Volatile anaesthetics reduce neutrophil inflammatory response by interfering with CXC receptor-2 signalling.

BACKGROUND: Growing evidence suggests a protective effect of volatile anaesthetics in ischaemia-reperfusion (I/R)-injury, and the accumulation of neutrophils is a crucial event. Pro-inflammatory cytokines carrying the C-X-C-motif including interleukin-8 (IL-8) and CXC-ligand 1 (CXCL1) activate CXC receptor-1 (CXCR1; stimulated by IL-8), CXC receptor-2 (CXCR2; stimulated by IL-8 and CXCL1), or both to induce CD11b-dependent neutrophil transmigration. Inhibition of CXCR1, CXCR2, or both reduces I/R-injury by preventing neutrophil accumulation. We hypothesized that interference with CXCR1/CXCR2 signalling contributes to the well-established beneficial effect of volatile anaesthetics in I/R-injury. METHODS: Isolated human neutrophils were stimulated with IL-8 or CXCL1 and exposed to volatile anaesthetics (sevoflurane/desflurane). Neutrophil migration was assessed using an adapted Boyden chamber. Expression of CD11b, CXCR1, and CXCR2 was measured by flow cytometry. Blocking antibodies against CXCR1/CXCR2/CD11b and phorbol myristate acetate were used to investigate specific pathways. RESULTS: Volatile anaesthetics reduced CD11b-dependent neutrophil transmigration induced by IL-8 by >30% and CD11b expression by 18 and 27% with sevoflurane/desflurane, respectively. This effect was independent of CXCR1/CXCR2 expression and CXCR1/CXCR2 endocytosis. Inhibition of CXCR1 signalling did not affect downregulation of CD11b with volatile anaesthetics. Blocking of CXCR2-signalling neutralized effects by volatile anaesthetics on CD11b expression. Specific stimulation of CXCR2 with CXCL1 was sufficient to induce upregulation of CD11b, which was impaired with volatile anaesthetics. No effect of volatile anaesthetics was observed with direct stimulation of protein kinase C located downstream of CXCR1/CXCR2. CONCLUSION: Volatile anaesthetics attenuate neutrophil inflammatory responses elicited by CXC cytokines through interference with CXCR2 signalling. This might contribute to the beneficial effect of volatile anaesthetics in I/R-injury.

Dabigatran anticoagulation and Stanford type A aortic dissection: lethal coincidence: Case report with literature review.

BACKGROUND: Novel oral anticoagulants are now encountered in patients needing emergency surgery. Knowledge and treatment options are limited. METHODS AND RESULT: We present the case of a 76-year-old patient who suffered from an acute Stanford type A aortic dissection, needing emergency surgical aortic repair. He was anticoagulated with dabigatran due to past atrial fibrillation. Despite haemodiafiltration, surgical revision and massive transfusion of packed red blood cells, fresh frozen plasma, platelets, coagulation factors, and recombinant factor VIIa, the patient died from intractable bleeding with sustained therapeutic levels of dabigatran. CONCLUSION: After reviewing the literature, we summarize the limited treatment options and show possible approaches for patients treated with dabigatran needing emergency surgery.

In vitro exposure of human fibroblasts to local anaesthetics impairs cell growth.

Lidocaine, bupivacaine or ropivacaine are used routinely to manage perioperative pain. Sparse data exist evaluating the effects of local anaesthetics (LA) on fibroblasts, which are involved actively in wound healing. Therefore, we investigated the effects of the three LA to assess the survival, viability and proliferation rate of fibroblasts. Human fibroblasts were exposed to 0·3 mg/ml and 0·6 mg/ml of each LA for 2 days, followed by incubation with normal medium for another 1, 4 or 7 days (group 1). Alternatively, cells were incubated permanently with LA for 3, 6 or 9 days (group 2). Live cell count was assessed using trypan blue staining. Viability was measured by the tetrazolium bromide assay. Proliferation tests were performed with the help of the colorimetric bromodeoxyuridine assay. Production of reactive oxygen species (ROS) was determined, measuring the oxidation of non-fluorescent-2,7'-dichlorofluorescin. Treatment of cells with the three LA showed a concentration-dependent decrease of live cells, mitochondrial activity and proliferation rate. Group arrangement played a significant role for cell count and proliferation, while exposure time influenced viability. Among the analysed LA, bupivacaine showed the most severe cytotoxic effects. Increased production of ROS correlated with decreased viability of fibroblasts in lidocaine- and bupivacaine-exposed cells, but not upon stimulation with ropivacaine. This study shows a concentration-dependent cytotoxic effect of lidocaine, bupivacaine and ropivacaine on fibroblasts in vitro, with more pronounced effects after continuous incubation. A possible mechanism of cell impairment could be triggered by production of ROS upon stimulation with lidocaine and bupivacaine.

