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.

Bothrops jararacussu snake venom-induces a local inflammatory response in a prostanoid- and neutrophil-dependent manner.

Local tissue reactions provoked by Bothrops venoms are characterized by edema, hemorrhage, pain, and inflammation; however, the mechanisms of tissue damage vary depending upon the species of snake. Here, we investigated the mechanisms involved in the local inflammatory response induced by the Bothrops jararacussu venom (BjcuV). Female Swiss mice were injected with either saline, BjcuV (0.125-8 µg/paw) or loratadine (an H1 receptor antagonist), compound 48/80 (for mast cell depletion), capsaicin (for C-fiber desensitization), infliximab (an anti-TNF-α antibody), indomethacin (a non-specific COX inhibitor), celecoxib (a selective COX-2 inhibitor) or fucoidan (a P- and L-selectins modulator) given before BjcuV injection. Paw edema was measured by plethysmography. In addition, paw tissues were collected for the measurement of myeloperoxidase activity, TNF-α and IL-1 levels, and COX-2 immunoexpression. The direct chemotactic effect of BjcuV and the in vitro calcium dynamic in neutrophils were also investigated. BjcuV caused an edematogenic response with increased local production of TNF-α and IL-1ß as well as COX-2 expression. Both edema and neutrophil migration were prevented by pretreatment with indomethacin, celecoxib or fucoidan. Furthermore, BjcuV induced a direct in vitro neutrophil chemotaxis by increasing intracellular calcium. Therefore, BjcuV induces an early onset edema dependent upon prostanoid production and neutrophil migration.

Dimensions of the cranium and of the cranial cavity andintracranial volume in goats (Capra hircus LINNAEUS, 1758)

The aim of this project is to determine the dimensions of the cranium and the cranial cavity and the intracranialvolume in goats, using 64 adults. The dimensions of the cranium and cranial cavity were measured throughmetric tape and paquimeter, considering the intervals of the largest distances. To determine the intracranialvolume, balloons of latex were introduced in the cranial cavity, through the magnum foramen, later on, filledwith water that was transferred for graduate test tube. The average and the standard deviation of length, widthand height of the cranium, in millimeters, were respectively: 218.01 ± 6.96, 120.17 ± 10.01 and 108.14 ± 4.46.The average and the standard deviation of length, width, height, in millimeters, and of the volume of thecranial cavity, in cubic centimeters, were respectively: 109.31 ± 7.25, 61.36 ± 4.51, 63.85 ± 2.88 and119.31 ± 12.21. It was observed that, the width of the cranium possesses positive significant correlationswith the length (r = 0.6865), with the height (r = 0.5644) and with the intracranial volume (r = 0.5436).They were still established, positive significant correlations among the height of the cranial cavity, with thelength (r = 0.5682) and with the intracranial volume (r = 0.5473). Differences were evidenced between malesand females, in relation to the dimensions of the cranium and cranial cavity. There wasn’t difference of theintracranial volume in function of the sex of the goats.