Tissular growth factors profile after teduglutide administration on an animal model of intestinal anastomosis.

BACKGROUND: Teduglutide is an enterotrophic analogue of glucagon-like peptide-2, with an indirect and poorly understood mechanism of action, approved for the rehabilitation of short-bowel syndrome. This study aims to analyze the response of tissue growth factors to surgical injury and teduglutide administration on an animal model of intestinal anastomosis. METHODS: Wistar rats (n = 59) were distributed into four groups: "ileal resection" or "laparotomy", each one subdivided into "postoperative teduglutide administration" or "no treatment"; and sacrificed at the third or the seventh day, with ileal sample harvesting. Gene expression of insulin-like growth factor 1 (Igf1), vascular endothelial growth factor a (Vegfa), transforming growth factor ß1 (Tgfß1), connective tissue growth factor (Ctgf), fibroblast growth factor 2 (Fgf2), fibroblast growth factor 7 (Fgf7), epidermal growth factor (Egf), heparin-binding epidermal-like growth factor (Hbegf), platelet-derived growth factor b (Pdgfb) and glucagon-like peptide 2 receptor (Glp2r)was studied by real-time polymerase chain reaction. RESULTS: Upregulation of Fgf7, Fgf2, Egf, Vegfaand Glp2rat the third day and of Pdgfat the seventh day was verified in the perianastomotic segment. Teduglutide administration was associated with higher fold-change of relative gene expression of Vegfa(3.6 ± 1.3 vs.1.9 ± 2.0, p = 0.0001), Hbegf(2.2 ± 2.3 vs. 1.1 ± 0.9, p = 0.001), Igf1(1.6 ± 7.6 vs. 0.9 ± 0.7, p = 0.002) and Ctgf(1.1 ± 2.1 vs. 0.6 ± 2.0, p = 0.013); and lower fold-change of Tgfß1, Fgf7and Glp2r. CONCLUSIONS: Those results underscore the recognized role of Igf1and Hbegfas molecular mediators of the effects of teduglutide and suggest that other humoral factors, like Vegfand Ctgf, may also be relevant in the perioperative context. Induction of Vegfa, Igf1and Ctgfgene expressions might indicate a favorable influence of teduglutide on the intestinal anastomotic healing.

Tissular growth factors profile after teduglutide administration on an animal model of intestinal anastomosis / Perfil tisular de factores de crecimiento postadministración de teduglutida en un modelo animal de anastomosis intestinal

Background: Teduglutide is an enterotrophic analogue of glucagon-like peptide-2, with an indirect and poorly understood mechanism of action, approved for the rehabilitation of short-bowel syndrome. This study aims to analyze the response of tissue growth factors to surgical injury and teduglutide administration on an animal model of intestinal anastomosis. Methods: Wistar rats (n = 59) were distributed into four groups: "ileal resection" or "laparotomy", each one subdivided into "postoperative teduglutide administration" or "no treatment"; and sacrificed at the third or the seventh day, with ileal sample harvesting. Gene expression of insulin-like growth factor 1 (Igf1), vascular endothelial growth factor a (Vegfa), transforming growth factor β1 (Tgfβ1), connective tissue growth factor (Ctgf), fibroblast growth factor 2 (Fgf2), fibroblast growth factor 7 (Fgf7), epidermal growth factor (Egf), heparin-binding epidermal-like growth factor (Hbegf), platelet-derived growth factor b (Pdgfb) and glucagon-like peptide 2 receptor (Glp2r)was studied by real-time polymerase chain reaction. Results: Upregulation of Fgf7, Fgf2, Egf, Vegfaand Glp2rat the third day and of Pdgfat the seventh day was verified in the perianastomotic segment. Teduglutide administration was associated with higher fold-change of relative gene expression of Vegfa (3.6 ± 1.3 vs.1.9 ± 2.0, p = 0.0001), Hbegf (2.2 ± 2.3 vs. 1.1 ± 0.9, p = 0.001), Igf1 (1.6 ± 7.6 vs. 0.9 ± 0.7, p = 0.002) and Ctgf (1.1 ± 2.1 vs. 0.6 ± 2.0, p = 0.013); and lower fold-change of Tgfβ1, Fgf7and Glp2r. Conclusions: Those results underscore the recognized role of Igf1and Hbegfas molecular mediators of the effects of teduglutide and suggest that other humoral factors, like Vegfand Ctgf, may also be relevant in the perioperative context. Induction of Vegfa, Igf1and Ctgfgene expressions might indicate a favorable influence of teduglutide on the intestinal anastomotic healing (AU)

