RESUMEN
The interpretation of way-finding symbols for healthcare facilities in a multicultural community was assessed in a cross-sectional study. One hundred participants recruited from Al Ain city in the United Arab Emirates were asked to interpret 28 healthcare symbols developed at Hablamos Juntos (such as vaccinations and laboratory) as well as 18 general-purpose symbols (such as elevators and restrooms). The mean age was 27.6 years (16-55 years) of whom 84 (84%) were females. Healthcare symbols were more difficult to comprehend than general-purpose signs. Symbols referring to abstract concepts were the most misinterpreted including oncology, diabetes education, outpatient clinic, interpretive services, pharmacy, internal medicine, registration, social services, obstetrics and gynecology, pediatrics and infectious diseases. Interpretation rates varied across cultural backgrounds and increased with higher education and younger age. Signage within healthcare facilities should be tested among older persons, those with limited literacy and across a wide range of cultures.
Asunto(s)
Diversidad Cultural , Directorios de Señalización y Ubicación , Adolescente , Adulto , Factores de Edad , Comprensión , Estudios Transversales , Femenino , Instituciones de Salud/normas , Alfabetización en Salud , Humanos , Directorios de Señalización y Ubicación/normas , Masculino , Persona de Mediana Edad , Emiratos Árabes Unidos , Adulto JovenRESUMEN
OBJECTIVES: When measuring physicians' competencies, there is no consensus as to what would constitute an optimum exposure in unintentional pediatric poisoning. In the absence of universal protocols and poison centers' support, the behavior responses of the physicians can vary depending on their exposure to cases. We sought to determine if there was a correlation between the case exposure and physicians' behavior choices that could affect quality and cost of care. METHODS: A cross-sectional study was conducted in 2010, and a self-reporting survey questionnaire was given to the physicians in the pediatric emergency departments and primary care centers in the city of Al Ain. The physicians' responses were plotted against (a) the number of cases the physicians have had managed in the preceding 12 months and (b) the number of years the physicians have had been in practice RESULTS: One hundred seven physicians partook in the survey. We found that the physicians who had managed more than 2 cases of childhood poisoning in the preceding year chose significantly more positive behavior responses when compared with those who had managed 2 cases or less. There was no significant difference when the responses were measured against the physicians' number of years of practice. CONCLUSIONS: Physicians' practice effectiveness may improve if they manage at least 3 cases of childhood poisoning in a year. Physicians training modules could be developed for those physicians who do not get the optimum exposure necessary in improving physicians' behaviors associated with effective quality and cost efficiency.
Asunto(s)
Servicios de Salud del Niño , Competencia Clínica , Servicio de Urgencia en Hospital , Pediatría , Intoxicación , Pautas de la Práctica en Medicina/estadística & datos numéricos , Atención Primaria de Salud , Atención Secundaria de Salud , Atención Terciaria de Salud , Adulto , Actitud del Personal de Salud , Niño , Servicios de Salud del Niño/economía , Conducta de Elección , Competencia Clínica/economía , Estudios Transversales , Servicio de Urgencia en Hospital/economía , Femenino , Adhesión a Directriz , Encuestas de Atención de la Salud , Humanos , Curva de Aprendizaje , Masculino , Persona de Mediana Edad , Padres , Admisión del Paciente , Pediatría/economía , Intoxicación/diagnóstico , Intoxicación/economía , Intoxicación/terapia , Guías de Práctica Clínica como Asunto , Pautas de la Práctica en Medicina/economía , Atención Primaria de Salud/economía , Relaciones Profesional-Familia , Atención Secundaria de Salud/economía , Encuestas y Cuestionarios , Atención Terciaria de Salud/economía , Factores de Tiempo , Emiratos Árabes UnidosRESUMEN
OBJECTIVES: Unintentional poisoning is a frequent presentation in the pediatric emergency care settings. We sought to determine the current incidence of unintentional poison ingestions in children who present to the emergency care in the city of Al Ain in United Arab Emirates, to create a profile of the products ingested, and to compare our data with a previous study conducted before the inception of a poison and drug information center. METHODS: We reviewed all cases of unintentional poisoning in children 10 years or younger, who presented at 2 tertiary level emergency care centers during January-December 2010. Two hundred cases met our inclusion criteria. Data on demographics, type and amount of noxious substance ingested, time of presentation, and outcomes were collected. Annual incidence was estimated, and data were compared with the previous study. RESULTS: The annual incidence of unintentional poisoning in the UAE is 2.35 per 1000 children 10 years or younger. The incidence is decreasing, especially for household chemical ingestions. The incidence is twice as high among native Emirati children compared with expatriate children. There was an increase in cosmetics- and synthetic hormone-related poisonings, as well as in the involvement of younger infants. CONCLUSIONS: The incidence of unintentional pediatric poisoning in the UAE is decreasing particularly in household chemical ingestions. Targeted health promotion campaigns by the poison center may have led to this drop. The sociological, environmental, and cultural factors that might be contributing to the greater use of emergency care in native children should be investigated.
