RESUMEN
Delayed gastric emptying symptoms are often reported after chemotherapy. This study aims to characterise the effects of chemotherapy on gastric neuro-muscular function. Patients undergoing elective surgery for oesophago-gastric cancer were recruited. Acetylcholinesterase, nNOS, ghrelin receptor and motilin expressions were studied in gastric sections from patients receiving no chemotherapy (n = 3) or oesophageal (n = 2) or gastric (n = 2) chemotherapy. A scoring system quantified staining intensity (0-3; no staining to strong). Stomach sections were separately suspended in tissue baths for electrical field stimulation (EFS) and exposure to erythromycin or carbachol; three patients had no chemotherapy; four completed cisplatin-based chemotherapy within 6 weeks prior to surgery. AChE expression was markedly decreased after chemotherapy (scores 2.3 ± 0.7, 0.5 ± 0.2 and 0 ± 0 in non-chemotherapy, oesophageal- and gastric-chemotherapy groups (p < 0.03 each) respectively. Ghrelin receptor and motilin expression tended to increase (ghrelin: 0.7 ± 0.4 vs 2.0 ± 0.4 and 1.2 ± 0.2 respectively; p = 0.04 and p = 0.2; motilin: 0.7 ± 0.5 vs 2.2 ± 0.5 and 2.0 ± 0.7; p = 0.06 and p = 0.16). Maximal contraction to carbachol was 3.7 ± 0.7 g and 1.9 ± 0.8 g (longitudinal muscle) and 3.4 ± 0.4 g and 1.6 ± 0.6 (circular) in non-chemotherapy and chemotherapy tissues respectively (p < 0.05 each). There were loss of AChE and reduction in contractility to carbachol. The tendency for ghrelin receptors to increase suggests an attempt to upregulate compensating systems. Our study offers a mechanism by which chemotherapy markedly alters neuro-muscular gastric function.
Asunto(s)
Adenocarcinoma/fisiopatología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias Esofágicas/fisiopatología , Músculo Liso/inervación , Neoplasias Gástricas/fisiopatología , Estómago/fisiopatología , Acetilcolinesterasa/metabolismo , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/metabolismo , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Capecitabina , Carbacol/farmacología , Quimioterapia Adyuvante , Agonistas Colinérgicos/farmacología , Cisplatino/administración & dosificación , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Epirrubicina/administración & dosificación , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/metabolismo , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/análogos & derivados , Ganglios Autónomos/patología , Vaciamiento Gástrico/efectos de los fármacos , Mucosa Gástrica/metabolismo , Humanos , Técnicas In Vitro , Masculino , Persona de Mediana Edad , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Músculo Liso/patología , Terapia Neoadyuvante , Estómago/efectos de los fármacos , Estómago/patología , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/metabolismoRESUMEN
Ghrelin, an orexigenic hormone of gastric origin that stimulates growth hormone secretion, may modulate inflammation. This experimental study examines the effect of ghrelin on NFκB (p65 subunit), a transcriptional factor involved in inflammation on a human B-lymphocyte cell (WILCL). After confirming the expression of ghrelin receptor protein using western blotting the cells were transferred to wells maintaining a density of 1 × 10(6) cells per ml and a proportion activated with phytohaemagluttinin. Activated and resting cells were exposed to octanoyl-, desoctanoyl ghrelin and a non-peptide ghrelin agonist (Pfizer CP-464709) in increasing concentrations for 6 h. Cell protein extracts were analyzed for NFκB activation using Trans AM NFκB p65 assay. IL-6, IL-8, IL-10, IL-13 and TNFα were measured in the media using Lincoplex human cytokine assay. In octanoyl ghrelin treated resting cells, NFκB activity (Optical Density OD(450 nm)) (mean ± SEM) in control cells was 0.42 ± 0.10 and increased to 0.61 ± 0.20 (P = 0.044), 0.54 ± 0.10 (P = 0.043), 0.52 ± 0.08 at 1, 10 and 100 nM concentrations respectively. No effect was detected with desoctanoyl ghrelin or ghrelin agonist and no specific change in cytokine production. In conclusion, Octanoyl ghrelin increased NFκB activation by up to 50% in a B-lymphocyte cell line suggesting an effect on the inflammatory process.