Introducción: teduglutida es un análogo intestinotrofico do peptido-2 similar al glucagon, con un mecanismo de acción indirecto y poco conocido, aprobado para la rehabilitación del síndrome de intestino corto. Este estudio propone analizar la respuesta de los factores de crecimiento tisulares a la agresión quirúrgica y a la administración de teduglutida en un modelo animal de anastomosis intestinal. Métodos: ratones Wistar (n = 59) fueron distribuidos en cuatro grupos: "resección ileal" o "laparotomia", cada uno subdividido en "administración post-operatoria de teduglutida" o "sin tratamiento"; y sacrificados en el tercero o el séptimo dia, con recogida de muestras ileales. La expresión genica de Igf1, Vegfa, Tgfβ1, Ctgf, Fgf2, Fgf7, Egf, Hbegf, Pdgfb y Glp2r fue analizada por qRT-PCR. Resultados: en el segmento perianastomotico se verifico una sobrerregulacion de Fgf7, Fgf2, Egf, Vegfa y Glp2r al tercer dia y de Pdg al séptimo día. La administración de teduglutida se asoció con mayor cambio de la expresión génica relativa de Vegfa (3.6 ± 1.3 vs. 1.9 ± 2.0, p = 0.0001), Hbegf (2.2 ± 2.3 vs. 1.1 ± 0.9, p = 0.001), Igf1 (1.6 ± 7.6 vs. 0.9 ± 0.7, p = 0.002) y Ctgf (1.1 ± 2.1 vs. 0.6 ± 2.0, p = 0.013); y menor cambio de Tgfβ1, Fgf7 y Glp2r. Conclusiones: estos resultados refuerzan el reconocido papel de Igf1 y Hbegf como mediadores moleculares de los efectos de la teduglutida y sugieren que otros factores humorales, como Vegf y Ctgf, también pueden ser relevantes en el contexto perioperatorio. La inducción de las expresiones de los genes Vegfa, Igf1 y Ctgf podría indicar una influencia favorable de teduglutida en la cicatrización anastomotica intestinal (AU)

Glutaminemia prognostic significance in critical surgical patients - An analysis of plasma aminogram profile.

BACKGROUND: Glutamine depletion is common in the critically-ill patients. Glutaminemia lower than 420 µmol/l has been considered as an independent predictive factor of mortality, but the indications for exogenous glutamine supplementation remain controversial. This study intends to determine the glutaminemia profile in critical surgical patients and to investigate its correlation with the severity indexes and the prognosis. METHODS: A prospective study of 28 adult critical surgical patients was performed. Plasma amino acid concentrations were quantified, by ion exchange chromatography, at the moment of admission and at the first and third days, and compared with those of 11 reference healthy individuals. Severity indexes and parameters of prognosis were registered. RESULTS: In critical surgical patients, mean glutaminemia at admission was lower than that of control individuals (385.1 ± 123.1 versus515 ± 57.9 µmol/l, p = 0.002) and decreased until the third day (p = 0.042). Prevalence of severe hypoglutaminemia (< 420 µmol/l) at admission was 64.3%. Baseline glutaminemia correlated with the Simplified Acute Physiology Score II (SAPS II score) (Pearson's correlation coefficient r = -39.4%, p = 0.042), and it was lower in cases of erythrocytes transfusion (339.9 ± 78.8 versus 454.9 ± 148.8 µmol/l, p = 0.013). Glutaminemia at the third day correlated with the duration of invasive ventilation support (r = -65%, p = 0 .012) and ICU stay (r = -66.5%, p = 0.009). Glutaminemia below 320 µmol/l, observed in 25% of the patients, was associated with higher in-hospital mortality (42.9 versus19%, statistically not significant [n.s.]) and lower actuarial survival (212.1 ± 77.9 versus 262.3 ± 32.4 days, n.s.). CONCLUSIONS: Those results underscore the relevance of hypoglutaminemia as an adverse predictive factor in the critical surgical patients. Determination of glutaminemia may contribute to a better definition of the indications for glutamine supplementation.

Intestinal inflammatory and redox responses to the perioperative administration of teduglutide in rats.

