RESUMEN
The acute phase response, as a component of the innate immune system, is part of the first line of defense against invading pathogens. The Stimulator of Interferon Genes (STING) pathway initiates innate immune responses upon recognition of exogenous bacterial and viral DNA. However, whether STING signaling pathway plays any roles in regulating acute phase response during bacterial infection remains unknown. In this study, we used STING-deficient (Tmem173gt) and wildtype mice to investigate acute phase responses to bacterial infection (Escherichia coli, E. coli) and test the effect of exogenous cyclic GMP-AMP (cGAMP, a STING agonist) treatment. Bacterial infection of STING-deficient mice resulted in an increase in mortality and bacterial dissemination. Also, inflammation-induced acute phase response was drastically reduced in STING-deficient mice, showing significant reduction in expression of cytokine TNF-α and acute phase proteins. In contrast, exogenous cGAMP treatment enhanced inflammation-induced acute phase response by increasing the expression of TNF-α and acute phase proteins. Also, cGAMP accelerated bacterial clearance and improved survival rate of wildtype mice, but not STING-deficient mice. Interestingly, cGAMP treatment mitigated bacterial infection induced liver injury in both wildtype and STING-deficient mice. Further in vitro evidence showed that cGAMP treatment retarded TNF-α-mediated hepatocyte apoptosis, potentially accelerating autophagy. Taken together, our results indicated that cGAMP/STING signaling pathway is critical for organism to initiate blood-borne innate immune-responses to defend bacterial infection, and cGAMP is envisaged as a drug candidate for further clinical trial.
Asunto(s)
Reacción de Fase Aguda/metabolismo , Reacción de Fase Aguda/prevención & control , AMP Cíclico/administración & dosificación , GMP Cíclico/administración & dosificación , Infecciones por Escherichia coli/metabolismo , Infecciones por Escherichia coli/prevención & control , Proteínas de la Membrana/deficiencia , Reacción de Fase Aguda/genética , Animales , Escherichia coli , Infecciones por Escherichia coli/genética , Hepatocitos/metabolismo , Hepatocitos/microbiología , Masculino , Proteínas de la Membrana/agonistas , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones TransgénicosRESUMEN
BACKGROUND: The acute phase response (APR) to CNS insults contributes to the overall magnitude and nature of the systemic inflammatory response. Aspects of this response are thought to drive secondary inflammatory pathology at the lesion site, and suppression of the APR can therefore afford some neuroprotection. In this study, we examined the APR in a mouse model of traumatic spinal cord injury (SCI), along with its relationship to neutrophil recruitment during the immediate aftermath of the insult. We specifically investigated the effect of IL-1 receptor antagonist (IL-1RA) administration on the APR and leukocyte recruitment to the injured spinal cord. METHODS: Adult female C57BL/6 mice underwent either a 70kD contusive SCI, or sham surgery, and tissue was collected at 2, 6, 12, and 24 hours post-operation. For IL-1RA experiments, SCI mice received two intraperitoneal injections of human IL-1RA (100mg/kg), or saline as control, immediately following, and 5 hours after impact, and animals were sacrificed 6 hours later. Blood, spleen, liver and spinal cord were collected to study markers of central and peripheral inflammation by flow cytometry, immunohistochemistry and qPCR. Results were analysed by two-way ANOVA or student's t-test, as appropriate. RESULTS: SCI induced a robust APR, hallmarked by elevated hepatic expression of pro-inflammatory marker genes and a significantly increased neutrophil presence in the blood, liver and spleen of these animals, as early as 2 hours after injury. This peripheral response preceded significant neutrophil infiltration of the spinal cord, which peaked 24 hours post-SCI. Although expression of IL-1RA was also induced in the liver following SCI, its response was delayed compared to IL-1ß. Exogenous administration of IL-1RA during this putative therapeutic window was able to suppress the hepatic APR, as evidenced by a reduction in CXCL1 and SAA-2 expression as well as a significant decrease in neutrophil infiltration in both the liver and the injured spinal cord itself. CONCLUSIONS: Our data indicate that peripheral administration of IL-1RA can attenuate the APR which in turn reduces immune cell infiltration at the spinal cord lesion site. We propose IL-1RA treatment as a viable therapeutic strategy to minimise the harmful effects of SCI-induced inflammation.
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Reacción de Fase Aguda/inmunología , Reacción de Fase Aguda/prevención & control , Proteína Antagonista del Receptor de Interleucina 1/administración & dosificación , Traumatismos de la Médula Espinal/tratamiento farmacológico , Traumatismos de la Médula Espinal/inmunología , Reacción de Fase Aguda/metabolismo , Animales , Femenino , Humanos , Inmunidad Celular/efectos de los fármacos , Inmunidad Celular/fisiología , Inflamación/inmunología , Inflamación/metabolismo , Inflamación/prevención & control , Inyecciones Intraperitoneales , Ratones , Ratones Endogámicos C57BL , Traumatismos de la Médula Espinal/metabolismo , Vértebras Torácicas/lesiones , Resultado del TratamientoRESUMEN
Surface modification by different quaternary ammonium compounds (QAC) makes nanoclays more compatible with various polymeric matrices, thereby expanding their potential applications. The growing industrial use of nanoclays could potentially pose a health risk for workers. Here, we assessed how surface modification of nanoclays modulates their pulmonary toxicity. An in vitro screening of the unmodified nanoclay Bentonite (montmorillonite) and four organomodified nanoclays (ONC); coated with various QAC, including benzalkonium chloride (BAC), guided the selection of the materials for the in vivo study. Mice were exposed via a single intratracheal instillation to 18, 54, and 162 µg of unmodified Bentonite or dialkyldimethyl-ammonium-coated ONC (NanofilSE3000), or to 6, 18, and 54 µg of a BAC-coated ONC (Nanofil9), and followed for one, 3, or 28 days. All materials induced dose- and time-dependent responses in the exposed mice. However, all doses of Bentonite induced larger, but reversible, inflammation (BAL neutrophils) and acute phase response (Saa3 gene expression in lung) than the two ONC. Similarly, highest levels of DNA strand breaks were found in BAL cells of mice exposed to Bentonite 1 day post-exposure. A significant increase of DNA strand breaks was detected also for NanofilSE3000, 3 days post-exposure. Only mice exposed to Bentonite showed increased Tgf-ß gene expression in lung, biomarker of pro-fibrotic processes and hepatic extravasation, 3 days post-exposure. This study indicates that Bentonite treatment with some QAC changes main physical-chemical properties, including shape and surface area, and may decrease their pulmonary toxicity in exposed mice.
