RESUMEN
Heart rate variability (HRV) as an index of cardiac autonomic control in acute lung injury (ALI) has been evaluated in anaesthetized rats intratracheally instilled with bacterial lipopolysaccharide (LPS) and ventilated with breathing frequency of 60/min, 40% oxygen, inspiratory time 40%, tidal volume of 6 mL/kg. ECG was recorded before and 30, 60, 120, 180 and 240 min after LPS or saline (control) administration. HRV was quantified by time and frequency-domain analysis (mean RR interval, SDRR, RMSSD and spectral power in high frequency (HF) band. Lactate in plasma, and oxidative stress, IL-1ß, IL-5, IL-12p70 and IL-13 and galectin-3 in heart tissue raised in LPS-injured rats. Overall HRV magnitude (SDRR) and marker of vagal heart rate control (RMSSD), as well as frequency domain parameter, spectral power HF was increased 120 and 180 min since ALI onset. In conclusion, LPS-induced ALI is accompanied by altered vagal cardiac control mediated by autonomic nervous system, likely based on the close relationship between immune response and vagally mediated autonomic nervous activity.
Asunto(s)
Lipopolisacáridos , Lesión Pulmonar , Ratas , Animales , Lipopolisacáridos/toxicidad , Corazón , Nervio Vago/fisiología , Sistema Nervioso Autónomo/fisiología , Frecuencia Cardíaca/fisiologíaRESUMEN
The inflammation present in acute respiratory distress syndrome (ARDS) and thereby associated injury to the alveolar-capillary membrane and pulmonary surfactant can potentiate respiratory failure. Even considering the high mortality rate of severe ARDS, glucocorticoids appear to be a reasonable treatment option along with an appropriate route of delivery to the distal lung. This study aimed to investigate the effect of budesonide therapy delivered intratracheally by high-frequency oscillatory ventilation (HFOV) on lung function and inflammation in severe ARDS. Adult New Zealand rabbits with respiratory failure (P/F<13.3 kPa) induced by intratracheal instillation of hydrochloric acid (HCl, 3 ml/kg, pH 1.5) followed by high tidal ventilation (VT 20 ml/kg) to mimic ventilator-induced lung injury (VILI) were treated with intratracheal bolus of budesonide (0.25 mg/kg, Pulmicort) delivered by HFOV (frequency 8 Hz, MAP 1 kPa, deltaP 0.9 kPa). Saline instead of HCl without VILI with HFOV delivered air bolus instead of therapy served as healthy control. All animals were subjected to lung-protective ventilation for 4 h, and respiratory parameters were monitored regularly. Postmortem, lung injury, wet-to-dry weight ratio, leukocyte shifts, and levels of cytokines in plasma and lung were evaluated. Budesonide therapy improved the lung function (P/F ratio, oxygenation index, and compliance), decreased the cytokine levels, reduced lung edema and neutrophils influx into the lung, and improved lung architecture in interstitial congestion, hyaline membrane, and atelectasis formation compared to untreated animals. This study indicates that HFOV delivered budesonide effectively ameliorated respiratory function, and attenuated acid-induced lung injury in a rabbit model of severe ARDS.
Asunto(s)
Lesión Pulmonar , Síndrome de Dificultad Respiratoria , Insuficiencia Respiratoria , Conejos , Animales , Budesonida , Inflamación , Síndrome de Dificultad Respiratoria/inducido químicamente , Síndrome de Dificultad Respiratoria/terapia , CitocinasRESUMEN
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
In this review, we discuss the role of pulmonary surfactant in the host defense against respiratory pathogens, including novel coronavirus SARS-CoV-2. In the lower respiratory system, the virus uses angiotensin-converting enzyme 2 (ACE2) receptor in conjunction with serine protease TMPRSS2, expressed by alveolar type II (ATII) cells as one of the SARS-CoV-2 target cells, to enter. ATII cells are the main source of surfactant. After their infection and the resulting damage, the consequences may be severe and may include injury to the alveolar-capillary barrier, lung edema, inflammation, ineffective gas exchange, impaired lung mechanics and reduced oxygenation, which resembles acute respiratory distress syndrome (ARDS) of other etiology. The aim of this review is to highlight the key role of ATII cells and reduced surfactant in the pathogenesis of the respiratory form of COVID-19 and to emphasize the rational basis for exogenous surfactant therapy in COVID-19 ARDS patients.
