RESUMEN
Sex seems to be a contributing factor in the pathogenesis of bronchial asthma. This study aimed to find sex-related differences in metabolome measured by hydrogen-1 nuclear magnetic resonance ((1)H NMR) spectroscopy in healthy and ovalbumin (OVA)-sensitized guinea pigs. Adult male and female animals were divided into controls and OVA-sensitized groups. OVA-sensitization was performed by OVA systemic and inhalational administration within 14 days; on day 15, animals were killed by anesthetic overdose followed by exsanguination. Blood was taken and differential white blood cell count was measured. Left lung was saline-lavaged and differential cell count in the bronchoalveolar lavage fluid (BALF) was measured. After blood centrifugation, plasma was processed for (1)H NMR analysis. Metabolomic data was evaluated by principal component analysis (PCA). Eosinophil counts elevated in the BALF confirming eosinophil-mediated inflammation in OVA-sensitized animals of both sexes. Sex differences for lactate, glucose, and citrate were found in controls, where these parameters were lower in males than in females. In OVA-sensitized males higher glucose and lower pyruvate were found compared to controls. OVA-sensitized females showed lower lactate, glucose, alanine, 3-hydroxy-butyrate, creatine, pyruvate, and succinate concentrations compared to controls. In OVA-sensitized animals, lactate concentration was lower in males. Data from females (healthy and OVA-sensitized) were generally more heterogeneous. Significant sex differences in plasma concentrations of metabolites were found in both healthy and OVA-sensitized animals suggesting that sex may influence the metabolism and may thereby contribute to different clinical picture of asthma in males and females.
Asunto(s)
Asma , Caracteres Sexuales , Femenino , Cobayas , Masculino , Animales , Ratones , Ovalbúmina , Modelos Animales de Enfermedad , Asma/inducido químicamente , Líquido del Lavado Bronquioalveolar , Alérgenos , Lactatos , Glucosa , Piruvatos , Ratones Endogámicos BALB CRESUMEN
The development of acute respiratory distress syndrome (ARDS) is known to be independently attributable to aspiration-induced lung injury. Mechanical ventilation as a high pressure/volume support to maintain sufficient oxygenation of a patient could initiate ventilator-induced lung injury (VILI) and thus contribute to lung damage. Although these phenomena are rare in the clinic, they could serve as the severe experimental model of alveolar-capillary membrane deterioration. Lung collapse, diffuse inflammation, alveolar epithelial and endothelial damage, leakage of fluid into the alveoli, and subsequent inactivation of pulmonary surfactant, leading to respiratory failure. Therefore, exogenous surfactant could be considered as a therapy to restore lung function in experimental ARDS. This study aimed to investigate the effect of modified porcine surfactant in animal model of severe ARDS (P/F ratio =13.3 kPa) induced by intratracheal instillation of hydrochloric acid (HCl, 3 ml/kg, pH 1.25) followed by VILI (V(T) 20 ml/kg). Adult rabbits were divided into three groups: untreated ARDS, model treated with a bolus of poractant alfa (Curosurf®, 2.5 ml/kg, 80 mg phospholipids/ml), and healthy ventilated animals (saline), which were oxygen-ventilated for an additional 4 h. The lung function parameters, histological appearance, degree of lung edema and levels of inflammatory and oxidative markers in plasma were evaluated. Whereas surfactant therapy with poractant alfa improved lung function, attenuated inflammation and lung edema, and partially regenerated significant changes in lung architecture compared to untreated controls. This study indicates a potential of exogenous surfactant preparation in the treatment of experimental ARDS.
Asunto(s)
Surfactantes Pulmonares , Síndrome de Dificultad Respiratoria , Lesión Pulmonar Inducida por Ventilación Mecánica , Animales , Porcinos , Conejos , Surfactantes Pulmonares/uso terapéutico , Surfactantes Pulmonares/farmacología , Tensoactivos/farmacología , Tensoactivos/uso terapéutico , Ácido Clorhídrico/toxicidad , Ácido Clorhídrico/uso terapéutico , Pulmón , Síndrome de Dificultad Respiratoria/inducido químicamente , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Lesión Pulmonar Inducida por Ventilación Mecánica/tratamiento farmacológico , Inflamación , EdemaRESUMEN
Herbal compounds including those already well-established in traditional Chinese medicine have been increasingly tested in the treatment of various diseases. Recent studies have shown that herbal compounds can be of benefit also for pulmonary silicosis as they can diminish changes associated with silica-induced inflammation, fibrosis, and oxidative stress. Due to a lack of effective therapeutic strategies, development of novel approaches which may be introduced particularly in the early stage of the disease, is urgently needed. This review summarizes positive effects of several alternative plant-based drugs in the models of experimental silicosis with a potential for subsequent clinical investigation and use in future.