Asunto(s)
Reacción de Fase Aguda/prevención & control , Bentonita/toxicidad , Daño del ADN , Pulmón/efectos de los fármacos , Nanopartículas/toxicidad , Compuestos de Amonio Cuaternario/química , Reacción de Fase Aguda/inmunología , Animales , Bentonita/química , Líquido del Lavado Bronquioalveolar/química , Línea Celular , Supervivencia Celular/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Células Epiteliales/inmunología , Femenino , Expresión Génica/efectos de los fármacos , Humanos , Inflamación , Pulmón/inmunología , Ratones , Ratones Endogámicos C57BL , Nanopartículas/química , Neutrófilos/efectos de los fármacos , Neutrófilos/inmunología , Tamaño de la Partícula , Propiedades de SuperficieRESUMEN
OBJECTIVE: It has been reported that acute-phase reactions (APR) after infusion of 5 mg zoledronic acid for the first time is common. This study surveyed the incidence and characteristics of APR in Chinese postmenopausal women receiving 5 mg zoledronic acid intravenously for osteoporosis and to evaluate the efficacy of non-steroidal anti-inflammatory drugs (NSAID) in preventing or alleviating APR following the first 5 mg zoledronic acid infusion. METHODS: A total of 2601 patients with an average age of 68.14 ± 9.89 years and a mean body mass index of 22.90 ± 3.24 kg/m2 from 62 centers in China were treated with 5 mg zoledronic acid intravenously for the first time. The incidence of fever and pain were observed in these patients, and the time of fever or pain onset and duration, and the intensity of fever and grade of pain were also recorded. The dosage, duration, and efficacy of NSAID and safety outcomes were also documented. RESULTS: At the end of the study, 18 patients are eliminated due to incomplete records of temperature. The incidence of fever was 28.65% (740/2583) within 7 days following zoledronic acid infusion; 98.34% (727/740) occurred at 1.03 ± 0.66 days after infusion and lasted 1.72 ± 0.93 days. A total of 456 (17.53%) patients had newly onset pain (312 of 1187, 26.28%) or experienced pain aggravation (144 of 1414, 10.18%), which mostly occurred within 3 days after zoledronic acid infusion. A total of 1246 (47.6%) patients had received NSAID for a median time of 2.63 ± 2.45 days. Using NSAID for at least 2 days could decrease body temperature by 0.54 ± 0.86°C, increase the percentage of pain-free patients by 6.17%, and reduce the percentage of patients with moderate to severe pain by 8.7%. CONCLUSIONS: Compared with Western populations, Chinese patients had a higher rate of fever and pain after their first zoledronic acid infusion. These symptoms were often mild to moderate in intensity and transient in duration. NSAID could effectively reduce the incidence and severity of such APR.
Asunto(s)
Reacción de Fase Aguda/inducido químicamente , Conservadores de la Densidad Ósea/efectos adversos , Difosfonatos/efectos adversos , Imidazoles/efectos adversos , Osteoporosis Posmenopáusica/tratamiento farmacológico , Reacción de Fase Aguda/epidemiología , Reacción de Fase Aguda/prevención & control , Anciano , Antiinflamatorios no Esteroideos/uso terapéutico , Conservadores de la Densidad Ósea/administración & dosificación , Conservadores de la Densidad Ósea/uso terapéutico , China/epidemiología , Difosfonatos/administración & dosificación , Difosfonatos/uso terapéutico , Femenino , Humanos , Imidazoles/administración & dosificación , Imidazoles/uso terapéutico , Incidencia , Infusiones Intravenosas , Persona de Mediana Edad , Osteoporosis Posmenopáusica/epidemiología , Dolor/inducido químicamente , Dolor/epidemiología , Dolor/prevención & control , Vigilancia de Productos Comercializados/métodos , Ácido ZoledrónicoRESUMEN
Zoledronic acid provokes an inflammatory reaction, or acute phase response, in some individuals. We examined whether treatment with dexamethasone could prevent this response. A single dose of dexamethasone 4 mg, given at the time of zoledronic acid infusion, did not influence the incidence or severity of the acute phase response. INTRODUCTION: The potent bisphosphonate zoledronic acid (ZOL) is used to treat osteoporosis, Paget's disease, and hypercalcemia of malignancy. This medication can provoke an inflammatory reaction, known as the acute phase response (APR). We examined whether glucocorticoid treatment at the time of first exposure to ZOL prevents the development of APR. METHODS: This double-blind, randomized, controlled trial assessed 40 adults receiving ZOL 5 mg intravenously for the first time. Participants received oral dexamethasone 4 mg (n = 20) or placebo (n = 20) at the time of ZOL infusion. Oral temperature was measured at baseline and three times a day for 3 days following infusion. Symptoms of APR were assessed via questionnaire at baseline then daily for 3 days and again at day 15 post-infusion. Use of rescue medications (paracetamol or ibuprofen) in the 3 days following infusion was evaluated. Primary outcome was between-group difference in temperature change from baseline. RESULTS: There was no significant difference in temperature change (p = 0.95) or symptom score (p = 0.42) in the 3 days following ZOL between dexamethasone and placebo recipients. Eleven (55%) in the dexamethasone group and 10 (50%) placebo recipients experienced a temperature increase of ≥1 °C (p = 0.99). Seven (35%) in the dexamethasone group and 9 (45%) in the placebo group experienced an increase in symptom score of ≥3 points (p = 0.75). Thirteen (65%) dexamethasone recipients and 12 (60%) in the placebo group required rescue medications (p = 0.99). Dexamethasone was well-tolerated. CONCLUSIONS: A single dose of dexamethasone 4 mg does not influence the incidence or severity of APR following first exposure to ZOL. TRIAL REGISTRATION: ACTRN12615000794505.
