Targeted inhibition of IL-18 attenuates irinotecan-induced intestinal mucositis in mice.

BACKGROUND AND PURPOSE: Intestinal mucositis is a common side-effect of irinotecan-based cancer chemotherapy regimens. This mucositis is associated with cytokine activation and NO synthesis. Production of IL-18 is up-regulated in patients suffering from inflammatory bowel disease. Therefore, we have investigated the role of IL-18 in the pathogenesis of irinotecan-induced intestinal mucositis. EXPERIMENTAL APPROACH: Wild type (WT), IL-18 or caspase-1 knockout mice were treated with either saline or irinotecan (60 mg·kg⁻¹ per 4 days, i.p.) or the IL-18 binding protein (IL-18bp, 10 mg·kg⁻¹) before irinotecan. On day 5, diarrhoea was monitored and proximal intestinal strips were obtained for histopathology, in vitro gut contractility, myeloperoxidase (MPO) and inducible NOS (iNOS) activity, and detection of IL-18 expression. KEY RESULTS: Irinotecan induced severe diarrhoea accompanied by intestinal injury (villi shortening and increased crypt depth). Additionally, irinotecan treatment increased MPO and iNOS activity, iNOS immunostaining and IL-18 expression in WT mice compared with saline treatment. The IL-18 production was associated with macrophages. In vitro, intestinal smooth muscle strips were hyperresponsive to ACh after irinotecan treatment. Increases in MPO and iNOS activity, intestinal contractility and diarrhoea were prevented in caspase-1 knockout and IL-18 knockout mice, and in IL-18bp-treated WT mice. Furthermore, the Survival of irinotecan-treated mice was increased and iNOS immunoexpression and IL-18 production prevented in IL-18 knockout mice. CONCLUSIONS AND IMPLICATIONS: Targeting IL-18 function may be a promising therapeutic approach to decreasing the severity of intestinal mucositis during irinotecan treatment regimens.

[Pregnancy and adolescence]. / Gravidez e adolescencia.

PIP: The objective of this study was to verify the occurrence of pregnancy complications in adolescents and neonatal complications in their children. From 1980-1983, 88 pregnant adolescents under 16 years of age were treated at the Hospital das Clinicas of UFMG, Belo Horizonte, Brazil. The patients ranged in age from 13 to 16 years. There was an increased incidence of pregnancy complications in this group when compared to the incidence of complications presented by 552 patients over 17 years of age. The high percentage of unmarried adolescents indicates that a large number of their pregnancies were unplanned. There was a significant increase in the incidence of pre-eclampsia, urinary infection, and anemia in the group of pregnant adolescents. An increase in perinatal morbidity or mortality was not observed. Because of the obstetric problems detected, all pregnant adolescents should receive special attention in the prenatal period and during parturition.^ieng