Asunto(s)
Antiinflamatorios/uso terapéutico , Antioxidantes/uso terapéutico , Pulmón/efectos de los fármacos , Preparaciones de Plantas/uso terapéutico , Fibrosis Pulmonar/tratamiento farmacológico , Silicosis/tratamiento farmacológico , Animales , Antiinflamatorios/efectos adversos , Humanos , Mediadores de Inflamación/metabolismo , Pulmón/metabolismo , Pulmón/patología , Estrés Oxidativo/efectos de los fármacos , Preparaciones de Plantas/efectos adversos , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/patología , Especies Reactivas de Oxígeno/metabolismo , Silicosis/metabolismo , Silicosis/patologíaRESUMEN
FeNO measurement is a validated non-invasive technique, which is used for diagnosis and monitoring of asthma. It would be desirable to find a reliable method to monitor allergic rhinitis (AR) via measurement of FeNO, and/or nasal nitric oxide (nNO). The aim of our study was the assessment of the efficacy of FeNO and nNO as markers in AR treatment. FeNO and nNO were measured with the portable NO analyser (NIOX MINO®) in healthy participants and in patients with AR. The patients were examined during the pollen season and out of it. The effect of local corticosteroids and antihistamine therapy was observed in patients with AR during pollen season after three weeks of therapy. There are significant differences between FeNO and nNO in patients with AR compared to healthy controls at all set points of measurements. While FeNO responded well to the treatment with both antihistamines and combined therapy, nNO decreased only after combined therapy with antihistamines and nasal corticosteroids. nNO monitoring alone is not a suitable method to monitor inflammation of the upper airways in AR and its suppression by anti-allergic treatment and should be correlated with other markers as FeNO or symptom scores.
Asunto(s)
Espiración/fisiología , Mucosa Nasal/metabolismo , Óxido Nítrico/metabolismo , Rinitis Alérgica/diagnóstico , Rinitis Alérgica/metabolismo , Administración Intranasal , Adolescente , Corticoesteroides/administración & dosificación , Adulto , Biomarcadores/análisis , Biomarcadores/metabolismo , Espiración/efectos de los fármacos , Femenino , Antagonistas de los Receptores Histamínicos/administración & dosificación , Humanos , Masculino , Persona de Mediana Edad , Mucosa Nasal/efectos de los fármacos , Óxido Nítrico/análisis , Rinitis Alérgica/tratamiento farmacológico , Adulto JovenRESUMEN
Acute lung injury is characterized by acute respiratory insufficiency with tachypnea, cyanosis refractory to oxygen, decreased lung compliance, and diffuse alveolar infiltrates on chest X-ray. The 1994 American-European Consensus Conference defined "acute respiratory distress syndrome, ARDS" by acute onset after a known trigger, severe hypoxemia defined by PaO2/FiO2=200 mm Hg, bilateral infiltrates on chest X-ray, and absence of cardiogenic edema. Milder form of the syndrome with PaO2/FiO2 between 200-300 mm Hg was named "acute lung injury, ALI". Berlin Classification in 2012 defined three categories of ARDS according to hypoxemia (mild, moderate, and severe), and the term "acute lung injury" was assigned for general description or for animal models. ALI/ARDS can originate from direct lung triggers such as pneumonia or aspiration, or from extrapulmonary reasons such as sepsis or trauma. Despite growing understanding the ARDS pathophysiology, efficacy of standard treatments, such as lung protective ventilation, prone positioning, and neuromuscular blockers, is often limited. However, there is an increasing evidence that direct and indirect forms of ARDS may differ not only in the manifestations of alterations, but also in the response to treatment. Thus, individualized treatment according to ARDS subtypes may enhance the efficacy of given treatment and improve the survival of patients.