Asunto(s)
Linfocitos B/efectos de los fármacos , Linfocitos B/metabolismo , Ghrelina/farmacología , FN-kappa B/metabolismo , Western Blotting , Línea Celular , Medios de Cultivo/farmacología , Citocinas/metabolismo , Humanos , Activación de Linfocitos/efectos de los fármacos , Receptores de Ghrelina/agonistas , Receptores de Ghrelina/metabolismoRESUMEN
BACKGROUND: Ghrelin, a potent orexigenic peptide produced by the stomach, may be affected by circulating inflammatory mediators. AIM: To assess the effect of an anti-TNFα antibody on ghrelin in patients with Crohn's disease (CD). METHODS: Fifteen patients with Crohn's receiving infliximab were studied before and 1 week after infusion. Following an overnight fast, blood was sampled before a meal and then every 20 min for 2 h. Total ghrelin and CRP were measured using ELISA. Acylated ghrelin and TNFα, IFNγ, IL-1ß and IL-6 were measured with bioplex. Harvey Bradshaw Activity Index was assessed. RESULTS: Median (95% CI) 2-h integrated plasma total ghrelin increased from 162 (99-311) before infliximab to 200 (128-387) pg/mL h, (P = 0.02) after. Following infliximab, 20 min postmeal, median acylated ghrelin decreased from 50.3 (24-64) to 38.6 (26-82) pg/mL, (P = 0.04) thus reverting to a traditional meal related ghrelin curve. Median (range) disease activity decreased from 5 (2-28) before to 3 (0-22), (P = 0.0001) and Median (95% CI) TNFα decreased from 2.8 (1.89-4.48) to 1.31 (0.73-2.06) pg/mL (P = 0.002). CONCLUSIONS: Infliximab increases circulating total ghrelin by 25% in CD and restores the postprandial response of acylated ghrelin to food intake. Acylated and de-sacyl ghrelin remain unchanged, suggesting that an alternate isoform could be affected by infliximab.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Enfermedad de Crohn/tratamiento farmacológico , Fármacos Gastrointestinales/uso terapéutico , Ghrelina/sangre , Mediadores de Inflamación/uso terapéutico , Factor de Necrosis Tumoral alfa/uso terapéutico , Adulto , Anticuerpos Monoclonales/sangre , Enfermedad de Crohn/sangre , Ensayo de Inmunoadsorción Enzimática , Femenino , Fármacos Gastrointestinales/sangre , Humanos , Mediadores de Inflamación/sangre , Infliximab , Masculino , Persona de Mediana Edad , Factor de Necrosis Tumoral alfa/sangre , Adulto JovenRESUMEN
BACKGROUND AND PURPOSE: Lubiprostone (Amitiza), a possible ClC-2 channel opener derived from prostaglandin E(1) and indicated for the treatment of constipation, increases chloride ion transport and fluid secretion into the intestinal lumen. As lubiprostone may also directly modulate gastrointestinal motility, we investigated its actions and the possible involvement of prostaglandin EP receptor activation on rat and human isolated gastrointestinal preparations. EXPERIMENTAL APPROACH: Rat and human isolated preparations were mounted in tissue baths for isometric recording. The effects of lubiprostone on muscle tension and on electrically stimulated, neuronal contractions were investigated in the absence and presence of EP receptor antagonists. KEY RESULTS: In rat and human stomach longitudinal muscle, lubiprostone induced a contraction (pEC(50) of 7.0+/-0.0, n=4 and 6.4+/-0.2, n=3, respectively), which was inhibited by pretreatment with the EP(1) receptor antagonist, EP(1)A 300 nM (pEC(50) reduced to 6.2+/-0.2, n=6), but not by the EP(3) or EP(4) receptor antagonists (L-798106 and GW627368X, respectively, 1 microM, P>0.05). Lubiprostone also reduced electrically stimulated, neuronal contractions in rat and human colon circular muscle preparations (pIC(50) of 8.9+/-0.4, n=7 and 8.7+/-0.9, n=6, respectively), an effect mediated pre-junctionally. This effect was reduced by the EP(4) receptor antagonist (pIC(50) of 6.7+/-1.1, n=7 and 7.7+/-0.4, n=6, respectively) but not by EP(1) or EP(3) receptor antagonists. CONCLUSIONS AND IMPLICATIONS: In rats and humans, lubiprostone contracts stomach longitudinal muscle and inhibits neuronally mediated contractions of colon circular muscle. Experiments are now needed to determine if this additional activity of lubiprostone contributes to its clinical efficacy and/or side-effect profile.