Histones of Neutrophil Extracellular Traps Directly Disrupt the Permeability and Integrity of the Intestinal Epithelial Barrier.

BACKGROUND: Increased neutrophil extracellular trap (NET) formation and abundant NET-associated proteins are frequently found in the inflamed colon of patients with inflammatory bowel disease. Peptidyl arginine deiminase 4 (PAD4) activation is essential for the generation of NET and NET-mediated pathogenesis. However, the role of PAD4-dependent NET formation in murine inflammatory bowel disease models and the molecular mechanisms responsible for the altered gut barrier function are unknown. METHODS: Wild-type and Pad4 knockout (Pad4-/-) mice were administrated 3% dextran sulfate sodium (DSS) in their drinking water. Caco-2 monolayers were used to test the effect of NETs on intestinal barrier function and cytotoxicity. Histones were intrarectally administrated to wild-type mice to determine their effects on intestinal barrier function and cytotoxicity in vivo. RESULTS: PAD4 deficiency reduced the severity of DSS-induced colitis with decreased intestinal NET formation and enhanced gut barrier function and integrity in mice. NETs disrupted the barrier function in intestinal epithelial Caco-2 monolayers through their protein, rather than DNA, components. Pretreatment of NETs with histone inhibitors abrogated the effects on epithelial permeability. Consistent with these observations, adding purified histone proteins to Caco-2 monolayers significantly damaged epithelial barrier function, which was associated with the abnormal distribution and integrity of tight junctions as well as with increased cell death. Furthermore, intrarectal administration of histones damaged the intestinal barrier integrity and induced cytotoxicity in the mouse colon epithelium. CONCLUSIONS: PAD4-mediated NET formation has a detrimental role in acute colitis. NET-associated histones directly inhibit intestinal barrier function, resulting in cytotoxicity in vitro and in vivo.

Peptidyl arginine deiminase 4­dependent neutrophil extracellular trap formation is detrimental to intestinal barrier function in acute colitis. Neutrophil extracellular trap­associated histones altered the integrity of tight junction and adherens junction proteins as well as induced intestinal epithelial cell death that resulted in increased gut epithelium permeability.

Sociodemographic Factors Associated with Request for Labor Epidural Analgesia in a Tertiary Obstetric Hospital in Vietnam.

This study is aimed at examining the sociodemographic factors associated with the utilization of labor epidural analgesia at a large obstetric and gynecology hospital in Vietnam. This was a cross-sectional study of women who underwent vaginal delivery in September 2018 at the Hanoi Obstetrics and Gynecology Hospital. The utilization of epidural analgesia during labor was determined. Univariate and multivariate regression models were applied to evaluate the association between patient demographic and socioeconomic factors and request for labor epidural analgesia. A total of 417 women had vaginal deliveries during the study period. 207 women utilized epidural analgesia for pain relief during labor, and 210 did not. Parturients older than 35 years of age (OR 2.84, 95% CI 1.11-8.17), multiparous women (OR 2.8 95% CI 1.85-4.25), women living from an urban area, women with higher income (OR 6.47, 95% CI 2.59-19.23), and women with higher level of education were more likely to utilize labor epidurals. Factors related to a parturient request for epidural analgesia during labor at our tertiary obstetric hospital included age greater than 35 years, multiparity, and high income and education levels. Educational outreach to women about the benefits of epidural analgesia can target women who do not share these demographic characteristics.