Asunto(s)
Lesión Pulmonar Aguda/fisiopatología , Lesión Pulmonar Aguda/terapia , Respiración Artificial/métodos , Síndrome de Dificultad Respiratoria/fisiopatología , Síndrome de Dificultad Respiratoria/terapia , Animales , HumanosRESUMEN
Acute respiratory distress syndrome (ARDS) is characterized by diffuse lung damage, inflammation, oedema formation, and surfactant dysfunction leading to hypoxemia. Severe ARDS can accelerate the injury of other organs, worsening the patient´s status. There is an evidence that the lung tissue injury affects the right heart function causing cor pulmonale. However, heart tissue changes associated with ARDS are still poorly known. Therefore, this study evaluated oxidative and inflammatory modifications of the heart tissue in two experimental models of ARDS induced in New Zealand rabbits by intratracheal instillation of neonatal meconium (100 mg/kg) or by repetitive lung lavages with saline (30 ml/kg). Since induction of the respiratory insufficiency, all animals were oxygen-ventilated for next 5 h. Total and differential counts of leukocytes were measured in the arterial blood, markers of myocardial injury [(troponin, creatine kinase - myocardial band (CK-MB), lactate dehydrogenase (LD)] in the plasma, and markers of inflammation [tumour necrosis factor (TNF)alpha, interleukin (IL)-6], cardiovascular risk [galectin-3 (Gal-3)], oxidative changes [thiobarbituric acid reactive substances (TBARS), 3-nitrotyrosine (3NT)], and vascular damage [receptor for advanced glycation end products (RAGE)] in the heart tissue. Apoptosis of heart cells was investigated immunohistochemically. In both ARDS models, counts of total leukocytes and neutrophils in the blood, markers of myocardial injury, inflammation, oxidative and vascular damage in the plasma and heart tissue, and heart cell apoptosis increased compared to controls. This study indicates that changes associated with ARDS may contribute to early heart damage what can potentially deteriorate the cardiac function and contribute to its failure.
Asunto(s)
Lesiones Cardíacas/patología , Inflamación/patología , Lesión Pulmonar/patología , Síndrome de Dificultad Respiratoria/patología , Animales , Apoptosis/fisiología , Biomarcadores/metabolismo , Modelos Animales de Enfermedad , Femenino , Lesiones Cardíacas/metabolismo , Inflamación/metabolismo , Lesión Pulmonar/metabolismo , Masculino , Síndrome de Aspiración de Meconio/metabolismo , Síndrome de Aspiración de Meconio/patología , Estrés Oxidativo/fisiología , Conejos , Síndrome de Dificultad Respiratoria/metabolismoRESUMEN
Mental disorders affect 10-20 % of the young population in the world. Major depressive disorder (MDD) is a common mental disease with a multifactorial and not clearly explained pathophysiology. Many cases remain undetected and untreated, which influences patients' physical and mental health and their quality of life also in adulthood. The aim of our pilot study was to assess the prediction value of selected potential biomarkers, including blood cell counts, blood cell ratios, and parameters like peroxiredoxin 1 (PRDX1), tenascin C (TNC) and type IV collagen (COL4) between depressive pediatric patients and healthy peers and to evaluate a short effect of antidepressant treatment. In this study, 27 young depressive patients and 26 non-depressed age-matched controls were included. Blood analyses and immunological assays using commercial kits were performed. Platelet count was the only blood parameter for which the case/control status was statistically significant (p=0.01) in a regression model controlling for the age and gender differences. The results from ELISA analyses showed that the case/control status is a significant predictor of the parameters PRDX1 (p=0.05) and COL4 (p=0.009) in respective regression model considering the age and gender differences between MDD patients and controls. A major finding of this study is that values of platelet count, monocyte to lymphocyte ratio, white blood cell, and monocyte counts were assessed by the Random Forest machine learning algorithm as relevant predictors for discrimination between MDD patients and healthy controls with a power of prediction AUC=0.749.
Asunto(s)
Trastorno Depresivo Mayor/epidemiología , Adolescente , Biomarcadores/análisis , Estudios de Casos y Controles , Trastorno Depresivo Mayor/diagnóstico , Trastorno Depresivo Mayor/psicología , Femenino , Humanos , Masculino , Proyectos Piloto , Calidad de Vida , Eslovaquia/epidemiologíaRESUMEN
Inflammation associated with acute respiratory distress syndrome (ARDS) can damage the alveolar epithelium and surfactant and worsen the respiratory failure. Glucocorticoids (GC) appear to be a rational therapeutic approach, but the effect is still unclear, especially for early administration and low-dose. In this study we compared two low doses of dexamethasone in early phase of surfactant-depleted model of acute respiratory distress syndrome (ARDS). In the study, lung-lavaged New Zealand rabbits with respiratory failure (PaO(2)<26.7 kPa in FiO(2) 1.0) were treated with intravenous dexamethasone (DEX): 0.5 mg/kg (DEX-0.5) and 1.0 mg/kg (DEX-1.0), or were untreated (ARDS). Animals without ARDS served as controls. Respiratory parameters, lung edema, leukocyte shifts, markers of inflammation and oxidative damage in the plasma and lung were evaluated. Both doses of DEX improved the lung function vs. untreated animals. DEX-1.0 had faster onset with significant improvement in gas exchange and ventilation efficiency vs. DEX-0.5. DEX-1.0 showed a trend to reduce lung neutrophils, local oxidative damage, and levels of TNFalpha, IL-6, IL-8 more effectively than DEX-0.5 vs. ARDS group. Both dosages of dexamethasone significantly improved the lung function and suppressed inflammation in early phase ARDS, while some additional enhancement was observed for higher dose (1 mg/kg) of DEX.