Asunto(s)
Reacción de Fase Aguda/prevención & control , Conservadores de la Densidad Ósea/efectos adversos , Dexametasona/uso terapéutico , Difosfonatos/efectos adversos , Glucocorticoides/uso terapéutico , Imidazoles/efectos adversos , Reacción de Fase Aguda/inducido químicamente , Administración Oral , Anciano , Anciano de 80 o más Años , Conservadores de la Densidad Ósea/administración & dosificación , Dexametasona/administración & dosificación , Difosfonatos/administración & dosificación , Método Doble Ciego , Femenino , Glucocorticoides/administración & dosificación , Humanos , Imidazoles/administración & dosificación , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Ácido ZoledrónicoRESUMEN
PURPOSE: Minimally invasive surgical techniques have been shown to reduce the inflammatory response related to a surgical procedure. The main objective of our study was to measure the inflammatory response in patients undergoing a totally laparoscopic versus open aortobifemoral bypass surgery. This is the first randomized trial on subjects in this population. PATIENTS AND METHODS: This is a substudy of a larger randomized controlled multicenter trial (Norwegian Laparoscopic Aortic Surgery Trial). Thirty consecutive patients with severe aortoiliac occlusive disease eligible for aortobifemoral bypass surgery were randomized to either a totally laparoscopic (n=14) or an open surgical procedure (n=16). The inflammatory response was measured by perioperative monitoring of serum interleukin-6 (IL-6), IL-8, and C-reactive protein (CRP) at six different time points. RESULTS: The inflammatory reaction caused by the laparoscopic procedure was reduced compared with open surgery. IL-6 was significantly lower after the laparoscopic procedure, measured by comparing area under the curve (AUC), and after adjusting for the confounding effect of coronary heart disease (P=0.010). The differences in serum levels of IL-8 and CRP did not reach statistical significance. CONCLUSION: In this substudy of a randomized controlled trial comparing laparoscopic and open aortobifemoral bypass surgeries, we found a decreased perioperative inflammatory response after the laparoscopic procedure measured by comparing AUC for serum IL-6.
Asunto(s)
Reacción de Fase Aguda/prevención & control , Enfermedades de la Aorta/cirugía , Arteriopatías Oclusivas/cirugía , Arteria Ilíaca/cirugía , Laparoscopía/efectos adversos , Procedimientos Quirúrgicos Vasculares/efectos adversos , Reacción de Fase Aguda/sangre , Reacción de Fase Aguda/diagnóstico , Reacción de Fase Aguda/etiología , Anciano , Enfermedades de la Aorta/diagnóstico por imagen , Arteriopatías Oclusivas/diagnóstico por imagen , Biomarcadores/sangre , Proteína C-Reactiva/metabolismo , Constricción Patológica , Femenino , Humanos , Arteria Ilíaca/diagnóstico por imagen , Mediadores de Inflamación/sangre , Interleucina-6/sangre , Interleucina-8/sangre , Masculino , Persona de Mediana Edad , Noruega , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del Tratamiento , Procedimientos Quirúrgicos Vasculares/métodosRESUMEN
The outcome of intracerebral hemorrhage (ICH) is mainly determined by the volume of the hemorrhage core and the secondary brain damage to penumbral tissues due to brain swelling, microcirculation disturbance and inflammation. The present study aims to investigate the protective effects of cerebrolysin on brain edema and inhibition of the inflammation response surrounding the hematoma core in the acute stage after ICH. The ICH model was induced by administration of type VII bacterial collagenase into the stratum of adult rats, which were then randomly divided into three groups: ICH + saline; ICH + Cerebrolysin (5 ml/kg) and sham. Cerebrolysin or saline was administered intraperitoneally 1 h post surgery. Neurological scores, extent of brain edema content and Evans blue dye extravasation were recorded. The levels of pro-inflammatory factors (IL-1ß, TNF-α and IL-6) were assayed by Real-time PCR and Elisa kits. Aquaporin-4 (AQP4) and tight junction proteins (TJPs; claudin-5, occludin and zonula occluden-1) expression were measured at multiple time points. The morphological and intercellular changes were characterized by Electron microscopy. It is found that cerebrolysin (5 ml/kg) improved the neurological behavior and reduced the ipsilateral brain water content and Evans blue dye extravasation. After cerebrolysin treated, the levels of pro-inflammatory factors and AQP4 in the peri-hematomal areas were markedly reduced and were accompanied with higher expression of TJPs. Electron microscopy showed the astrocytic swelling and concentrated chromatin in the ICH group and confirmed the cell junction changes. Thus, early cerebrolysin treatment ameliorates secondary injury after ICH and promotes behavioral performance during the acute phase by reducing brain edema, inflammatory response, and blood-brain barrier permeability.
