RESUMO
Inflammation can interfere with endometrial receptivity. We examined how interleukin 1ß (IL-1ß) affects expression of the uterine gap junction protein connexin 43 (Cx43), which is known to be critical for embryonic implantation. We used an in vitro model of human endometrial stromal cells (ESCs), Western blotting, and a combination of validated, selective kinase inhibitors to evaluate five canonical IL-1ß signaling pathways. Cx43 and two other markers of ESC differentiation (prolactin and VEGF) were inhibited predominantly via IL-1ß-activated ERK1/2 and p38 MAP kinase cascades. The findings were corroborated using small interfering RNA to silence critical genes in either pathway. By contrast, upregulation of endogenous pro-IL-1α and pro-IL-1ß following recombinant IL-1ß treatment was mediated via the Jun N-terminal kinase pathway. The clinicopharmacological significance of our findings is that multiple signaling cascades may need to be neutralized to reverse deleterious effects of IL-1ß on human endometrial function.
Assuntos
Conexina 43/metabolismo , Interleucina-1beta/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Células Estromais/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Western Blotting , Células Cultivadas , Conexina 43/genética , Decídua/metabolismo , Endométrio/citologia , Feminino , Humanos , Interleucina-1beta/genética , Interleucina-1beta/farmacologia , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/genética , Interferência de RNA , Receptores de Interleucina-1/genética , Receptores de Interleucina-1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Células Estromais/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/genéticaRESUMO
BACKGROUND: It is unclear whether recognition of epidural catheter failures is delayed with combined spinal epidural technique (CSE) compared to traditional epidural technique (EPID) when used for labor analgesia. The authors hypothesized that recognition of failed catheters is not delayed by CSE. METHODS: Anesthetic, obstetric, and quality assurance records from 2,395 labor neuraxial procedures (1,440 CSE and 955 EPID) performed at Forsyth Medical Center (Winston-Salem, North Carolina) between June 30 and December 31, 2012, were retrospectively analyzed. The primary outcome was catheter survival (failure-free) time during labor analgesia. A proportional hazards model with the counting method was used to assess relationships between the techniques and survival (failure-free) time of catheters, while controlling for subjects' body mass index and providers' level of training in the final best-fit multivariable regression model. RESULTS: Cumulative incidence of epidural catheter failures was 6.6% for CSE and 11.6% for EPID (P = 0.001). In the multivariable regression model, catheters placed with CSE versus epidural were less likely to fail (hazard ratio, 0.58; 95% CI, 0.43 to 0.79; P = 0.0002) for labor analgesia. Among the catheters that failed, there was no overall difference in failure time course between the techniques (hazard ratio, 1.17; 95% CI, 0.89 to 1.54; P = 0.26) even though more failed catheters with CSE (48.4%) than with EPID (30.6%) were recognized within the first 30 min of placement (P = 0.009). CONCLUSIONS: In this cohort, CSE has a significantly lower risk of overall epidural catheter failures than EPID and does not delay recognition of epidural catheter failures. Choice of CSE versus EPID should be based on overall risk of failure, efficacy, and side effects.