Asunto(s)
Antiinflamatorios/administración & dosificación , Dexametasona/administración & dosificación , Inflamación/tratamiento farmacológico , Pulmón/efectos de los fármacos , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Animales , Líquido del Lavado Bronquioalveolar/citología , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Femenino , Recuento de Leucocitos , Masculino , Conejos , Síndrome de Dificultad Respiratoria/sangre , Síndrome de Dificultad Respiratoria/inmunología , Pruebas de Función RespiratoriaRESUMEN
Acute respiratory distress syndrome (ARDS) is characterized by acute hypoxemia, neutrophil-mediated inflammation, and lung edema formation. Whereas lung damage might be alleviated by nitric oxide (NO), goal of this study was to evaluate if intratracheal NO donor S-nitroso-N-acetylpenicillamine (SNAP) can positively influence the lung functions in experimental model of ARDS. New Zealand rabbits with respiratory failure induced by saline lavage (30 ml/kg, 9+/-3 times) were divided into: ARDS group without therapy, ARDS group treated with SNAP (7 mg/kg i.t.), and healthy Control group. During 5 h of ventilation, respiratory parameters (blood gases, ventilatory pressures) were estimated. After anesthetics overdosing, left lung was saline-lavaged and cell count, cell viability and protein content in bronchoalveolar lavage fluid (BALF) were measured. Right lung tissue was used for estimation of wet/dry weight ratio, concentration of NO metabolites, and histomorphological investigation. Repetitive lung lavage induced lung injury, worsened gas exchange, and damaged alveolar-capillary membrane. Administration of SNAP reduced cell count in BALF, lung edema formation, NO metabolites, and histopathological signs of injury, and improved respiratory parameters. Treatment with intratracheal SNAP alleviated lung injury and edema and improved lung functions in a saline-lavaged model of ARDS suggesting a potential of NO donors also for patients with ARDS.
Asunto(s)
Pulmón/efectos de los fármacos , Donantes de Óxido Nítrico/uso terapéutico , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , S-Nitroso-N-Acetilpenicilamina/uso terapéutico , Animales , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Femenino , Pulmón/metabolismo , Pulmón/patología , Masculino , Nitratos/metabolismo , Donantes de Óxido Nítrico/farmacología , Nitritos/metabolismo , Conejos , Síndrome de Dificultad Respiratoria/patología , S-Nitroso-N-Acetilpenicilamina/farmacologíaRESUMEN
Pulmonary surfactant has a relaxing effect on the airway smooth muscle (ASM), which suggests its role in the pathogenesis of respiratory diseases associated with hyperreactivity of the ASM, such as asthma and chronic obstructive pulmonary disease (COPD). The ASM tone may be directly or indirectly modified by bacterial wall component lipopolysaccharide (LPS). This study elucidated the effect of LPS on the ASM reactivity and the role of surfactant in this interaction. The experiments were performed using ASM of adult guinea pigs by in vitro method of tissue organ bath (ASM unexposed-healthy or exposed to LPS under in vitro conditions) and ASM of animals intraperitoneally injected with LPS at a dose 1 mg/kg of b.w. once a day during 4-day period. Variable response of LPS was controlled by cyclooxygenase inhibitor indomethacin and relaxing effect of exogenous surfactant was studied using leukotriene and histamine receptor antagonists. The exogenous surfactant has relaxing effect on the ASM, but does not reverse LPS-induced smooth muscle contraction. The results further indicate participation of prostanoids and potential involvement of leukotriene and histamine H1 receptors in the airway smooth muscle contraction during LPS exposure.