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Reacción de Fase Aguda/prevención & control , Aminoácidos/uso terapéutico , Edema Encefálico/prevención & control , Hemorragias Intracraneales/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Reacción de Fase Aguda/metabolismo , Reacción de Fase Aguda/fisiopatología , Animales , Acuaporina 4/metabolismo , Edema Encefálico/metabolismo , Edema Encefálico/fisiopatología , Claudina-5/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Hemorragias Intracraneales/metabolismo , Hemorragias Intracraneales/fisiopatología , Masculino , Ocludina/metabolismo , Ratas Sprague-Dawley , Factor de Necrosis Tumoral alfa/metabolismo , Proteína de la Zonula Occludens-1/metabolismoRESUMEN
BACKGROUND: The aim of this study was to determine the ability of two feed additives, a fumarate-malate (FM) and a polyphenol-essential oil mixture (PM), in attenuating the drop of ruminal pH and the metabolic and immune response resulting from an excessively high grain diet. Six heifers were used in a 3 × 3 Latin square experiment and fed a low starch (LS) diet for 14 d, followed by a high starch (HS) diet for 8 d (NDF 33.6%, starch 30.0% DM). In the last 5 days of each period, barley meal was added to decrease rumen pH. During HS feeding all animals were randomly assigned to one of the following three dietary treatments: no supplement/control (CT), a daily dose of 60 g/d of FM, or 100 g/d of PM. Reticular pH was continuously recorded using wireless boluses. On d 21 of each period, rumen fluid was collected by rumenocentesis (1400 h), together with blood (0800 h) and fecal samples (0800, 1400, and 2100 h). RESULTS: The correlation coefficient of pH values obtained using the boluses and rumenocentesis was 0.83. Compared with CT and PM, the FM treatment led to a lower DMI. Nadir pH was lowest during CT (5.40, 5.69, and 5.62 for CT, FM and PM, respectively), confirming the effectiveness of both supplements in reducing the pH drop caused by high grain feeding. This result was confirmed by the highest average time spent daily below 5.6 pH (199, 16 and 18 min/d) and by the highest acetate to propionate ratio of the CT fed heifers. The PM decreased the concentrations of neutrophils (2.9, 3.2, and 2.8 10(9)/L) and acute phase proteins: SAA (37.1, 28.6 and 20.1 µg/mL), LBP (4.1, 3.8, and 2.9 µg/mL), and Hp (675, 695 and 601 µg/mL). Free lipopolysaccharides (LPS) were detected in blood and feces, but their concentrations were not affected by treatments, as the remaining blood variables. CONCLUSIONS: Data suggest that both additives could be useful in attenuating the effects of excessive grain feeding on rumen pH, but the PM supplement was more effective than FM in reducing the inflammatory response compared to CT.
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Reacción de Fase Aguda/veterinaria , Enfermedades de los Bovinos/prevención & control , Ácidos Dicarboxílicos/uso terapéutico , Dieta/veterinaria , Aditivos Alimentarios/uso terapéutico , Polifenoles/uso terapéutico , Reticulum/efectos de los fármacos , Reacción de Fase Aguda/prevención & control , Animales , Bovinos , Enfermedades de los Bovinos/etiología , Dieta/efectos adversos , Ingestión de Alimentos , Grano Comestible/efectos adversos , Femenino , Fumaratos/uso terapéutico , Concentración de Iones de Hidrógeno , Malatos/uso terapéutico , Reticulum/metabolismo , Rumen/efectos de los fármacos , Rumen/metabolismoRESUMEN
BACKGROUND: The current study evaluated the role of delivery system (solution, conventional liposomes and PEG-ylated liposomes) on superoxide dismutase (SOD) antioxidant and antiinflammatory properties in a rat model of lipopolysaccharide (LPS)-induced peritonitis. METHODS: Fifty male albino rats (Wistar-Bratislava) were divided into five groups (n=10). Control group received saline and the other four groups received intraperitoneal injections of LPS (5mg/kg). Among the LPS-injected groups, one was LPS control group and the other three groups received the endotoxin injection 30min after receiving the same dose of SOD (500U/kg, ip) in different delivery systems: saline solution (SOD-S), conventional liposomes (SOD-L) or PEG-ylated liposomes (SOD-PL). The animals were euthanized 6h after LPS injection, blood samples were collected and acute phase response (total and differential leukocytes count; tumor necrosis factor α), antioxidants (total antioxidants; reduced glutathione), oxidative stress (total oxidants; lipid peroxidation) and nitrosative stress (nitric oxide metabolites; nitrotyrosine) were evaluated. RESULTS: Intraperitoneal administration of LPS to rats induced a marked inflammatory and oxidative response in plasma. On the other hand, all SOD formulations had protective effect against endotoxin-induced inflammation and oxidative/nitrosative stress, but PEG-ylated liposomes had the most significant activity. Thus, SOD-PL administration significantly reduced the effects of LPS on bone marrow acute phase response, the oxidative status and production of nitric oxide metabolites, while increasing the markers of antioxidant response in a significant manner. CONCLUSION: SOD supplementation interferes both with inflammatory and oxidative pathways involved in LPS-induced acute inflammation, PEG-ylated liposomal formulation being of choice among the tested delivery systems.
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Reacción de Fase Aguda/prevención & control , Antioxidantes/uso terapéutico , Sistemas de Liberación de Medicamentos , Peritonitis/tratamiento farmacológico , Superóxido Dismutasa/uso terapéutico , Reacción de Fase Aguda/sangre , Reacción de Fase Aguda/enzimología , Reacción de Fase Aguda/inmunología , Animales , Antioxidantes/administración & dosificación , Antioxidantes/metabolismo , Modelos Animales de Enfermedad , Endotoxinas/farmacología , Recuento de Leucocitos , Peroxidación de Lípido/efectos de los fármacos , Liposomas , Masculino , Óxido Nítrico/metabolismo , Estrés Oxidativo/efectos de los fármacos , Peritonitis/sangre , Peritonitis/enzimología , Peritonitis/inmunología , Ratas Wistar , Superóxido Dismutasa/administración & dosificaciónRESUMEN
A study was conducted to determine the effect of feeding yeast cell wall (YCW) products on the physiological and acute phase responses of crossbred, newly-received feedlot heifers to an endotoxin challenge. Heifers (n = 24; 219 ± 2.4 kg) were separated into treatment groups receiving either a control diet (n = 8), YCW-A (2.5 g/heifer/d; n = 8) or YCW-C (2.5 g/heifer/d; n = 8) and were fed for 52 d. On d 37 heifers were challenged i.v. with LPS (0.5 µg/kg body mass) and blood samples were collected from -2 h to 8 h and again at 24 h relative to LPS challenge. There was an increase in vaginal temperature in all heifers post-LPS, with YCW-C maintaining a lower vaginal temperature post-LPS than control and YCW-A heifers. Sickness behavior scores increased post-LPS in all heifers, but were not affected by treatment. Cortisol concentrations were greatest in control heifers post-LPS compared with YCW-A or YCW-C heifers. Concentrations of IFN-γ and TNF-α increased post-LPS, but were not affected by treatment. Serum IL-6 concentrations increased post-LPS and were greater in control heifers than YCW-A and YCW-C heifers. These data indicate that YCW supplementation can decrease the physiological and acute phase responses of newly-received heifers following an endotoxin challenge.