Asunto(s)
Células Epiteliales Alveolares/metabolismo , COVID-19/metabolismo , Pulmón/metabolismo , Proteínas Asociadas a Surfactante Pulmonar/metabolismo , SARS-CoV-2/patogenicidad , Células Epiteliales Alveolares/efectos de los fármacos , Células Epiteliales Alveolares/inmunología , Células Epiteliales Alveolares/virología , Enzima Convertidora de Angiotensina 2/metabolismo , Animales , COVID-19/inmunología , COVID-19/virología , Interacciones Huésped-Patógeno , Humanos , Pulmón/efectos de los fármacos , Pulmón/inmunología , Pulmón/virología , Surfactantes Pulmonares/uso terapéutico , Receptores Virales/metabolismo , SARS-CoV-2/inmunología , Serina Endopeptidasas/metabolismo , Internalización del Virus , Tratamiento Farmacológico de COVID-19RESUMEN
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
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
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
The respiratory system is constantly exposed to pathogens which enter the lungs by inhalation or via blood stream. Lipopolysaccharide (LPS), also named endotoxin, can reach the airspaces as the major component of the outer membrane of Gram-negative bacteria, and lead to local inflammation and systemic toxicity. LPS affects alveolar type II (ATII) cells and pulmonary surfactant and although surfactant molecule has the effective protective mechanisms, excessive amount of LPS interacts with surfactant film and leads to its inactivation. From immunological point of view, surfactant specific proteins (SPs) SP-A and SP-D are best characterized, however, there is increasing evidence on the involvement of SP-B and SP-C and certain phospholipids in immune reactions. In animal models, the instillation of LPS to the respiratory system induces acute lung injury (ALI). It is of clinical importance that endotoxin-induced lung injury can be favorably influenced by intratracheal instillation of exogenous surfactant. The beneficial effect of this treatment was confirmed for both natural porcine and synthetic surfactants. It is believed that the surfactant preparations have anti-inflammatory properties through regulating cytokine production by inflammatory cells. The mechanism by which LPS interferes with ATII cells and surfactant layer, and its consequences are discussed below.
Asunto(s)
Productos Biológicos/antagonistas & inhibidores , Productos Biológicos/metabolismo , Lipopolisacáridos/metabolismo , Fosfolípidos/antagonistas & inhibidores , Fosfolípidos/metabolismo , Surfactantes Pulmonares/antagonistas & inhibidores , Surfactantes Pulmonares/metabolismo , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/metabolismo , Animales , Humanos , Lipopolisacáridos/toxicidad , Pulmón/efectos de los fármacos , Pulmón/metabolismo , PorcinosRESUMEN
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
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
Acute lung injury (ALI) is characterized by diffuse alveolar damage, inflammation, and transmigration and activation of inflammatory cells. This study evaluated if intravenous dexamethasone can influence lung inflammation and apoptosis in lavage-induced ALI. ALI was induced in rabbits by repetitive saline lung lavage (30 ml/kg, 9+/-3-times). Animals were divided into 3 groups: ALI without therapy (ALI), ALI treated with dexamethasone i.v. (0.5 mg/kg, Dexamed; ALI+DEX), and healthy non-ventilated controls (Control). After following 5 h of ventilation, ALI animals were overdosed by anesthetics. Total and differential counts of cells in bronchoalveolar lavage fluid (BAL) were estimated. Lung edema was expressed as wet/dry weight ratio. Concentrations of IL-1beta, IL-8, esRAGE, S1PR3 in the lung were analyzed by ELISA methods. In right lung, apoptotic cells were evaluated by TUNEL assay and caspase-3 immunohistochemically. Dexamethasone showed a trend to improve lung functions and histopathological changes, reduced leak of neutrophils (P<0.001) into the lung, decreased concentrations of pro-inflammatory IL-1beta (P<0.05) and marker of lung injury esRAGE (P<0.05), lung edema formation (P<0.05), and lung apoptotic index (P<0.01), but increased immunoreactivity of caspase-3 in the lung (P<0.001). Considering the action of dexamethasone on respiratory parameters and lung injury, the results indicate potential of this therapy in ALI.