Asunto(s)
Músculo Liso/efectos de los fármacos , Surfactantes Pulmonares/farmacología , Acetatos , Animales , Ciclopropanos , Cobayas , Lipopolisacáridos , Masculino , Relajación Muscular/efectos de los fármacos , Pirilamina , Quinolinas , SulfurosRESUMEN
Acute lung injury (ALI) is associated with deterioration of alveolar-capillary lining and transmigration and activation of inflammatory cells. Sildenafil, phosphodiesterase 5 (PDE5) inhibitor, inhibits degradation of cyclic guanosine monophosphate (cGMP) by competing with cGMP for binding site of PDE5. Positive effects of sildenafil treatment result from influencing proliferation of regulatory T cells and production of proinflammatory cytokines and autoantibodies as well as from modulation of platelet activation, angiogenesis, and pulmonary vasoreactivity. This study evaluated if intravenous sildenafil can influence inflammation, edema formation, apoptosis, and respiratory parameters in rabbits with a model of ALI induced by repetitive lung lavage by saline (30 ml/kg). animals were divided into 3 groups: ALI without therapy (ALI), ALI treated with sildenafil intravenously (1 mg/kg; ALI + Sil), and healthy ventilated controls (Control) which were oxygen-ventilated for 4 hours following treatment administration. during this period, respiratory parameters (ventilator pressures, lung compliance, blood gases, oxygenation indexes etc.) were regularly measured. at the end of experiment, animals were overdosed by anesthetics. The left lung was saline-lavaged and total and differential cell counts and protein content in the bronchoalveolar lavage fluid (BAL) were estimated. The right lung was used for determination of lung edema formation expressed as wet/dry lung weight ratio, for detection of inflammation and oxidative stress markers by ELISA methods, and for detection of lung epithelial cells apoptosis by TUNEL methods and level of caspase-3. Sildenafil treatment reduced leak of cells (P < 0.05), particularly of neutrophils (P < 0.001) into the lung, release of pro-inflammatory mediators (TNF-α, P < 0.001; IL-8 and IL-6, P < 0.01), level of nitrite/nitrate (P < 0.001), markers of oxidative damage (3-nitrotyrosine and malondialdehyde, both P < 0.01), lung edema formation (P < 0.01), protein content in BAL (P < 0.001), and apoptosis of epithelial cells (P < 0.01), and improved respiratory parameters. Concluding, the results indicate a future potential of PDE5 inhibitors also for the therapy of ALI.
Asunto(s)
Lesión Pulmonar Aguda/tratamiento farmacológico , Antiinflamatorios/uso terapéutico , Inhibidores de Fosfodiesterasa 5/uso terapéutico , Citrato de Sildenafil/uso terapéutico , Lesión Pulmonar Aguda/inmunología , Lesión Pulmonar Aguda/fisiopatología , Animales , Antiinflamatorios/farmacología , Apoptosis/efectos de los fármacos , Lavado Broncoalveolar , Citocinas/inmunología , Modelos Animales de Enfermedad , Células Epiteliales/efectos de los fármacos , Neutrófilos/efectos de los fármacos , Neutrófilos/inmunología , Nitratos/inmunología , Nitritos/inmunología , Inhibidores de Fosfodiesterasa 5/farmacología , Ventilación Pulmonar/efectos de los fármacos , Conejos , Solución Salina , Citrato de Sildenafil/farmacologíaRESUMEN
Damage of alveolar-capillary barrier, inflammation, oxidative injury, and lung cell apoptosis represent the key features of acute lung injury (ALI). This study evaluated if selective phosphodiesterase (PDE)-4 inhibitor roflumilast can reduce the mentioned changes in lavage-induced model of ALI. Rabbits with ALI were divided into 2 groups: ALI without therapy (A group) and ALI treated with roflumilast i.v. (1 mg/kg; A+R group). One group of healthy animals without ALI served as ventilated controls (C group). All animals were oxygen-ventilated for further 4 h. At the end of experiment, total and differential counts of cells in bronchoalveolar lavage fluid (BALF) and total and differential counts of white blood cells were estimated. Lung edema formation was assessed from determination of protein content in BALF. Pro-inflammatory cytokines (TNFalpha, IL-6 and IL-8) and markers of oxidation (3-nitrotyrosine, thiobarbituric-acid reactive substances) were detected in the lung tissue and plasma. Apoptosis of lung cells was investigated immunohistochemically. Treatment with roflumilast reduced leak of cells, particularly of neutrophils, into the lung, decreased concentrations of cytokines and oxidative products in the lung and plasma, and reduced lung cell apoptosis and edema formation. Concluding, PDE4 inhibitor roflumilast showed potent anti-inflammatory actions in this model of ALI.