Asunto(s)
Centros de Control de Intoxicaciones/organización & administración , Intoxicación/prevención & control , Prevención Primaria , Niño , Preescolar , Servicio de Urgencia en Hospital , Femenino , Humanos , Incidencia , Lactante , Masculino , Intoxicación/epidemiología , Factores de Riesgo , Emiratos Árabes Unidos/epidemiología , Población UrbanaRESUMEN
BACKGROUND: During the 1980s, approximately three million people migrated from Afghanistan to Pakistan and sought refuge in several cities including the city of Karachi. After the initial settlement of the refugees, the international organizations transitioned the health care of these refugees to the two local non-profit service agencies in Karachi. One of these agencies subsidized health care to the refugees under their care and the other agency encouraged the refugees under their care to utilize governmental and non-governmental private health resources at the disposal of general public. Our objective was to measure the effect of health subsidy on the uptake of contraception among Afghan refugee women and compare them to the group of Afghan women without such a subsidy. METHODOLOGY/PRINCIPAL FINDINGS: A randomly selected group of 650 married Afghan women--325 women in each group--participated in a detailed survey regarding the knowledge, attitude and practices of family planning and contraceptive use. 90 percent of the women in the health subsidy group had had heard of family planning, compared to the 45 percent in the non-subsidized group. The use of contraceptives was greater than two-fold in the former versus the latter. Results of logistic regression analysis revealed that the refugee women who had had access to subsidized healthcare were significantly more likely to use the contraceptive methods with advancing age as compared to the women in the non-health subsidy group. The difference remained significant after adjusting for other variables. CONCLUSIONS/SIGNIFICANCE: Refugee women who are provided subsidized healthcare are more inclined to use contraceptives. It is therefore important that Afghan refugee women living elsewhere in Pakistan be provided healthcare subsidy, whereby their reproductive health indicators could improve with reduced fertility. We strongly encourage facilities introducing such subsidies to refugees in resource poor settings to assess the impact through similar inquiry.
Asunto(s)
Anticoncepción/métodos , Conocimientos, Actitudes y Práctica en Salud , Adolescente , Adulto , Afganistán , Factores de Edad , Conducta Anticonceptiva , Anticonceptivos/uso terapéutico , Estudios Transversales , Servicios de Planificación Familiar/métodos , Femenino , Comunicación en Salud , Humanos , Persona de Mediana Edad , Modelos Estadísticos , Pakistán , Refugiados/estadística & datos numéricos , Análisis de Regresión , Encuestas y CuestionariosRESUMEN
A 14-month-old girl presented with the recurring bouts of vomiting and diarrhoea and failure to thrive. At 7 months of age, the baby was found to be exclusively breast fed and her blood tests revealed low calcium, low phosphorous and markedly elevated alkaline phosphatase. She was started on vitamin D and calcium supplements. Five months later, she came in with lower-limb bowing, irritability, vomiting and loose stools. The laboratory studies revealed very low serum hydroxyvitamin D, and high serum dihydroxyvitamin D. Vitamin D dose was doubled. Ten weeks later, her growth velocity had fallen and she continued to have intermittent loose stools. The oesophagogastroduodenoscopy was done and the biopsies showed Helicobacter pylori gastritis and mild duodenitis. After eradication of H pylori, there was a dramatic improvement in her growth and activity and upon 6 months follow- up there was no clinical or radiologic evidence of rickets.