PURPOSE:: To investigate the inflammatory and redox responses to teduglutide on an animal model of laparotomy and intestinal anastomosis. METHODS:: Wistar rats (n=62) were allocated into four groups: "Ileal Resection and Anastomosis" vs. "Laparotomy", each one split into "Postoperative Teduglutide Administration" vs. "No Treatment"; and euthanized at the third or the seventh day. Ileal and blood samples were recovered at the baseline and at the euthanasia. Flow cytometry was used to study the inflammatory response (IL-1α, MCP-1, TNF-α, IFN-γ and IL-4 levels), oxidative stress (cytosolic peroxides, mitochondrial reactive species, intracellular glutathione and mitochondrial membrane potential) and cellular viability and death (annexin V/propidium iodide double staining). RESULTS:: Postoperative teduglutide treatment was associated with higher cellular viability index and lower early apoptosis ratio at the seventh day; higher cytosolic peroxides level at the third day and mitochondrial overgeneration of reactive species at the seventh day; higher tissue concentration of IL-4 and lower local pro-to-anti-inflammatory cytokines ratio at the seventh day. CONCLUSION:: Those findings suggest an intestinal pro-oxidative and anti-inflammatory influence of teduglutide on the peri-operative context with a potential interference in the intestinal anastomotic healing.

Intestinal inflammatory and redox responses to the perioperative administration of teduglutide in rats

Abstract Purpose: To investigate the inflammatory and redox responses to teduglutide on an animal model of laparotomy and intestinal anastomosis. Methods: Wistar rats (n=62) were allocated into four groups: "Ileal Resection and Anastomosis" vs. "Laparotomy", each one split into "Postoperative Teduglutide Administration" vs. "No Treatment"; and euthanized at the third or the seventh day. Ileal and blood samples were recovered at the baseline and at the euthanasia. Flow cytometry was used to study the inflammatory response (IL-1α, MCP-1, TNF-α, IFN-γ and IL-4 levels), oxidative stress (cytosolic peroxides, mitochondrial reactive species, intracellular glutathione and mitochondrial membrane potential) and cellular viability and death (annexin V/propidium iodide double staining). Results: Postoperative teduglutide treatment was associated with higher cellular viability index and lower early apoptosis ratio at the seventh day; higher cytosolic peroxides level at the third day and mitochondrial overgeneration of reactive species at the seventh day; higher tissue concentration of IL-4 and lower local pro-to-anti-inflammatory cytokines ratio at the seventh day. Conclusion: Those findings suggest an intestinal pro-oxidative and anti-inflammatory influence of teduglutide on the peri-operative context with a potential interference in the intestinal anastomotic healing.

Intestinal dysfunction in the critical trauma patients - An early and frequent event.

BACKGROUND: Small-bowel dysfunction exerts a relevant prognostic impact in the critically ill patients. Citrullinemia has been used in the evaluation of the intestinal function and it is considered an objective parameter of the functional enterocyte mass. Present study proposes to determine the intestinal dysfunction prevalence and the citrullinemia kinetic profile in severe trauma patients and to investigate its correlation with severity indicators and clinical outcome. METHODS: A prospective study including 23 critical trauma patients was performed. Aminoacidemias were quantified, by ion exchange chromatography, at the admission and at the first and third days. Severity and outcome parameters were registered. RESULTS: In severe trauma patients, severe hypocitrullinemia (< 20 µmol/L) prevalence at admission was high (69.6%) and mean citrullinemia was low (19.5 ± 11.1 µmol/L). Baseline citrullinemia was inversely and significantly correlated with shock index (r = -55.1%, p = 0.008) and extent of invasive ventilation support (r = -42.7%, p = 0.042). Citrullinemia < 13.7 µmol/L at admission, observed in 17.4% of patients, was associated with higher shock index (1.27 ± 0.10 versus 0.75 ± 0.18, p = 0.0001) and longer duration of invasive ventilation support (20.3 ± 7 versus 11.2 ± 7.1 days, p = 0.029) and intensive care unit stay (22 ± 5.9 versus 12.2 ± 8.8 days, p = 0.048). A citrullinemia decrease in the first day after admittance superior to 12.7% constituted a significant predictive factor of in-hospital mortality (75 versus 14.3%, p = 0.044; odds ratio = 7.8; accuracy = 65.2%; specificity = 92.3%; negative predictive value = 85.7%] and lower actuarial survival (69.8 ± 41.6 versus 278.1 ± 37.4 days, p = 0.034). CONCLUSIONS: Those results confirm the high prevalence and the prognostic relevance of hypocitrullinemia, considered a biomarker of enterocyte dysfunction, in severe trauma patients.