Asunto(s)
Lesión Pulmonar Aguda/metabolismo , Apoptosis/efectos de los fármacos , Líquido del Lavado Bronquioalveolar/citología , Dexametasona/administración & dosificación , Modelos Animales de Enfermedad , Mediadores de Inflamación/metabolismo , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/patología , Animales , Antiinflamatorios/administración & dosificación , Apoptosis/fisiología , Mediadores de Inflamación/antagonistas & inhibidores , Infusiones Intravenosas , Pulmón/citología , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Masculino , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , ConejosRESUMEN
Acute lung injury is characterized by lung edema, surfactant dysfunction, and inflammation. The main goal of our study was to evaluate effects of S-nitroso-N-acetyl-penicillamine (SNAP) on migration of cells into the lung and their activation, inducible NO synthase (iNOS) activity, and apoptosis in experimental acute lung injury (ALI) in rabbits. ALI was induced by repetitive lung lavage with saline. The animals were divided into the following groups: (1) ALI without therapy, (2) lung injury treated with SNAP (ALI + SNAP), and (3) healthy animals (Control). After 5 h of ventilation, total and differential counts of cells in the bronchoalveolar lavage fluid (BALF) were assessed. Concentrations of interleukins (IL)-1ß, IL-6, and IL-8, endogenous secretory receptor for advanced glycation endproducts (esRAGE), sphingosine-1-phosphate receptor (S1PR)3, caspase-3, and mRNA expression of inducible NO synthase (iNOS) in lung tissue and nitrite/nitrate in plasma were analyzed. In the right lung, apoptotic cells were evaluated by TUNEL assay. In the animals with ALI, higher counts of cells, mainly neutrophils, in BALF and increased production of pro-inflammatory substances were observed compared with controls. SNAP therapy reduced a leak of cells into the lung and decreased concentrations of pro-inflammatory and apoptotic markers, reduced mRNA expression of iNOS, and decreased apoptotic index in the lung.
Asunto(s)
Lesión Pulmonar Aguda/tratamiento farmacológico , Apoptosis/efectos de los fármacos , Mediadores de Inflamación/metabolismo , Inflamación/tratamiento farmacológico , Pulmón/patología , Óxido Nítrico Sintasa de Tipo II/metabolismo , S-Nitroso-N-Acetilpenicilamina/farmacología , Lesión Pulmonar Aguda/etiología , Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/patología , Animales , Biomarcadores/metabolismo , Lavado Broncoalveolar/efectos adversos , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Femenino , Inflamación/etiología , Inflamación/metabolismo , Inflamación/patología , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Masculino , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/genética , ConejosRESUMEN
Patients with acute lung injury are ventilated by conventional mechanical ventilation (CMV) rather than high-frequency jet ventilation (HFJV). This study estimated the potential usefulness of HFJV in acute lung injury. The issue was addressed by comparing the effects on lung function of CMV and HFJV in two rabbit models of neonatal acute lung injury: repetitive saline lung lavage (LAV) and meconium aspiration syndrome (MAS) induced by intratracheal meconium instillation. The animals were then ventilated with either HFJV or CMV for 4 h. Ventilatory pressures, blood gases, and indexes of gas exchange were assessed. Lung edema formation was expressed as wet-dry lung weight ratio. Both LAV and MAS significantly decreased lung compliance, increased airway resistance, and caused severe hypoxemia, hypercarbia, and acidosis. Although CMV was superior to HFJV at 1 h of ventilation, there were no clinically relevant differences in lung function or edema formation between CMV and LAV in both models of respiratory insufficiency at 4 h of ventilation. We conclude that, HFJV may be used for ventilation in acute non-homogenous lung injury.