Asunto(s)
Insuficiencia de Crecimiento/etiología , Gastritis/complicaciones , Gastritis/microbiología , Infecciones por Helicobacter/complicaciones , Helicobacter pylori , Raquitismo/complicaciones , Deficiencia de Vitamina D/complicaciones , Femenino , Humanos , Lactante , Raquitismo/etiologíaRESUMEN
This report describes a 10-month-old infant who presented with generalised tonic clonic seizures following 2 days of vomiting, diarrhoea and a low-grade fever. The patient was moderately dehydrated and the blood investigations were remarkable for hyponatraemia (126 mEq/l), leukocytosis (19.4 × 10(3)/l (46% lymphocytes)), thrombocytosis (637 × 10(3)/l), hypoalbuminaemia (albumin 1.9 g/dl) and elevated C reactive protein (96 mg/l). Stool was positive for white and red blood cells but the cultures for bacteria were negative. Rotavirus antigen in stool was positive. There was microscopic haematuria without proteinuria and the nasogastric aspirate was coffee ground. Generalised oedema with pleural and peritoneal effusions ensued requiring drainage, correction of fluid and electrolytes imbalance and albumin infusions. Over the next 72 h, the patient descended into shock and disseminated intravascular coagulopathy which required packed red blood cells and fresh frozen plasma transfusions. By day 12 the patient was clinically and biochemically normal.
Asunto(s)
Edema/etiología , Gastroenteritis/complicaciones , Gastroenteritis/virología , Infecciones por Rotavirus/complicaciones , Convulsiones/etiología , Síndrome de Respuesta Inflamatoria Sistémica/etiología , Edema/terapia , Femenino , Gastroenteritis/terapia , Humanos , Lactante , Inducción de Remisión , Infecciones por Rotavirus/terapia , Convulsiones/terapia , Síndrome de Respuesta Inflamatoria Sistémica/terapiaRESUMEN
PECAM-1 is expressed on endothelial cells and leukocytes. Its extracellular domain has been implicated in leukocyte diapedesis. In this study, we used PECAM-1(-/-) mice and relevant cells derived from them to assess the role of PECAM-1 in an experimental model of acute colonic inflammation with a predominant innate immune response, i.e., 2,4,6-trinitrobenzine sulfonic acid (TNBS). Using chimeric approaches, we addressed the points of control exerted by PECAM-1 along the macrophage-endothelial cell-polymorphonuclear neutrophil (PMN) axis. In vivo, TNBS-induced colitis was ameliorated in PECAM-1(-/-) mice, an event attributed to PECAM-1 on hematopoietic cells rather than to PECAM-1 on endothelial cells. The in vivo innate immune response was mimicked in vitro by using a construct of the vascular-interstitial interface, i.e., PMN transendothelial migration was induced by colonic lavage fluid (CLF) from TNBS mice or macrophages (MPhi) challenged with CLF. Using the construct, we confirmed that endothelial cell PECAM-1 does not play a role in PMN transendothelial migration. Although MPhi activation (NF-kappaB nuclear binding) and function (keratinocyte-derived chemokine production) induced by CLF was diminished in PECAM-1(-/-) MPhi, this did not affect their ability to promote PMN transendothelial migration. By contrast, PECAM-1(-/-) PMN did not adhere to or migrate across endothelial cell monolayers in response to CLF. Further, as compared with PECAM-1(+/+) PMN, PECAM-1(-/-) PMN were less effective in orientating their CXCR2 receptors (polarization) in the direction of a chemotactic gradient. Collectively, our findings indicate that PECAM-1 modulation of PMN function (at a step before diapedesis) most likely contributes to the inflammation in a colitis model with a strong innate immune component.
