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1.
Br J Surg ; 102(12): 1506-16, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26313905

RESUMEN

BACKGROUND: The pathophysiology of adhesion formation after abdominal and pelvic surgery is still largely unknown. The aim of the study was to investigate the role of macrophage polarization and the effect of peroxisome proliferator-activated receptor (PPAR) γ stimulation on adhesion formation in an animal model. METHODS: Peritoneal adhesion formation was induced by the creation of ischaemic buttons within the peritoneal wall and the formation of a colonic anastomosis in wild-type, interleukin (IL) 10-deficient (IL-10(-/-) ), IL-4-deficient (IL-4(-/-) ) and CD11b-Cre/PPARγ(fl) (/fl) mice. Adhesions were assessed at regular intervals, and cell preparations were isolated from ischaemic buttons and normal peritoneum. These samples were analysed for macrophage differentiation and its markers, and expression of cytokines by quantitative PCR, fluorescence microscopy, arginase activity and pathological examination. Some animals underwent pioglitazone (PPAR-γ agonist) or vehicle treatment to inhibit adhesion formation. Anastomotic healing was evaluated by bursting pressure measurement and collagen gene expression. RESULTS: Macrophage M2 marker expression and arginase activity were raised in buttons without adhesions compared with buttons with adhesions. IL-4(-/-) and IL-10(-/-) mice were not affected, whereas CD11b-Cre/PPARγ(fl) (/fl) mice showed decreased arginase activity and increased adhesion formation. Perioperative pioglitazone treatment increased arginase activity and decreased adhesion formation in wild-type but not CD11b-Cre/PPARγ(fl) (/fl) mice. Pioglitazone had no effect on anastomotic healing. CONCLUSION: Endogenous macrophage-specific PPAR-γ signalling affected arginase activity and macrophage polarization, and counter-regulated peritoneal adhesion manifestation. Pharmacological PPAR-γ agonism induced a shift towards macrophage M2 polarization and ameliorated adhesion formation in a macrophage-dependent manner. Surgical relevance Postoperative adhesion formation is frequently seen after abdominal surgery and occurs in response to peritoneal trauma. The pathogenesis is still unknown but includes an imbalance in fibrinolysis, collagen production and inflammatory mechanisms. Little is known about the role of macrophages during adhesion formation. In an experimental model, macrophage M2 marker expression was associated with reduced peritoneal adhesion formation and involved PPAR-γ-mediated arginase activity. Macrophage-specific PPAR-γ deficiency resulted in reduced arginase activity and aggravated adhesion formation. Pioglitazone, a PPAR-γ agonist, induced M2 polarization and reduced postoperative adhesion formation without compromising anastomotic healing in mice. Pioglitazone ameliorated postoperative adhesion formation without compromising intestinal wound healing. Therefore, perioperative PPAR-γ agonism might be a promising strategy for prevention of adhesion formation after abdominal surgery.


Asunto(s)
Regulación de la Expresión Génica , Macrófagos Peritoneales/metabolismo , PPAR gamma/genética , Enfermedades Peritoneales/genética , ARN/genética , Animales , Células Cultivadas , Modelos Animales de Enfermedad , Laparotomía/efectos adversos , Macrófagos Peritoneales/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Microscopía Fluorescente , PPAR gamma/biosíntesis , Enfermedades Peritoneales/etiología , Enfermedades Peritoneales/metabolismo , Reacción en Cadena de la Polimerasa , Transducción de Señal , Adherencias Tisulares/genética , Adherencias Tisulares/metabolismo , Adherencias Tisulares/patología
2.
Neurogastroenterol Motil ; 27(7): 1038-49, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25929169

RESUMEN

BACKGROUND: Abdominal surgery results in neuronal mediator release and subsequent acute intestinal hypomotility. This phase is followed by a longer lasting inflammatory phase resulting in postoperative ileus (POI). Calcitonin gene-related peptide (CGRP) has been shown to induce motility disturbances and in addition may be a candidate mediator to elicit neurogenic inflammation. We hypothesized that CGRP contributes to intestinal inflammation and POI. METHODS: The effect of CGRP in POI was tested in mice treated with the highly specific CGRP receptor antagonist BIBN4096BS and in CGRP receptor-deficient (RAMP-1(-/-) ) mice. POI severity was analyzed by cytokine expression, muscular inflammation and gastrointestinal (GI) transit. Peritoneal and muscularis macrophages and mast cells were analyzed for CGRP receptor expression and functional response to CGRP stimulation. KEY RESULTS: Intestinal manipulation (IM) resulted in CGRP release from myenteric nerves, and a concurrent increased interleukin (IL)-6 and IL-1ß transcription and leukocyte infiltration in the muscularis externa and increased GI transit time. CGRP potentiates IM-induced cytokine transcription within the muscularis externa and peritoneal macrophages. BIBN4096BS reduced cytokine levels and leukocyte infiltration and normalized GI transit. RAMP1(-/-) mice showed a significantly reduced leukocyte influx. CGRP receptor was expressed in muscularis and peritoneal macrophages but not mast cells. CGRP mediated macrophage activation but failed to induce mast cell degranulation and cytokine expression. CONCLUSIONS & INFERENCES: CGRP is immediately released during abdominal surgery and induces a neurogenic inflammation via activation of abdominal macrophages. BIBN4096BS prevented IM-induced inflammation and restored GI motility. These findings suggest that CGRP receptor antagonism could be instrumental in the prevention of POI.


Asunto(s)
Ileus/prevención & control , Inflamación/tratamiento farmacológico , Intestinos/efectos de los fármacos , Laparotomía/efectos adversos , Piperazinas/uso terapéutico , Quinazolinas/uso terapéutico , Receptores de Péptido Relacionado con el Gen de Calcitonina/metabolismo , Animales , Tránsito Gastrointestinal/efectos de los fármacos , Ileus/etiología , Ileus/metabolismo , Inflamación/metabolismo , Inflamación/patología , Intestinos/patología , Ratones , Ratones Noqueados , Músculo Liso/efectos de los fármacos , Piperazinas/farmacología , Periodo Posoperatorio , Quinazolinas/farmacología
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