Efecto protector de oleuropeina en inflamación intestinal

La colitis ulcerosa (CU) es un desorden inflamatorio intestinal crónico que se caracteriza por la inflamación recurrente del colon. Debido a su desconocida etiología, la búsqueda de nuevos tratamientos farmacológicos está enfocada a mejorar la calidad de vida de los pacientes y reducir la inflamación. Sin embargo, aún con un amplio espectro de medicamentos, un cierto porcentaje de pacientes son resistentes a estas terapias, y además, los efectos secundarios asociados son elevados y, algunos de ellos muy graves. A esto se le suma la aparición de cáncer colorectal asociado a colitis en un 25-40% de los pacientes, tras 40 años de enfermedad. En este sentido, la búsqueda en la medicina complementaria alternativa, en concreto en el uso de plantas medicinales y productos naturales, ha resurgido en los últimos años. Oleuropeina es un secoiridoide aislado de las hojas del olivo y los frutos verdes de Olea oleuropaea L. El efecto antiinflamatorio de oleuropeina se ha comprobado en numerosos modelos de inflamación y en la presente Tesis Doctoral, se evalúa el efecto protector de oleuropeina en inflamación intestinal. Tras llevar a cabo un modelo de colitis aguda inducida por dextrano sulfato sódico (DSS) al 5% en ratones Balb/C, la administración de 1% de oleuropeina en la dieta protege frente los signos cínicos de la inflamación, reduce la concentración en tejido de marcadores inflamatorios e inhibe la activación de distintas vías de señalización. Por otra parte, el incremento de la expresión génica de la proteína antiinflamatoria anexina A1, deja entrever un posible efecto sobre los mecanismos protectores endógenos. Además, en este mismo modelo, reduce la respuesta th17. En un modelo de colitis crónica inducida por 4 ciclos de DSS al 1-2% en ratones C57BL/6, se volvió a comprobar que oleuropeina, en este caso a 0,25% suplementada en la dieta, reduce la inflamación intestinal, inhibe la liberación y expresión de proteínas proinflamatorias, aumenta la expresión de anexina A1, reduce la fosforilación de p38 MAPK y aumenta la activación del factor Nrf2, encargado de sintetizar enzimas anti-oxidantes. Una vez observada la actividad antiinflamatoria de oleuropeina en la inflamación intestinal, se procede al estudio del efecto quimiopreventivo del compuesto en un modelo de CRC asociado a CU inducido por azoximetano (AOM) y DSS en ratones C57BL/6. El tratamiento de oleuropeina a 100 mg/kg reduce la aparición de tumores en el colon y mejora los síntomas clínicos asociados al CRC. Además, inhibe la proliferación celular en el intestino, reduce los niveles de citocinas y proteínas inflamatorias, y actúa sobre la activación de vías de señalización implicadas en el CRC. Oleuropeina también posee un efecto cicatrizante, tal y como se demuestra en un modelo de cicatrización en placa con la línea celular IEC-18. Sin embargo, en macrófagos peritoneales, se observa que oleuropeina no presenta ningún efecto, sino que es su metabolito, el hidroxitirosol, el que inhibe la activación de las células. En resumen, oleuropeina presenta un efecto protector frente a la inflamación intestinal, actúa como agente quimiopreventivo en un modelo de CRC en animales, lo que podría presentarse como un tratamiento potencial para la colitis ulcerosa

Targeted delivery of Cyclosporine A by polymeric nanocarriers improves the therapy of inflammatory bowel disease in a relevant mouse model

The therapy of inflammatory bowel diseases is still rather inefficient, and about 80% of patients require surgery at some stage. Improving the treatments by more efficient medication is, therefore, an urgent medical need. The objective of this project was to demonstrate targeted delivery of Cyclosporine-A (CYA) to the inflamed areas of the intestinal mucosa after oral administration, enabling improved alleviation of the symptoms and, at the same time, reduced systemic drug absorption and associated adverse effects. As had already been demonstrated in previous studies, nano- to micrometer-sized drug particles will accumulate at inflamed mucosal areas, providing a platform for such purposes. CYA as incorporated in poly-(lactic-co-glycolic-Acid) (PLGA) nano- and mirocarriers, respectively, each homogeneous in size and providing controlled drug release over 24 h at intestinal pH-value. For comparative reasons, a commercial formulation (Sandimmun Neoral®) was included in the study. In an acute model of DSS-induced inflammation in Balb/c mice, up to three doses were administered for each formulation: 50 mg/kg, 25 mg/kg and 12.5 mg/kg. Drug-free particles were included as control. The following parameters were evaluated: body weight, colon length, colon weight/length ratio, cytokine expression and histological analysis. Plasma levels of CYA were analysed to compare systemic bioavailability. While disease parameters, such as, e.g. colon length, always improved with an optimum dose of 25 mg/kg, the commercial and the microparticulate formulations led to measurable plasma levels and adverse effects in terms of body weight loss at the highest dose. In contrast, when administering the same doses as nanoparticles, plasma concentrations remained always below the detection limit, and the body weight of the animals remained unchanged. In conclusion, this study corroborates the potential of nanocarriers enabling an improved topical delivery of CYA to the inflamed gut mucosa after oral administration yielding the same improvement of disease parameters at only half the dose in comparison to microparticles and a commercial oral formulation, respectively, and at the same time minimizing systemic exposure and associated adverse effect

Programming of Intestinal Epithelial Differentiation by IL-33 Derived from Pericryptal Fibroblasts in Response to Systemic Infection

The intestinal epithelium constitutes an efficient barrier against the microbial flora. Here, we demonstrate an unexpected function of IL-33 as a regulator of epithelial barrier functions. Mice lacking IL-33 showed decreased Paneth cell numbers and lethal systemic infection in response to Salmonella typhimurium. IL-33 was produced upon microbial challenge by a distinct population of pericryptal fibroblasts neighboring the intestinal stem cell niche. IL-33 programmed the differentiation of epithelial progenitors toward secretory IEC including Paneth and goblet cells. Finally, IL-33 suppressed Notch signaling in epithelial cells and induced expression of transcription factors governing differentiation into secretory IEC. In summary, we demonstrate that gut pericryptal fibroblasts release IL-33 to translate bacterial infection into an epithelial response to promote antimicrobial defense

Down syndrome as risk factor for respiratory syncytial virus hospitalization : A prospective multicenter epidemiological study

Respiratory syncytial virus (RSV) infection in childhood, particularly in premature infants, is associated with significant morbidity and mortality. To compare the hospitalization rates due to RSV infection and severity of disease between infants with and without Down syndrome (DS) born at term and without other associated risk factors for severe RSV infection. In a prospective multicentre epidemiological study, 93 infants were included in the DS cohort and 68 matched by sex and data of birth (±1 week) and were followed up to 1 year of age and during a complete RSV season. The hospitalization rate for all acute respiratory infection was significantly higher in the DS cohort than in the non-DS cohort (44.1% vs 7.7%, P<.0001). Hospitalizations due to RSV were significantly more frequent in the DH cohort than in the non-DS cohort (9.7% vs 1.5%, P=.03). RSV prophylaxis was recorded in 33 (35.5%) infants with DS. The rate of hospitalization according to presence or absence of RSV immunoprophylaxis was 3.0% vs 15%, respectively. Infants with DS showed a higher rate of hospitalization due to acute lower respiratory tract infection and RSV infection compared to non-DS infants. Including DS infants in recommendations for immunoprophylaxis of RSV disease should be considered