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Ropivacaine Causes Inflammation and Apoptosis in Human Umbilical Vein Endothelial and Placental Cells
Abstract Number: T4B-6
Abstract Type: Original Research
Epidural analgesia is a common procedure for analgesia during labor and delivery. Up to 20% of women receiving epidural analgesia experience epidural-related maternal fever (ERMF) – which may be caused by sterile inflammation triggered by local anesthetics. Importantly, intrapartum maternal fever is associated with increased perinatal mortality and neonatal morbidity (1). This study aims to investigate the dose-dependent effects of ropivacaine on inflammation and cytotoxicity in human umbilical vein endothelial (HUVECs) and in human placental cells (HPCs).
Therefore, isolated HUVECs and HPCs were incubated for 1, 4, and 24 hours, with increasing concentrations of ropivacaine from 0.001 to 0.1% (intervention group) with or without the addition of dexamethasone, or with an equal volume of 0.9% NaCl (control group). Cells health and morphology was assessed by phase-contrast microscopy. Apoptosis and cytotoxicity was detected by flow cytometry and by lactate dehydrogenase (LDH) release. Pro-inflammatory mediators (IL-6, IL-8, PGE2) in the supernatant were measured by ELISA, while activation/deactivation of signaling pathways was detected by Western blotting. Additionally, live cell imaging was used to detect reactive oxygen species (ROS).
Compared to controls, our results showed that ropivacaine exposure causes apoptosis and cell cytotoxicity in HUVECs (p<0.01). In the intervention groups significantly increased IL-6 and PGE2 concentrations were found in HUVECs (p<0.01), while in HPCs IL-6 and IL-8 was significantly increased (p<0.01). Western blotting could identify that caspase-3, NFκB and p38 MAP-kinase pathways have been activated. Interestingly, we found a transient dephosphorylation of ERK and a more persistent dephosphorylation of Akt – indicating a deactivation of these “survival kinases” in presence of an increased ROS production. Moreover, we found that the above mentioned effects could be reversed by dexamethasone (i.e., significant reduction of apoptosis, LDH, IL-6 and PGE2; all p<0.01).
These results are in-line with the known evidence that local anesthetics can disrupt the respiratory chain in mitochondria (2). Ropivacaine seems to induce ROS release through dysfunctional mitochondria – thus contributing to sterile inflammation and cellular apoptosis via the intrinsic apoptotic pathway. These mechanisms result in release of LDH and pro-inflammatory mediators that play a key role in the development of fever. Although these concepts warrant further studies in patients, the observed involvement of ROS in this context prospects for potential future therapeutic concepts.
1 Greenwell et al., 2012, Intrapartum temperature elevation, epidural use, and adverse outcome in term infants. – Pediatrics
2 Cela et al., 2010, Bupivacaine uncouples the mitochondrial oxidative phosphorylation, inhibits respiratory chain complexes I and III and enhances ROS production: results of a study on cell cultures. – Mitochondrium