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Reacción de Fase Aguda/inmunología , Pared Celular/inmunología , Endotoxinas/inmunología , Interleucina-6/metabolismo , Lipopolisacáridos/inmunología , Saccharomyces cerevisiae/inmunología , Reacción de Fase Aguda/prevención & control , Administración Intravenosa , Animales , Temperatura Corporal/efectos de los fármacos , Cruzamiento , Bovinos , Citocinas/genética , Citocinas/metabolismo , Suplementos Dietéticos , Regulación de la Expresión Génica/efectos de los fármacos , Hidrocortisona/sangre , Interleucina-6/genéticaRESUMEN
BACKGROUND: Inadequate gut function is common and may adversely affect prognosis. However, it is difficult to measure and treatment options are limited. This study evaluated whether gut-specific nutrients (GSNs) could stimulate the return of gut function in critically ill patients, and assessed what effect, if any, this would have on patient outcomes. METHODS: Consecutive critically ill patients intolerant to enteral feeding were randomized to receive a cocktail of GSNs or placebo. Administration was for 1 month and patients were followed for 3 months. The primary endpoint was the time to return of normal gut function. RESULTS: Twenty-five patients were randomized to each group. GSN administration was associated with a quicker return of normal gut function (median 164 versus 214 h; P = 0.016), attenuation of the acute-phase response and a lower incidence of sepsis (4 versus 13 patients, P = 0.015) compared with placebo. There were fewer deaths by 3 months in the GSN group but this did not achieve significance (2 versus 7 deaths; P = 0.138). CONCLUSION: GSNs expedite the return of gut function in the critically ill and improve outcomes. Inadequate gut function may be associated with poor prognosis similar to that of other single organ failures. REGISTRATION NUMBER: ISRCTN61157513 (http://www.controlled-trials.com).
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Enfermedad Crítica/terapia , Suplementos Dietéticos , Dipéptidos/uso terapéutico , Tracto Gastrointestinal/fisiopatología , Recuperación de la Función , Vitaminas/uso terapéutico , Reacción de Fase Aguda/prevención & control , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Sepsis/prevención & control , Resultado del TratamientoRESUMEN
PURPOSE: This study was conducted to evaluate the effect of bevacizumab on postoperative inflammation and adhesion after strabismus surgery in rabbits. METHODS: Fifteen New Zealand White rabbits were used for this study. Both eyes of each of 15 rabbits underwent reinsertion of the superior rectus muscle (SRM). The right eye of each animal received a subconjunctival bevacizumab injection (2.5 mg/0.1 mL). As controls, normal saline was injected subconjunctivally in the contralateral eye. To assess acute inflammation changes, macrophages, neutrophils, and monocytes were localized in the SRM using an anti-CD11b antibody at postoperative day 1. At 4 weeks, the sites of muscle reattachment were evaluated grossly for postoperative adhesion score and histologically for collagen formation. RESULTS: Infiltration of acute inflammatory cells showing CD11b+ was significantly reduced in the bevacizumab injection group (P=0.001). The difference in adhesion (SRM/conjunctiva and SRM/sclera) scores between the two groups was statistically insignificant (P=0.93 and P=0.85). Histopathologic findings revealed that muscle changes and fibrosis showed no significant difference (P=0.69) between the treated eyes and the control eyes. CONCLUSIONS: The intraoperative use of bevacizumab reduced inflammatory cell infiltration in the early stage of the procedure, but it was insufficient to prevent postoperative adhesion in rabbit eyes after extraocular muscle surgery.
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Inhibidores de la Angiogénesis/farmacología , Anticuerpos Monoclonales/farmacología , Inflamación/tratamiento farmacológico , Complicaciones Posoperatorias/tratamiento farmacológico , Estrabismo/cirugía , Reacción de Fase Aguda/tratamiento farmacológico , Reacción de Fase Aguda/prevención & control , Animales , Anticuerpos Monoclonales Humanizados , Bevacizumab , Antígeno CD11b/metabolismo , Conjuntiva , Fibrosis/tratamiento farmacológico , Fibrosis/prevención & control , Inflamación/prevención & control , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Músculos Oculomotores/cirugía , Complicaciones Posoperatorias/prevención & control , Conejos , Adherencias Tisulares/tratamiento farmacológico , Adherencias Tisulares/prevención & controlRESUMEN
BACKGROUND & AIMS: The hypothesis of reverse epidemiology holds that some cardiovascular risk factors, such as obesity, hypercholesterolemia and hypertension, in the elderly or in some chronic diseases are not harmful but permit better survival. However, this phenomenon is controversial and the underlying reasons are poorly understood. OBJECTIVE: To search for factors simultaneously linked to reverse epidemiology and to short or long term survival. METHODS: We included 400 patients, older than 60 years, hospitalized in a general internal medicine unit; 61 died in hospital and 338 were followed up by telephone. RESULTS: Obesity, higher blood pressure and serum cholesterol, besides being related to lower mortality both in hospital and after discharge, were associated with better nutrition and functional capacity, less intense acute phase reaction and organ dysfunction, and lower incidence of high-mortality diseases such as dementia, pneumonia, sepsis or cancer. These associations may explain why obesity and other reverse epidemiology data are inversely related to mortality. Weight loss was related to mortality independently of BMI. Patients with BMI under 30 kg/m(2) who died in hospital showed more weight loss than those who survived; the lower the BMI, the greater the weight loss. In contrast, patients with BMI over 30 kg/m(2) who died in hospital gained more weight than those who survived; the higher the BMI, the greater the weight gain. CONCLUSION: In patients over 60 years of age admitted to an internal medicine ward, obesity did not show independent survival value, being displaced by other nutritional parameters, functional capacity, acute phase reaction, organ dysfunction and diseases with poor prognosis.