Asunto(s)
Lesión Pulmonar Aguda/terapia , Ventilación con Chorro de Alta Frecuencia , Respiración Artificial , Animales , Animales Recién Nacidos , Lavado Broncoalveolar , Modelos Animales de Enfermedad , Femenino , Masculino , Síndrome de Aspiración de Meconio/fisiopatología , ConejosRESUMEN
The aim of the study was to evaluate short-term heart rate variability (HRV) as an index of cardiac autonomic control in rats with lipopolysaccharide (LPS)-induced endotoxemia. Animals were injected intraperitoneally with LPS (100 microg/kg b.w.) and control group with an equivalent volume of saline. ECG recordings were done before (base) and 60, 120, 180, 240 and 300 min after LPS or saline administration. HRV magnitude was quantified by time and frequency-domain analysis (mean RR interval, SDRR, RMSSD, spectral powers in low (LF) and high frequency (HF) bands. Heart tissue homogenates and plasma were analyzed to determine interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-alpha) and oxidative stress level (TBARS). Administration of lipopolysaccharide was followed by continuous rise in colonic body temperature compared to saline-treated controls. Endotoxemia in rats was accompanied by significant decrease in HRV spectral activity in high-frequency range at maximal body temperature (logHFpower: 1.2+/-0.5 vs. 1.9+/-0.6 ms(2), P<0.01). Increased IL-6 was found in heart tissue homogenates of LPS rats (8.0+/-0.6 vs. 26.4+/-4.8 pg/ml, (P<0.05). In conclusions, reduced HRV in HF band may indicate a decreased parasympathetic activity in LPS-induced endotoxemia as basic characteristics of altered cardiac control during response to endotoxemia.
Asunto(s)
Sistema Nervioso Autónomo/fisiopatología , Bradicardia/fisiopatología , Endotoxemia/sangre , Endotoxemia/fisiopatología , Frecuencia Cardíaca , Corazón/inervación , Mediadores de Inflamación/sangre , Inflamación/sangre , Lipopolisacáridos , Miocardio/metabolismo , Animales , Regulación de la Temperatura Corporal , Bradicardia/inducido químicamente , Modelos Animales de Enfermedad , Endotoxemia/inducido químicamente , Inflamación/inducido químicamente , Inflamación/fisiopatología , Interleucina-6/sangre , Masculino , Malondialdehído/sangre , Estrés Oxidativo , Ratas Wistar , Factores de Tiempo , Factor de Necrosis Tumoral alfa/sangreRESUMEN
OBJECTIVE: The study was designed to determine whether there is an association between the comorbidity as atopy, bronchial asthma, aspirin intolerance and eosinophil infiltration of the upper airways, severity of the sinonasal disease and rate of revision sinus surgery in patients with nasal polyps. MATERIAL AND METHODS: One hundred and fifty patients were enrolled in the prospective study. Differences in CT score, rate of revision surgery, concentration of eotaxin and eosinophil cationic protein in nasal lavage fluid (NALF) and distribution of eosinophils in NALF and nasal tissue in patients with chronic rhinosinusitis with nasal polyps (CRSwNP), chronic rhinosinusitis without nasal polyps (CRSsNP) and control group were investigated. We focused on the relationship between presence of comorbidity (atopy, bronchial asthma and aspirin intolerance) and severity of the disease, the need of revision surgery and markers of eosinophil inflammation in upper airways in patients with CRSwNP. RESULTS: Patients with CRSwNP had more severe form of the sinonasal disease, higher rate of revision FESS and significant higher presence of markers of eosinophil inflammation in NALF and nasal tissue than patients with CRSsNP (P < 0.05). Atopic and non-atopic asthma as well as aspirin sensitivity significantly more often coexisted with CRSwNP. Comorbidity did not influence eosinophil infiltration or severity of the disease in patients with CRSwNP. CONCLUSION: Presence of comorbidity (atopy, bronchial asthma and aspirin intolerance) has no impact on severity of the disease or eosinophil content in the upper airways in patients with CRSwNP.