Asunto(s)
Colitis/inmunología , Colitis/metabolismo , Células Endoteliales/inmunología , Inmunidad Innata/inmunología , Macrófagos/inmunología , Neutrófilos/inmunología , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Enfermedad Aguda , Animales , Adhesión Celular , Movimiento Celular/inmunología , Células Cultivadas , Colitis/inducido químicamente , Colitis/patología , Macrófagos/citología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Imitación Molecular/inmunología , Neutrófilos/citología , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/genética , Ácido Trinitrobencenosulfónico/farmacologíaRESUMEN
BACKGROUND AND AIMS: Although the CD40-CD40 ligand (CD40L) signaling pathway has been implicated in the pathogenesis of a variety of diseases, including inflammatory bowel disease, the nature of its contribution to intestinal inflammation remains poorly understood. The aim of this study was to determine whether CD40-CD40L contributes to the intestinal inflammatory response, tissue injury, and disease activity elicited by dextran sodium sulphate (DSS) through the modulation of leukocyte and platelet recruitment in the colonic microvasculature. METHODS: Wild-type (WT), CD40(-/-), and CD40L(-/-) mice were fed DSS drinking water. On day 6, intravital videomicroscopy was performed to monitor leukocyte and platelet recruitment in colonic venules, with measurements obtained for tissue myeloperoxidase and histology. CD40 expression on colonic endothelium was measured using the dual-radiolabeled antibody technique. RESULTS: A comparison of the responses to DSS-induced colitis in CD40(-/-) and CD40L(-/-) mice to WT mice revealed a significant attenuation of disease activity and histologic damage, as well as profound reductions in the recruitment of adherent leukocytes and platelets in the mutant mice. Similar down-regulation of the blood cell recruitment responses to DSS was noted in WT mice treated with the CD40-CD40L pathway inhibitor Trapidil. CD40 expression in the colonic vasculature was greatly elevated during DSS-induced inflammation in WT mice, but not in CD40(-/-) mice. CONCLUSIONS: These findings implicate CD40-CD40L in the pathogenesis of DSS-induced intestinal inflammation, and suggest that modulation of leukocyte and platelet recruitment by activated, CD40-positive endothelial cells in colonic venules may represent a major action of this signaling pathway.
Asunto(s)
Plaquetas/metabolismo , Antígenos CD40/metabolismo , Ligando de CD40/metabolismo , Quimiotaxis de Leucocito , Colitis/metabolismo , Colon/metabolismo , Leucocitos/metabolismo , Transducción de Señal , Animales , Plaquetas/efectos de los fármacos , Antígenos CD40/antagonistas & inhibidores , Antígenos CD40/deficiencia , Antígenos CD40/genética , Ligando de CD40/antagonistas & inhibidores , Ligando de CD40/deficiencia , Ligando de CD40/genética , Adhesión Celular , Colitis/tratamiento farmacológico , Colitis/patología , Colitis/fisiopatología , Colon/irrigación sanguínea , Colon/efectos de los fármacos , Colon/patología , Colon/fisiopatología , Sulfato de Dextran , Modelos Animales de Enfermedad , Endotelio Vascular/metabolismo , Endotelio Vascular/fisiopatología , Rodamiento de Leucocito , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microscopía por Video , Peroxidasa/análisis , Adhesividad Plaquetaria , Inhibidores de Agregación Plaquetaria/farmacología , Inhibidores de Agregación Plaquetaria/uso terapéutico , Índice de Severidad de la Enfermedad , Transducción de Señal/efectos de los fármacos , Factores de Tiempo , Trapidil/farmacología , Vénulas/metabolismo , Vénulas/fisiopatologíaRESUMEN
It is well known that transfer of CD4+CD45RBhigh (naïve) T cells into syngeneic lymphocyte-deficient mice induces chronic colitis. However, no studies have reported the presence of small bowel inflammation in this T cell-dependent model. Therefore, the objective of this study was to evaluate and compare small and large bowel inflammation induced by transfer of naïve T cells into two different immunodeficient recipient mice. T and B cell-deficient recombinase activating gene 1-deficient [RAG knockout (KO)] and T cell-deficient T cell receptor-beta x T cell receptor-delta double-deficient (TCR KO) mice were reconstituted with wild-type naïve T cells and observed for signs of disease. We found that reconstituted RAG KO mice developed moderate to severe colitis and inflammation of the entire small intestine at 6-8 wk after T cell transfer. Adoptive transfer of naïve T cells into TCR KO mice induced a milder form of chronic colitis and small bowel inflammation that was confined primarily to the duodenum at 10-12 wk after T cell transfer. T helper cell 1 and macrophage-derived proinflammatory cytokine mRNA levels correlated well with the localization and severity of the chronic large and small bowel inflammation. In addition, we observed comparable homing and expansion of donor lymphocytes in the gut and secondary lymphoid tissues of both recipients. Taken together, our data demonstrate that transfer of naïve T cells into immunodeficient recipient mice induces both chronic small and large bowel inflammation and that the presence of B cells in the TCR KO recipients may play a role in regulating chronic intestinal inflammation.