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Hipercolesterolemia/mortalidad , Hipertensión/mortalidad , Obesidad/mortalidad , Reacción de Fase Aguda/complicaciones , Reacción de Fase Aguda/epidemiología , Reacción de Fase Aguda/prevención & control , Anciano , Anciano de 80 o más Años , Índice de Masa Corporal , Demencia/complicaciones , Demencia/epidemiología , Demencia/prevención & control , Femenino , Hospitales Universitarios , Humanos , Hipercolesterolemia/complicaciones , Hipertensión/complicaciones , Masculino , Persona de Mediana Edad , Neoplasias/complicaciones , Neoplasias/epidemiología , Neoplasias/prevención & control , Estado Nutricional , Obesidad/complicaciones , Neumonía/complicaciones , Neumonía/epidemiología , Neumonía/prevención & control , Sepsis/complicaciones , Sepsis/epidemiología , Sepsis/prevención & control , Análisis de Supervivencia , Pérdida de PesoRESUMEN
INTRODUCTION: An experimental study was conducted to investigate the effects of erythropoietin on the acute phase of esophageal burn damage induced by sodium hydroxide. MATERIALS AND METHODS: A standard esophageal alkaline burn was produced by the application of 10% sodium hydroxide to the distal esophagus in an in vivo rat model. Fifty-six female rats were allocated into three groups: Group BC (baseline control, n = 8) rats were uninjured and untreated, Group PC (positive control, n = 24) rats were injured but untreated and Group EPO (erythropoietin-treated, n = 24) rats were injured and given subcutaneous erythropoietin (1,000 IU/kg per day), 15 min, 24, and 48 h after administration of the NaOH solution. Six animals from Group PC and six from Group EPO were killed at 4, 24, 48, and 72 h after application of NaOH to the esophagus. All of animals in Group BC were killed 4 h after exposure to 0.9% NaCl. Oxidative damage was assessed by measuring levels of malondialdehyde (MDA) and nitric oxide (NO), and activities of superoxide dismutase (SOD) and catalase (CAT) in homogenized samples of esophageal tissue. Histologic damage to esophageal tissue was scored by a single pathologist blind to groups. RESULTS: MDA levels in the BC and EPO groups were significantly lower than those in the PC group (p < 0.05). CAT and SOD activities, and NO levels in the BC and EPO groups were significantly higher than in the PC group (p < 0.05). Esophageal tissue damage measured at 4, 24, 48, and 72 h after NaOH application was significantly less in the EPO group than in the PC group (p < 0.05). CONCLUSIONS: When administered early after an esophageal burn induced by 10% sodium hydroxide in this rat model, erythropoietin significantly attenuated oxidative damage, as measured by biochemical markers and histologic scoring.
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Reacción de Fase Aguda/prevención & control , Quemaduras Químicas/tratamiento farmacológico , Eritropoyetina/uso terapéutico , Esófago/lesiones , Estrés Oxidativo/efectos de los fármacos , Reacción de Fase Aguda/etiología , Reacción de Fase Aguda/patología , Animales , Quemaduras Químicas/metabolismo , Quemaduras Químicas/patología , Catalasa/metabolismo , Cáusticos/toxicidad , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Esófago/metabolismo , Esófago/patología , Femenino , Inyecciones Subcutáneas , Malondialdehído/metabolismo , Óxido Nítrico/metabolismo , Ratas , Ratas Sprague-Dawley , Hidróxido de Sodio/toxicidad , Superóxido Dismutasa/metabolismo , Índices de Gravedad del Trauma , Resultado del TratamientoRESUMEN
The pathogenesis of lung injury by exposure to highly toxic sulfur and nitrogen mustards involves alkylating damage of the respiratory epithelium followed by an acute inflammatory response and lung edema. The acute phase is followed by long-term respiratory complications characterized by bronchitis, lung fibrosis, and airway hyperreactivity. In this study, we utilized a mouse model for airway inflammation induced by inhalation exposure to the alkylating nitrogen mustard melphalan, in order to investigate possible beneficial treatment effects by the corticosteroid dexamethasone. In addition, we investigated therapeutic efficacy of liposome-encapsuled vitamin E, an antioxidant formulation previously shown to be efficient in counteracting inflammatory conditions. Influx of inflammatory cells to airways, edema formation, and expression of different cytokines were analyzed 6 and 18 hours after exposure to melphalan. In order to evaluate long-term lung effects, we also investigated collagen deposition and accumulation of lymphocytes at 2 and 4 weeks after exposure. A single intraperitoneal injection of dexamethasone (10 mg/kg body weight) 1 hour after melphalan exposure significantly reduced interleukin (IL)-1 and IL-6 in bronchoalveolar lavage fluid (BALF) and diminished the acute airway inflammation. Our results also indicate that early single-dose treatment with dexamethasone protects against long-term effects observed 2-4 weeks after melphalan exposure, as indicated by reduced lymphocytic response in airways and decreased collagen deposition. Furthermore, our results indicate that also vitamin E (50 mg/kg) reduces acute inflammatory cell influx, and suppresses collagen formation in lung tissue, indicating that this drug could be used in combination with corticosteroids for protection against chemical-induced lung injury.
