inhibits Lipopolysaccharide-Stimulated TNF-α but Not Oxylipin Induction in n-3/n-6 PUFA-Enriched Cultures of Circumventricular Organs.

Sensory circumventricular organs (sCVOs) are pivotal brain structures involved in immune-to-brain communication with a leaky blood-brain barrier that detect circulating mediators such as lipopolysaccharide (LPS). Here, we aimed to investigate the potential of sCVOs to produce n-3 and n-6 oxylipins after LPS-stimulation. Moreover, we investigated if norepinephrine (NE) co-treatment can alter cytokine- and oxylipin-release. Thus, we stimulated rat primary neuroglial sCVO cultures under n-3- or n-6-enriched conditions with LPS or saline combined with NE or vehicle. Supernatants were assessed for cytokines by bioassays and oxylipins by HPLC-MS/MS. Expression of signaling pathways and enzymes were analyzed by RT-PCR. Tumor necrosis factor (TNF)α bioactivity and signaling, IL-10 expression, and cyclooxygenase (COX)2 were increased, epoxide hydroxylase (Ephx)2 was reduced, and lipoxygenase 15-(LOX) was not changed by LPS stimulation. Moreover, LPS induced increased levels of several n-6-derived oxylipins, including the COX-2 metabolite 15d-prostaglandin-J2 or the Ephx2 metabolite 14,15-DHET. For n-3-derived oxylipins, some were down- and some were upregulated, including 15-LOX-derived neuroprotectin D1 and 18-HEPE, known for their anti-inflammatory potential. While the LPS-induced increase in TNFα levels was significantly reduced by NE, oxylipins were not significantly altered by NE or changes in TNFα levels. In conclusion, LPS-induced oxylipins may play an important functional role in sCVOs for immune-to-brain communication.

Serum uromodulin predicts graft failure in renal transplant recipients.

OBJECTIVE AND METHODS: Test the ability of serum uromodulin concentrations 1-3 months after renal transplantation to predict all-cause mortality (ACM) and graft loss (GL) in 91 patients. RESULTS: uromodulin predicted GL equivalently to the other markers studied: the risk for GL was reduced by 0.21 per one standard deviation (SD) increase (cystatin C: hazard ratio [HR] 4.57, creatinine: HR 4.53, blood-urea-nitrogen [BUN]: HR 2.50, estimated glomerular filtration rate [eGFR]: HR 0.10). In receiver-operating-characteristic (ROC) analysis, uromodulin predicted GL with an area-under-the curve of 0.782 at an optimal cut-off (OCO) of 24.0 ng/ml with a sensitivity of 90.0% and a specificity of 70.2%. CONCLUSION: Serum uromodulin predicted GL equivalently compared to conventional biomarkers of glomerular filtration.