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Síndromes de Inmunodeficiencia/genética , Intestino Grueso/inmunología , Intestino Grueso/patología , Intestino Delgado/inmunología , Intestino Delgado/patología , Traslado Adoptivo , Animales , Femenino , Genes RAG-1/genética , Síndromes de Inmunodeficiencia/inmunología , Masculino , Ratones , Ratones Noqueados , Receptores de Antígenos de Linfocitos T alfa-beta/deficiencia , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Trasplante IsogénicoRESUMEN
The antiatherogenic properties of apoA-IV suggest that this protein may act as an anti-inflammatory agent. We examined this possibility in a mouse model of acute colitis. Mice consumed 3% dextran sulfate sodium (DSS) in their drinking water for 7 days, with or without daily intraperitoneal injections of recombinant human apoA-IV. apoA-IV significantly and specifically delayed the onset, and reduced the severity and extent of, DSS-induced inflammation, as assessed by clinical disease activity score, macroscopic appearance and histology of the colon, and tissue myeloperoxidase activity. Intravital fluorescence microscopy of colonic microvasculature revealed that apoA-IV significantly inhibited DSS-induced leukocyte and platelet adhesive interactions. Furthermore, apoA-IV dramatically reduced the upregulation of P-selectin on colonic endothelium during DSS-colitis. apoA-IV knockout mice exhibited a significantly greater inflammatory response to DSS than did their WT littermates; this greater susceptibility to DSS-induced inflammation was reversed upon exogenous administration of apoA-IV to knockout mice. These results provide the first direct support for the hypothesis that apoA-IV is an endogenous anti-inflammatory protein. This anti-inflammatory effect likely involves the inhibition of P-selectin-mediated leukocyte and platelet adhesive interactions.
Asunto(s)
Antiinflamatorios/metabolismo , Apolipoproteínas A/metabolismo , Colitis/metabolismo , Animales , Antiinflamatorios/inmunología , Apolipoproteínas A/genética , Apolipoproteínas A/inmunología , Colitis/inducido químicamente , Colitis/inmunología , Colitis/patología , Colon/anatomía & histología , Colon/patología , Sulfato de Dextran/administración & dosificación , Sulfato de Dextran/toxicidad , Modelos Animales de Enfermedad , Células Epiteliales/citología , Células Epiteliales/metabolismo , Humanos , Indicadores y Reactivos/administración & dosificación , Indicadores y Reactivos/toxicidad , Inflamación/inmunología , Inflamación/metabolismo , Mucosa Intestinal/citología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Leucocitos/inmunología , Leucocitos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Selectina-P/metabolismo , Adhesividad Plaquetaria/fisiología , Proteínas Recombinantes/genética , Proteínas Recombinantes/inmunología , Proteínas Recombinantes/metabolismoRESUMEN
Ischemia/reperfusion (I/R) is an important problem in liver resection and transplantation that is associated with hepatocellular dysfunction and injury. This study was designed to investigate whether a difference in hepatocyte susceptibility occurs in the periportal (PP) and/or perivenous (PV) zones in response to hypoxia/reoxygenation (H/R), and to delineate the mechanisms underlying this susceptibility. H/R was induced in an in situ perfused mouse liver model with deoxygenated Krebs-Henseleit buffer followed by oxygenated buffer. Selective destruction of PP or PV sites was achieved by digitonin perfusion into the portal or inferior vena cava, and was confirmed by histological evaluations and zone-specific enzymes. Hepatocellular injury was assessed by alanine aminotransferase (ALT) release. In whole liver, H/R significantly increased perfusate ALT. H/R of PP-enriched zones caused ALT release that was similar to that of whole liver (80 + 10 vs. 70 + 12 U/mg protein), consistent with significant PP hepatocyte injury. Minimal ALT release occurred in PV zones (10 + 5 U/mg protein). Administration of N-acetyl L-cysteine or a chimeric superoxide dismutase (SOD)-SOD2/3, a genetically engineered SOD-abrogated ALT release in H/R-perfused PP zones, implicating a role for superoxide (O(2) (-)). This elevated ALT release was attenuated by gadolinium chloride pretreatment, indicating that Kupffer cells are the O(2) (-) source. Enzymatic inhibition of cellular nitric oxide synthase (NOS) or genetic depletion of endothelial nitric oxide synthase (eNOS) aggravated hypoxia injury while exogenous NO and inducible nitric oxide synthase (iNOS) deficiency abolished reoxygenation injury. In conclusion, PP hepatocytes are more vulnerable to H/R; this injury is mediated directly or indirectly by Kupffer cell derived O(2) (-) and is limited by eNOS-derived NO.