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Antiinflamatorios/uso terapéutico , Antioxidantes/uso terapéutico , Quemaduras Químicas/tratamiento farmacológico , Dexametasona/uso terapéutico , Lesión Pulmonar/tratamiento farmacológico , Vitamina E/uso terapéutico , Reacción de Fase Aguda/prevención & control , Animales , Antioxidantes/administración & dosificación , Líquido del Lavado Bronquioalveolar/citología , Colágeno/metabolismo , Citocinas/biosíntesis , Portadores de Fármacos , Femenino , Liposomas , Lesión Pulmonar/patología , Linfocitos/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Infiltración Neutrófila/efectos de los fármacos , Edema Pulmonar/patología , Edema Pulmonar/prevención & control , Fibrosis Pulmonar/patología , Fibrosis Pulmonar/prevención & control , Vitamina E/administración & dosificaciónRESUMEN
Lipopolysaccharide (LPS), a glycolipid component of the cell wall of gram-negative bacteria can elicit a systemic inflammatory process leading to septic shock and death. Acute phase response is characterized by fever, leucocytosis, thrombocytopenia, altered metabolic responses and redox balance by inducing excessive reactive oxygen species (ROS) generation. Resveratrol (trans-3,5,4' trihydroxystilbene) is a natural polyphenol exhibiting antioxidant and anti-inflammatory properties. We investigated the protective effect of resveratrol on endotoxemia-induced acute phase response in rats. When acutely administered by i.p. route, resveratrol (40 mg/kg b.w.) counteracted the effect of a single injection of LPS (4 mg/kg b.w.) which induced fever, a decrease in white blood cells (WBC) and platelets (PLT) counts. When i.p. administered during 7 days at 20 mg/kg per day (subacute treatment), resveratrol abrogated LPS-induced erythrocytes lipoperoxidation and catalase (CAT) activity depression to control levels. In the plasma compartment, LPS increased malondialdehyde (MDA) via nitric monoxide (NO) elevation and decreased iron level. All these deleterious LPS effects were reversed by a subacute resveratrol pre-treatment via a NO independent way. Resveratrol exhibited potent protective effect on LPS-induced acute phase response in rats.
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Reacción de Fase Aguda/prevención & control , Antioxidantes/farmacología , Endotoxemia/prevención & control , Estilbenos/farmacología , Reacción de Fase Aguda/sangre , Reacción de Fase Aguda/inducido químicamente , Animales , Plaquetas/efectos de los fármacos , Plaquetas/patología , Temperatura Corporal/efectos de los fármacos , Catalasa/metabolismo , Modelos Animales de Enfermedad , Antagonismo de Drogas , Endotoxemia/sangre , Endotoxemia/inducido químicamente , Eritrocitos/efectos de los fármacos , Eritrocitos/enzimología , Fiebre/inducido químicamente , Fiebre/tratamiento farmacológico , Inyecciones Intraperitoneales , Hierro/sangre , Leucocitos/efectos de los fármacos , Leucocitos/patología , Peroxidación de Lípido/efectos de los fármacos , Lipopolisacáridos/toxicidad , Masculino , Malondialdehído/metabolismo , Óxido Nítrico/sangre , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , ResveratrolRESUMEN
OBJECTIVE: To investigate the therapeutic effects of alprostadil (Lipo-PGE1) and Ulinastatin on inflammatory response and lung injury after cardiopulmonary bypass (CPB) in pediatric patients with congenital heart diseases. METHODS: 58 children with congenital heart diseases, including atrial septal defect, ventricular septal defect, and atrioventricular septal defect, scheduled to undergo CPB, aged 4 - 72 months, were randomly divided into 4 groups: alprostadil Group P (n = 15) receiving alprostadil 10 ng/ml added into the prime solution and continuous pump infusion of alprostadil 10 ngxkg(-1)xmin(-1) via central vein until the end of operation, Group U (n = 15) receiving ulinastatin 20 000 U/kg divided into several doses to be added into the prime solution, Group PU (n = 14) receiving alprostadil and ulinastatin according to the above protocols, and Group C (control group, n = 14) receiving normal saline of the equal volume. Electrocardiogram (ECG), heart rate (HR), pulse oxygen saturation (SpO(2)), and mean arterial pressure (MAP) were continuously monitored during operation. Duration of mechanical ventilation and staying in ICU were also recorded. Plasma neutrophil (PMN), IL-6, IL-8, IL-10, tumor necrosis factor (TNF)-alpha and matrix metalloproteinase (MMP-9) levels in the radial arterial blood samples were measured after induction of anesthesia before CPB (T(1)), 30 minutes and (T(2)), 2 hours (T(3)), 6 hours (T(4)), and 24 hours (T(5)) after the declamping of aorta. Inhaled oxygen concentration and arterial blood gas analysis were recorded at T(1), T(2), and T(3) for calculation of oxygenation index (OI). RESULTS: There were no significant differences in the MAP and HR among these four groups at any time points (all P > 0.05). The umbers of PMN and the levels of IL-6, IL-8, and TNF-alpha at T(2) and T(3) of Groups P, U, and PU were all significantly lower than that of Group C (all P < 0.05), with those of Group PU being the lowest. The IL-10 levels at T(2) and T(3) of Groups U and PU were significantly higher than that of Group C (both P < 0.05), the level of MMP-9 at T(2) and T(3) of Groups U and PU were significantly lower than that of Group C (all P < 0.05), however, there was not significant difference between Group P and Group C (P > 0.05). The OIs at T(2) of Groups P, U, and PU were significantly higher than that of Group C (all P < 0.05). The mechanical ventilation time of Groups P, U, and PU were all significantly shorter than that of Group C, and that of Group PU was significantly shorter than that of group C (P < 0.05). CONCLUSION: Decreasing the inflammatory response after CPB, alprostadil and ulinastatin used during CPB effectively reduce the pulmonary injury via inhibition of the neutrophil activation and cytokines release.