4-Amino-1,8-naphthalimide: a novel inhibitor of poly(ADP-ribose) polymerase and radiation sensitizer.

PURPOSE: Poly(ADP-ribose) polymerase (PARP; EC 2.4.2.30) is a chromatin-bound enzyme which is known to regulate chromatin structure by poly(ADP-ribosyl)ation of nuclear proteins, to facilitate DNA base excision repair, and to contribute to cellular recovery following DNA damage. Because inhibitors of PARP are able to potentiate the cell-killing effects of some DNA-damaging agents and to inhibit the repair of induced DNA strand breaks, such compounds may enhance the anti-tumour efficacy of radiotherapy or cytotoxic drug treatment. The PARP-inhibitory effects and radiosensitization of a new compound, 4-amino-1,8-naphthalimide (ANI), were examined. MATERIALS AND METHODS: The inhibition of radiation-induced poly(ADP-ribosyl)ation (50 Gy; 60Co gamma-radiation) was evaluated by immunofluorescence assay using MoAb 10H directed against poly(ADP-ribose). Cell survival was assessed by colony forming assay (CFA) to determine the cytotoxicity of radiosensitization potential in exponentially growing hamster lung fibroblasts (V79), rat prostate carcinoma (R3327-AT1) and human prostate carcinoma (DU145) cells. RESULTS: At concentrations above 30 nmol x dm(-3) ANI, radiation-induced poly(ADP-ribose) was not detectable by immunofluorescence in V79, AT1 and DU145 cells. At the highest concentration tested for chronic exposure (20 micromol x dm(-3)), ANI was not cytotoxic and significantly potentiates the cytotoxicity of gamma-irradiation. The level of radiation enhancement was directly proportional to drug concentration. Survival curves for the three cell lines using 20 micromol x dm(-3) ANI revealed sensitizer enhancement ratios of 1.3 for V79, 1.5 for AT1 and 1.3 for DU145. CONCLUSIONS: In living cells, ANI is about 1000-fold more potent at inhibiting PARP activity compared with 3-aminobenzamide (3-ABA). CFA studies demonstrated that ANI is a radiation sensitizer at non-toxic and lower concentrations (20 micromol x dm(-3)) than 3-ABA (10 mmol x dm(-3)).

Neutral and ionic aluminum, gallium, and indium compounds carrying two or three terminal ethynyl groups.

The syntheses of the ionic compounds [Li(+).2 dioxane (2,6-iPr(2)C(6)H(3)N(SiMe(3))Al(C triplebond CSiMe(3))(3))(-)].0.75 dioxane (1), [(Li(+))(2).(dioxane)(7)](0.5) [2,6-iPr(2)C(6)H(3)N(SiMe(3))Ga(C triplebond CSiMe(3))(3)(-)].1.5 dioxane (2), and [(Li(+))(2).(dioxane)(7)](0.5) [2,6-iPr(2)C(6)H(3)N(SiMe(3))In(C triplebond CSiMe(3))(3)(-)].1.5 dioxane (3) by the reaction of the corresponding organo metal chloride with LiC triplebond CSiMe(3) are reported. The neutral ethynyl compounds Br-Al(C triplebond CtBu)(2).2 THF (4), Cl-Ga(C triplebond CtBu)(2).THF (5), Cl-In(C triplebond CtBu)(2).2 THF (6), Al(C triplebond CtBu)(3).C[N(Me)CMe](2) (7), Ga(C triplebond CtBu)(3).dioxane (8), and In(C triplebond CtBu)(3).NEt(3) (9) have been obtained in good yields from the reaction of AlBr(3), GaCl(3), and InCl(3) with LiC triplebond CtBu in the presence of a Lewis base. Compound 7 is the first heterocyclic carbene substituted ethynyl derivative. Aluminum and gallium compounds with three terminal ethynyl groups Al(C triplebond CPh)(3).NMe(3) (10) and Ga(C triplebond CPh)(3).NMe(3) (11) have been prepared by the reaction of AlH(3).NMe(3) or GaH(3).NMe(3) with three equivalents of phenylethyne. All the above-mentioned compounds have been structurally studied. In compound 1 the lithium ion is coordinated to the three terminal ethynyl groups, whereas in compounds 2 and 3 the lithium is coordinated to the solvent (dioxane). Compound 8 crystallizes as a coordination polymer with dioxane molecules bridging the individual gallium units.