Asunto(s)
Hipoxia de la Célula , Hepatocitos/fisiología , Macrófagos del Hígado/metabolismo , Óxido Nítrico/fisiología , Oxígeno/administración & dosificación , Animales , Digitonina/administración & dosificación , Hepatocitos/efectos de los fármacos , Hepatocitos/enzimología , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
Estrogen (E(2)) exerts its effect on target organs principally by interacting with specific estrogen receptors (ER) such as ER-alpha or ER-beta. The role that these E(2) receptors play in mediating the protective effects observed in RSL+I/R induced injury remains to be defined. To study the role of ER-alpha, we anesthetized female and male wild type (wt; C57Bl/6) and ER-alpha-deficient (alphaERKO) mice and subjected them to 70% liver ischemia for 45 min followed by resection of the remaining 30% nonischemic lobes and reperfusion of the ischemic tissue. For some experiments, wt and alphaERKO male mice were injected with E(2). Survival was monitored on a daily basis while liver injury was assessed by quantifying serum alanine aminotransferase (ALT) levels and histopathology. Hepatic eNOS mRNA levels were evaluated using semi-quantitative RT-PCR. Our data showed that untreated females or males treated with E(2) survived RSL+I/R surgery indefinitely whereas all male mice given vehicle died within 3-5 days following surgery. This protective effect was diminished in alphaERKO female mice such that only 40% of alphaERKO females survived 7 d following RSL+I/R. Furthermore, liver injury was significantly higher in alphaERKO females compared with their wt counterparts and similar to those seen in wild type males and alphaERKO males. The protective effect observed in wild type females or E(2) treated males correlated well with increases in hepatic eNOS message whereas both male and female alphaERKO mice exhibited significantly lower levels of eNOS mRNA. We conclude that this protection may in part be due to the E(2)/ER-alpha-mediated activation of eNOS.
Asunto(s)
Hígado/irrigación sanguínea , Receptores de Estrógenos/fisiología , Daño por Reperfusión , Caracteres Sexuales , Animales , Secuencia de Bases , Cartilla de ADN , Receptor alfa de Estrógeno , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Óxido Nítrico Sintasa/genética , Óxido Nítrico Sintasa de Tipo II , Óxido Nítrico Sintasa de Tipo III , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
The objective of this study was to assess the roles of NK cells, B cells and/or intraepithelial lymphocytes (IEL) in suppressing the development of colitis in nude mice reconstituted with CD4(+)CD45RB(high) T cells. BALB/c nude mice were lethally irradiated and reconstituted with bone marrow from different immunodeficient mice to generate athymic chimeras devoid of one or more lymphocyte populations. Transfer of CD4(+)C45RB(high) T cells into chimeric recipients devoid of B cells, T cells and IEL produced severe colitis within 6-8 weeks, whereas transfer of these same T cells into B cell- and T cell-deficient or T cell-deficient chimeras produced little to no gut inflammation. In addition, we found that nude mice depleted of NK cells or RAG-1(-/-) mice reconstituted with IEL failed to develop colitis following transfer of CD45RB(high) T cells. Severe colitis could, however, be induced in nude mice by transfer of activated/T(h)1 CD4(+)CD45RB(low) T cells. Taken together, our data suggest that IEL, but not B cells or NK cells, play an important role in suppressing the development of chronic colitis in this model. In addition, our data demonstrate that suppression of disease may be due to polarization of naive CD4(+) cells toward a non-pathogenic and/or regulatory phenotype.