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Reacción de Fase Aguda/prevención & control , Alprostadil/uso terapéutico , Antiinflamatorios/uso terapéutico , Puente Cardiopulmonar , Glicoproteínas/uso terapéutico , Lesión Pulmonar/prevención & control , Reacción de Fase Aguda/etiología , Puente Cardiopulmonar/efectos adversos , Niño , Preescolar , Citocinas , Femenino , Cardiopatías Congénitas/cirugía , Humanos , Lesión Pulmonar/etiología , Masculino , NeutrófilosRESUMEN
OBJECTIVES: To evaluate whether robotically assisted laparoscopic prostatectomy (RALP) is less invasive than radical retropubic prostatectomy (RRP), as experimental studies suggest that the acute phase reaction is proportional to surgery-induced tissue damage. PATIENTS AND METHODS: Between May and November 2006, all patients undergoing RRP or RALP in our department were prospectively assessed. Blood samples were collected 24 h before (T0), during surgery (T1), at the end of anaesthesia (T2), and 12 (T3) and 24 h after surgery (T4), and assayed for interleukin(IL)-6 and IL-1 alpha, C-reactive protein (CRP), and lactate. The Mann-Whitney U-, Student's t- and Friedman tests were used to compare continuous variables, and the Pearson chi-square and Fisher test for categorical variables, with a two-sided P < 0.05 considered to indicate significance. RESULTS: In all, 35 and 26 patients were assessed for RALP and RRP, respectively; the median (interquartile range) age was 62 (56-68) and 68.5 (59.2-71.2) years, respectively (P < 0.009). Baseline levels (T0) of IL-1, IL-6, CRP and lactate were comparable in both arms. IL-6, CRP and lactates levels increased during both kinds of surgery. The mean IL-6 and CPR values were higher for RRP at T1 (P = 0.01 and 0.001), T2 (P = 0.001 and <0.001), T3 (P = 0.002 and <0.001) and T4 (P < 0.001 and 0.02), respectively. Lactate was higher for RRP at T2 (P = 0.001), T3 (P = 0.001) and T4 (P = 0.004), although remaining within the normal ranges. IL-1 alpha did not change at the different sample times. CONCLUSIONS: This study showed for the first time that RALP induces lower tissue trauma than RRP.
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Reacción de Fase Aguda/prevención & control , Laparoscopía , Complicaciones Posoperatorias/prevención & control , Prostatectomía/métodos , Neoplasias de la Próstata/cirugía , Robótica , Anciano , Proteína C-Reactiva/análisis , Humanos , Interleucina-1alfa/sangre , Interleucina-6/sangre , Ácido Láctico/sangre , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Prostatectomía/efectos adversos , Neoplasias de la Próstata/sangre , Estadísticas no Paramétricas , Resultado del TratamientoRESUMEN
AIMS: The aim of this article is to review the current state of knowledge with regard to the importance of C-reactive protein (CRP) in patients undergoing hepatic resection for malignancy both in terms of its role as an acute phase reactant and predictor of outcome. METHODS: An electronic search was performed of the medical literature using the MEDLINE database to identify relevant articles that included the search terms: C-reactive protein; CRP; hepatocellular carcinoma; colorectal liver metastases; hepatic resection; and liver resection. RESULTS: The limited published data in relation to CRP and liver resection is contradictory. There are studies correlating an acute phase reactant-type postoperative rise in CRP with both good and poor outcome following colorectal liver metastases resection. In relation to prognosis, the only available publication indicates that a high preoperative CRP is a poor prognostic indicator in relation to patient survival. Data for CRP and resection of HCC is equally as limited with early evidence suggesting a correlation between CRP and stage of disease, and documenting an acute temporary elevation in CRP following resection. CONCLUSIONS: The importance of CRP as a marker of both early postoperative outcome and long-term prognosis in patients with hepatic malignancies is at present unclear. Further studies are required to clarify the changes and more accurately define the mechanism by which CRP is being up-regulated.
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Reacción de Fase Aguda/prevención & control , Proteína C-Reactiva/metabolismo , Hepatectomía/efectos adversos , Neoplasias Hepáticas/cirugía , Reacción de Fase Aguda/etiología , Biomarcadores/sangre , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/cirugía , Neoplasias Colorrectales/patología , Humanos , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/secundario , PronósticoRESUMEN
Serum amyloid A protein (SAA) is an acute phase protein, known to be a sensitive indicator of inflammation. We have characterized the time course of the SAA response and inflammatory reaction to silver nitrate injection s.c. in mice and studied the effects of dexamethasone and macrolide antibiotics. 2% Sterile silver nitrate solution was injected s.c. into female BALB/c mice and blood collected by capillary action from the tail vein of each mouse at different time points. Hematological variables were determined, albumin by spectrophotometry and SAA and cytokines by ELISA. Animals were treated with either a single i.p. dose of dexamethasone (5-30 mg/kg) 1 h after or daily oral doses of macrolide antibiotics for 3 days. SAA concentrations after silver nitrate injection peaked at 24 h, preceded by increases in serum IL-1 beta and IL-6, associated with decreases in blood leukocytes and local tissue inflammation. Single dexamethasone treatment and daily dosing for 3 days with azithromycin, clarithromycin and roxithromycin (20-80 mg/kg p.o.), but not erythromycin (100-150 mg/kg p.o.), inhibited the increase in SAA but with varying time courses. SAA, measured continuously, is a useful marker of sterile inflammation in mice and is differentially inhibited by macrolide antibiotics.