Asunto(s)
Lesión Pulmonar Aguda/tratamiento farmacológico , Aminopiridinas/uso terapéutico , Apoptosis/efectos de los fármacos , Benzamidas/uso terapéutico , Estrés Oxidativo/efectos de los fármacos , Inhibidores de Fosfodiesterasa 4/uso terapéutico , Neumonía/tratamiento farmacológico , Lesión Pulmonar Aguda/metabolismo , Aminopiridinas/farmacología , Animales , Apoptosis/fisiología , Benzamidas/farmacología , Líquido del Lavado Bronquioalveolar , Ciclopropanos/farmacología , Ciclopropanos/uso terapéutico , Modelos Animales de Enfermedad , Femenino , Masculino , Estrés Oxidativo/fisiología , Inhibidores de Fosfodiesterasa 4/farmacología , Neumonía/metabolismo , ConejosRESUMEN
Inflammation and other immune responses are involved in the variety of diseases and disorders. The acute response to endotoxemia includes activation of innate immune mechanisms as well as changes in autonomic nervous activity. The autonomic nervous system and the inflammatory response are intimately linked and sympathetic and vagal nerves are thought to have anti-inflammation functions. The basic functional circuit between vagus nerve and inflammatory response was identified and the neuroimmunomodulation loop was called cholinergic anti-inflammatory pathway. Unique function of vagus nerve in the anti-inflammatory reflex arc was found in many experimental and pre-clinical studies. They brought evidence on the cholinergic signaling interacting with systemic and local inflammation, particularly suppressing immune cells function. Pharmacological/electrical modulation of vagal activity suppressed TNF-alpha and other proinflammatory cytokines production and had beneficial therapeutic effects. Many questions related to mapping, linking and targeting of vagal-immune interactions have been elucidated and brought understanding of its basic physiology and provided the initial support for development of Tracey´s inflammatory reflex. This review summarizes and critically assesses the current knowledge defining cholinergic anti-inflammatory pathway with main focus on studies employing an experimental approach and emphasizes the potential of modulation of vagally-mediated anti-inflammatory pathway in the treatment strategies.
Asunto(s)
Antiinflamatorios/inmunología , Neuronas Colinérgicas/inmunología , Neuroinmunomodulación/fisiología , Transducción de Señal/fisiología , Nervio Vago/inmunología , Animales , Antiinflamatorios/metabolismo , Colinérgicos/inmunología , Colinérgicos/metabolismo , Neuronas Colinérgicas/metabolismo , Humanos , Inflamación/inmunología , Inflamación/metabolismo , Nervio Vago/metabolismoRESUMEN
Nitric oxide (NO) is an important endogenous neurotransmitter and mediator. It participates in regulation of physiological processes in different organ systems including airways. Therefore, it is important to clarify its role in the regulation of both airway and vascular smooth muscle, neurotransmission and neurotoxicity, mucus transport, lung development and in the. surfactant production. The bioactivity of NO is highly variable and depends on many factors: the presence and activity of NO-producing enzymes, activity of competitive enzymes (e.g. arginase), the amount of substrate for the NO production, the presence of reactive oxygen species and others. All of these can change NO primary physiological role into potentially harmful. The borderline between them is very fragile and in many cases not entirely clear. For this reason, the research focuses on a comprehensive understanding of NO synthesis and its metabolic pathways, genetic polymorphisms of NO synthesizing enzymes and related effects. Research is also motivated by frequent use of exhaled NO monitoring in the clinical manifestations of respiratory diseases. The review focuses on the latest knowledge about the production and function of this mediator and understanding the basic physiological processes in the airways.
Asunto(s)
Pulmón/metabolismo , Óxido Nítrico/fisiología , Trastornos Respiratorios/metabolismo , Mecánica Respiratoria/fisiología , Animales , Humanos , Pulmón/patología , Óxido Nítrico Sintasa de Tipo II/biosíntesis , Trastornos Respiratorios/patologíaRESUMEN
Acute lung injury in the preterm newborns can originate from prematurity of the lung and insufficient synthesis of pulmonary surfactant. This situation is known as respiratory distress syndrome (RDS). In the term neonates, the respiratory insufficiency is related to a secondary inactivation of the pulmonary surfactant, for instance, by action of endotoxins in bacterial pneumonia or by effects of aspirated meconium. The use of experimental models of the mentioned situations provides new information on the pathophysiology of these disorders and offers unique possibility to test novel therapeutic approaches in the conditions which are very similar to the clinical syndromes. Herewith we review the advantages and limitations of the use of experimental models of RDS and meconium aspiration syndrome (MAS) and their value for clinics.
Asunto(s)
Lesión Pulmonar Aguda/fisiopatología , Modelos Animales de Enfermedad , Síndrome de Aspiración de Meconio/fisiopatología , Síndrome de Dificultad Respiratoria del Recién Nacido/fisiopatología , Lesión Pulmonar Aguda/metabolismo , Animales , Humanos , Recién Nacido , Síndrome de Aspiración de Meconio/metabolismo , Síndrome de Dificultad Respiratoria del Recién Nacido/metabolismoRESUMEN
Acute lung injury (ALI) is associated with deterioration of alveolar-capillary lining and transmigration and activation of inflammatory cells. Whereas a selective phosphodiesterase-4 (PDE4) inhibitor roflumilast has exerted potent anti-inflammatory properties, this study evaluated if its intravenous delivery can influence inflammation, edema formation, and respiratory parameters in rabbits with a lavage-induced model of ALI. ALI was induced by repetitive saline lung lavage (30 ml/kg). Animals were divided into 3 groups: ALI without therapy (ALI), ALI treated with roflumilast i.v. (1 mg/kg; ALI+Rofl), and healthy ventilated controls (Control), and were ventilated for following 4 h. Respiratory parameters (blood gases, ventilatory pressures, lung compliance, oxygenation indexes etc.) were measured and calculated regularly. At the end of experiment, animals were overdosed by anesthetics. Total and differential counts of cells in bronchoalveolar lavage fluid (BAL) were estimated microscopically. Lung edema was expressed as wet/dry lung weight ratio. Treatment with roflumilast reduced leak of cells (P<0.01), particularly of neutrophils (P<0.001), into the lung, decreased lung edema formation (P<0.01), and improved respiratory parameters. Concluding, the results indicate a future potential of PDE4 inhibitors also in the therapy of ALI.