Asunto(s)
Linfocitos B/inmunología , Colitis/inmunología , Células Asesinas Naturales/inmunología , Subgrupos de Linfocitos T/trasplante , Traslado Adoptivo , Animales , Linfocitos T CD4-Positivos/inmunología , Quimera , Enfermedad Crónica , Femenino , Citometría de Flujo , Proteínas de Homeodominio/metabolismo , Antígenos Comunes de Leucocito/inmunología , Activación de Linfocitos/inmunología , Masculino , Ratones , Ratones Desnudos , Subgrupos de Linfocitos T/inmunologíaRESUMEN
The dextran sulfate (DSS) model of colitis causes intestinal injury sharing many characteristics with inflammatory bowel disease, e.g., leukocyte infiltration, loss of gut epithelial barrier, and cachexia. These symptoms are partly mediated by entrapped leukocytes binding to multiple endothelial adhesion molecules (MAdCAM-1, VCAM-1, ICAM-1, and E-selectin). Pravastatin, an 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitor, has anti-inflammatory potency in certain inflammation models; therefore, in this study, we measured the effects of pravastatin in DSS-induced colitis. The administration of pravastatin (1 mg/kg) relieved DSS-induced cachexia, hematochezia, and intestinal epithelial permeability, with no effect on serum cholesterol. Histopathologically, pravastatin prevented leukocyte infiltration and gut injury. Pravastatin also blocked the mucosal expression of MAdCAM-1. DSS treatment promoted mucosal endothelial nitric-oxide synthase (eNOS) mRNA degradation, an effect that was blocked by pravastatin. Importantly, the protective effects of pravastatin in DSS-induced colitis were not found in eNOS-deficient mice. Our results demonstrate that HMG-CoA reductase inhibitors preserve intestinal integrity in colitis, most likely via increased eNOS expression and activity, independent of cholesterol metabolism.
Asunto(s)
Colitis/tratamiento farmacológico , Inhibidores Enzimáticos/uso terapéutico , Hidroximetilglutaril-CoA Reductasas/metabolismo , Pravastatina/uso terapéutico , Animales , Moléculas de Adhesión Celular , Permeabilidad de la Membrana Celular/efectos de los fármacos , Colesterol/sangre , Colitis/inducido químicamente , Colitis/patología , Sulfato de Dextran , Modelos Animales de Enfermedad , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Expresión Génica/efectos de los fármacos , Inmunoglobulinas/análisis , Inmunohistoquímica , Inflamación/tratamiento farmacológico , Inflamación/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mucoproteínas/análisis , Óxido Nítrico Sintasa/biosíntesis , Óxido Nítrico Sintasa/genética , Óxido Nítrico Sintasa de Tipo II , Óxido Nítrico Sintasa de Tipo III , ARN Mensajero/biosíntesisRESUMEN
We have recently reported that female mice are protected to a much greater extent from the injurious effects of reduced-size liver ischemia and reperfusion (RSL+I/R) than are males by an estrogen-dependent mechanism. The objective of this study was to examine the possibility that the protective effect observed in female mice depends on the up-regulation and/or activation of endothelial cell NO synthase (eNOS). Anesthetized female and male wild-type or eNOS-deficient C57BL/6 mice were subjected to 70% liver ischemia for 45 min followed by resection of the remaining 30% nonischemic lobes and reperfusion of ischemic tissue. Survival was monitored daily, whereas liver injury was quantified by using serum alanine aminotransferase determinations and histopathology. Hepatic eNOS mRNA, protein, and enzymatic activity were determined in male and female mice subjected to RSL+I/R. We found that liver injury was reduced and survival increased in female mice compared with males. This protective effect correlated with significant increases in hepatic eNOS message levels and enzyme activity but not protein expression compared with males subjected to the surgery. Furthermore, N(omega)-nitro-L-arginine methyl ester-treated or eNOS-deficient female mice responded to RSL+I/R with dramatic increases in liver injury and 100% mortality within 2 days of surgery. Finally, we found that pravastatin pretreatment significantly attenuated hepatocellular injury and increased survival of male mice, which was associated with enhanced expression of eNOS message. We conclude that the protective effect afforded female mice is due to the activation of hepatic eNOS activity and enhanced NO production.
Asunto(s)
Isquemia/enzimología , Hígado/irrigación sanguínea , Óxido Nítrico Sintasa/fisiología , Daño por Reperfusión/enzimología , Caracteres Sexuales , Animales , Femenino , Hígado/enzimología , Hígado/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Óxido Nítrico Sintasa de Tipo II , Óxido Nítrico Sintasa de Tipo III , Pravastatina/farmacologíaRESUMEN
The objective of this study was to define the relationship among Kupffer cells, O(2)(-) production, and TNF-alpha expression in the pathophysiology of postischemic liver injury following short and long periods of ischemia. Using different forms of superoxide dismutase with varying circulating half-lives, a monoclonal antibody directed against mouse TNF-alpha, and NADPH oxidase-deficient mice, we found that 45 or 90 min of partial (70%) liver ischemia and 6 h of reperfusion (I/R) produced time-dependent increases in liver injury and TNF-alpha expression in the absence of neutrophil infiltration. Furthermore, we observed that hepatocellular injury induced by short periods of ischemia were not dependent on formation of TNF-alpha but were dependent on Kupffer cells and NADPH oxidase-independent production of O(2)(-). However, liver injury induced by extended periods of ischemia appeared to require the presence of Kupffer cells, NADPH oxidase-derived O(2)(-), and TNF-alpha expression. We conclude that the sources for O(2)(-) formation and the relative importance of TNF-alpha in the pathophysiology of I/R-induced hepatocellular injury differ depending on the duration of ischemia.
Asunto(s)
Isquemia/patología , Circulación Hepática/fisiología , Hígado/patología , Alanina Transaminasa/metabolismo , Animales , Citocinas/metabolismo , Hepatectomía , Humanos , Macrófagos del Hígado/patología , Ratones , Ratones Endogámicos C57BL , Mutación , NADPH Oxidasas/genética , Consumo de Oxígeno/fisiología , Peroxidasa/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Superóxido Dismutasa/metabolismo , Factores de Tiempo , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
The present study was designed to assess the role of endothelial cell and inducible nitric oxide synthase (eNOS, iNOS)-derived NO in ischemia/reperfusion (I/R)-induced pro-inflammatory cytokine expression and tissue injury in a murine model of hepatic I/R. Forty-five min of partial hepatic ischemia and 3 h of reperfusion resulted in a significant increase in liver injury as assessed by serum alanine aminotransferase and histopathology which occurred in the absence of neutrophil infiltration. Both iNOS and eNOS deficient mice exhibited enhanced liver injury when compared to their wild type (wt) controls again in the absence of neutrophil infiltration. Interestingly, message expression for both tumor necrosis factor-alpha (TNF-alpha) and interleukin 12 (IL-12) were enhanced in eNOS, but not iNOS-deficient mice at 1 h post-ischemia when compared to their wt controls. In addition, eNOS message expression appeared to be up-regulated between 1 and 3 h ofreperfusion in wt mice while iNOS deficient mice exhibited substantial increases at I but not 3 h. Taken together, these data demonstrate the ability of eNOS and iNOS to protect the post-ischemic liver, however their mechanisms of action may be very different.
Asunto(s)
Hígado/metabolismo , Hígado/patología , Óxido Nítrico/metabolismo , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Animales , Quimiotaxis de Leucocito , Modelos Animales de Enfermedad , Ratones , Ratones Noqueados , Neutrófilos/citología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa/deficiencia , Óxido Nítrico Sintasa/genética , Óxido Nítrico Sintasa/metabolismo , Daño por Reperfusión/enzimología , Factores de TiempoRESUMEN
One of the most consistent and dramatic findings in both experimental and human inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis) is the enhanced expression of the inducible isoform of nitric oxide synthase (iNOS) and the sustained overproduction of the free radical nitric oxide (NO). The role that iNOS-derived NO plays in the pathophysiology of inflammatory bowel disease remains the subject of intense investigation and active debate. Although several different studies using a variety of animal models of acute and chronic gut inflammation suggest that NO may promote intestinal inflammation, an equally impressive number of investigations suggest that iNOS may play no role or may act to attenuate or to limit the extent of inflammatory tissue injury. This review discusses some of the basic concepts related to the immunoregulation of chronic gut inflammation and summarizes the current state of knowledge of the role that NO may play in modulating inflammatory tissue injury.