Asunto(s)
Lesión Pulmonar Aguda/tratamiento farmacológico , Aminopiridinas/administración & dosificación , Benzamidas/administración & dosificación , Lavado Broncoalveolar/efectos adversos , Modelos Animales de Enfermedad , Inhibidores de Fosfodiesterasa 4/administración & dosificación , Cloruro de Sodio/toxicidad , Lesión Pulmonar Aguda/etiología , Lesión Pulmonar Aguda/fisiopatología , Administración Intravenosa , Animales , Líquido del Lavado Bronquioalveolar , Ciclopropanos/administración & dosificación , Femenino , Pulmón/efectos de los fármacos , Pulmón/fisiología , Masculino , Conejos , Resultado del TratamientoRESUMEN
Nitric oxide (NO) is an important endogenous mediator with significant role in the respiratory system. Many endogenous and exogenous factors influence the synthesis of NO and its level is significantly changed during the inflammation. Analysis of nasal nitric oxide (nNO) is not validated so far as the diagnostic method. There is a lack of reference values with possible identification of factors modulating the nNO levels. In healthy adult volunteers (n=141) we studied nasal NO values by NIOX MINO® (Aerocrine, Sweden) according to the recommendations of the ATS & ERS. Gender, age, height, body weight, waist-to-hip ratio, FEV1/FVC, PEF and numbers of leukocytes, eosinophils, basophils and monocytes were studied as potential variables influencing the levels of nNO. The complexity of the results allowed us to create a homogenous group for nasal NO monitoring and these data can be used further as the reference data for given variables. Because of significant correlation between nNO and exhaled NO, our results support the "one airway - one disease" concept. Reference values of nasal NO and emphasis of the individual parameters of tested young healthy population may serve as a starting point in the non-invasive monitoring of the upper airway inflammation.
Asunto(s)
Mucosa Nasal/química , Mucosa Nasal/metabolismo , Óxido Nítrico/análisis , Óxido Nítrico/metabolismo , Adolescente , Adulto , Femenino , Humanos , Masculino , Valores de Referencia , Pruebas de Función Respiratoria/métodos , Adulto JovenRESUMEN
Meconium aspiration syndrome (MAS) in newborns is characterized mainly by respiratory failure due to surfactant dysfunction and inflammation. Previous meta-analyses did not prove any effect of exogenous surfactant treatment nor glucocorticoid administration on final outcome of children with MAS despite oxygenation improvement. As we supposed there is the need to intervene in both these fields simultaneously, we evaluated therapeutic effect of combination of exogenous surfactant and selective inhibitor of NF-kappaB (IKK-NBD peptide). Young New Zealand rabbits were instilled by meconium suspension and treated by surfactant alone or surfactant in combination with IKK-NBD, and oxygen-ventilated for 5 h. PaO(2)/FiO(2), oxygenation index, oxygen saturation and ventilation efficiency index were evaluated every hour; post mortem, total and differential leukocyte counts were investigated in bronchoalveolar lavage fluid (BALF) and inflammatory, oxidative and apoptotic markers were assessed in lung tissue homogenates. Exogenous surfactant combined with IKK-NBD improved oxygenation, reduced neutrophil count in BALF and levels of IL-1beta, IL-6, p38 MAPK and caspase 3 in comparison with surfactant-only therapy. It seems that inhibition of inflammation may be strong supporting factor in surfactant treatment of MAS.
Asunto(s)
Lesión Pulmonar/tratamiento farmacológico , Lesión Pulmonar/metabolismo , Meconio , FN-kappa B/antagonistas & inhibidores , FN-kappa B/metabolismo , Surfactantes Pulmonares/uso terapéutico , Animales , Animales Recién Nacidos , Femenino , Mediadores de Inflamación/antagonistas & inhibidores , Mediadores de Inflamación/metabolismo , Lesión Pulmonar/inducido químicamente , Masculino , Surfactantes Pulmonares/farmacología , Conejos , Distribución AleatoriaRESUMEN
Selective phosphodiesterase (PDE) 4 inhibitors have recently been introduced into the therapy of chronic obstructive pulmonary disease. However, suppression of airway reactivity and eosinophilic inflammation by increased intracellular cAMP could be beneficial in bronchial asthma as well. PDE5 inhibitors are used for the therapy of erectile dysfunction, pulmonary hypertension, and other cardiovascular diseases, but an expression of PDE5 in several immune cells suggests its perspectives in inflammation, as well. To bring a new information on the therapeutically relevant potential of PDE4 and PDE5 inhibitors in allergic inflammation, this study evaluated the effects of 7-days administration of PDE5 inhibitor tadalafil and PDE4 inhibitor roflumilast in experimentally-induced allergic inflammation and compared their action with effects of a corticosteroid dexamethasone. In the study, male adult guinea pigs were used. Control group was non-sensitized, while other animals were ovalbumin-sensitized over two weeks and thereafter treated intraperitoneally for 7 days with tadalafil or roflumilast (daily dose 1.0 mg/kg b.w. each), with their combination (0.5 mg/kg b.w. each), with dexamethasone (1.0 mg/kg b.w.), or with vehicle. Both tadalafil and roflumilast reduced the specific airway resistance after nebulization of histamine (a marker of in vivo airway reactivity), and decreased the in vitro airway reactivity to cumulative doses of histamine and acetylcholine in tracheal strips (significant for roflumilast) and in lung tissue strips (significant for both agents), analyzed by organ bath method. These changes were associated with decreased numbers of circulating leukocytes and eosinophils and lower production of interleukins 4 and 5, nuclear factor kappa B and tumor necrosis factor alpha in the lung. Similar effects were observed also for dexamethasone. Roflumilast and tadalafil, but not their combination with reduced doses, lowered lung TBARS, a marker of lipid oxidation. Selective PDE5 inhibition alleviated allergic airway inflammation, but it was less potent than PDE4 inhibition, whereas anti-inflammatory action of the PDE inhibitors was comparable to the effects of dexamethasone.
Asunto(s)
Aminopiridinas/uso terapéutico , Benzamidas/uso terapéutico , Mediadores de Inflamación/antagonistas & inhibidores , Inhibidores de Fosfodiesterasa 4/uso terapéutico , Inhibidores de Fosfodiesterasa 5/uso terapéutico , Hipersensibilidad Respiratoria/tratamiento farmacológico , Tadalafilo/uso terapéutico , Aminopiridinas/farmacología , Animales , Benzamidas/farmacología , Biomarcadores/metabolismo , Ciclopropanos/farmacología , Ciclopropanos/uso terapéutico , Cobayas , Mediadores de Inflamación/metabolismo , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Masculino , Técnicas de Cultivo de Órganos , Ovalbúmina/toxicidad , Inhibidores de Fosfodiesterasa 4/farmacología , Inhibidores de Fosfodiesterasa 5/farmacología , Distribución Aleatoria , Hipersensibilidad Respiratoria/inducido químicamente , Hipersensibilidad Respiratoria/metabolismo , Tadalafilo/farmacología , Resultado del TratamientoRESUMEN
Meconium aspiration syndrome (MAS) triggers inflammatory and oxidative pathways which can inactivate both pulmonary surfactant and therapeutically given exogenous surfactant. Glucocorticoid budesonide added to exogenous surfactant can inhibit inflammation and thereby enhance treatment efficacy. Neonatal meconium (25 mg/ml, 4 ml/kg) was administered intratracheally (i.t.) to rabbits. When the MAS model was prepared, animals were treated with budesonide i.t. (Pulmicort, 0.25 mg/kg, M+B); with surfactant lung lavage (Curosurf®, 10 ml/kg, 5 mg phospholipids/ml, M+S) followed by undiluted Curosurf® i.t. (100 mg phospholipids/kg); with combination of budesonide and surfactant (M+S+B); or were untreated (M); or served as controls with saline i.t. instead of meconium (C). Animals were oxygen-ventilated for additional 5 h. Cell counts in the blood and bronchoalveolar lavage fluid (BAL), lung edema formation (wet/dry weight ratio), oxidative damage of lipids/ proteins and inflammatory expression profiles (IL-2, IL-6, IL-13, TNF-alpha) in the lung homogenate and plasma were determined. Combined surfactant+budesonide therapy was the most effective in reduction of neutrophil counts in BAL, oxidative damage, levels and mRNA expression of cytokines in the lung, and lung edema formation compared to untreated animals. Curosurf fortified with budesonide mitigated lung inflammation and oxidative modifications what indicate the perspectives of this treatment combination for MAS therapy.