Asunto(s)
Asma/complicaciones , Eosinofilia/etiología , Rinitis/complicaciones , Sinusitis/complicaciones , Adulto , Comorbilidad , Eosinófilos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Líquido del Lavado Nasal/inmunología , Mucosa Nasal/inmunología , Pólipos Nasales , Estudios Prospectivos , Rinitis/inmunología , Sinusitis/inmunologíaRESUMEN
Beside alveoli, surface active material plays an important role in the airway physiology. In the upper airways it primarily serves in local defense. Lower airway surfactant stabilizes peripheral airways, provides the transport and defense, has barrier and anti-edematous functions, and possesses direct relaxant effect on the smooth muscle. We tested in vitro the effect of two surfactant preparations Curosurf® and Alveofact® on the precontracted smooth muscle of intra- and extra-pulmonary airways. Relaxation was more pronounced for lung tissue strip containing bronchial smooth muscle as the primary site of surfactant effect. The study does not confirm the participation of ATP-dependent potassium channels and cAMP-regulated epithelial chloride channels known as CFTR chloride channels, or nitric oxide involvement in contractile response of smooth muscle to surfactant.By controlling wall thickness and airway diameter, pulmonary surfactant is an important component of airway physiology. Thus, surfactant dysfunction may be included in pathophysiology of asthma, COPD, or other diseases with bronchial obstruction.
Asunto(s)
Pulmón/efectos de los fármacos , Relajación Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Surfactantes Pulmonares/farmacología , Tráquea/efectos de los fármacos , Animales , Productos Biológicos/farmacología , Regulador de Conductancia de Transmembrana de Fibrosis Quística/antagonistas & inhibidores , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Gliburida/farmacología , Glicina/análogos & derivados , Glicina/farmacología , Cobayas , Humanos , Hidrazinas/farmacología , Canales KATP/antagonistas & inhibidores , Canales KATP/metabolismo , Pulmón/fisiología , Relajación Muscular/fisiología , Músculo Liso/fisiología , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa/metabolismo , Fosfolípidos/farmacología , Técnicas de Cultivo de Tejidos , Tráquea/fisiologíaRESUMEN
Exogenous pulmonary surfactant is a potential delivery system for topical medications via the conducting airways. Due to the sensitivity to inactivation of surfactant, mutual interaction with the shipped drug should be evaluated. Little is known about the interactions between surfactant and antimicrobial drugs. The aim of the present study was to evaluate whether biophysical properties of animal-derived surfactants are modified by the bactericidal antibiotic rifampicin. An intracellular activity and a broad antimicrobiotic spectrum toward Gram-negative and Gram-positive bacteria make rifampicin an interesting substance against pulmonary infections. Curosurf® (porcine surfactant from minced lungs) and Survanta® (bovine surfactant extract) were diluted to 2.5-5.0 mg/ml of phospholipids in 0.9 % NaCl and rifampicin (RIF) was added at 1, 5, and 10 % (w/w). Minimum (γ(min)) and maximum (γ(max)) surface tension of a cyclically compressed bubble in the mixture was assessed with a pulsating bubble surfactometer. After 5 min, γ(min) of Survanta at a concentration of 3 mg/ml was significantly increased after addition of 5 and 10 % RIF (both p < 0.001). At 1 % RIF, the γ(min) of Survanta was ≈10 mN/m and this value was not significantly different to that of Survanta alone. The γ(min) of Curosurf at 3 mg/ml was increased with 10 % RIF (p < 0.001), but not with 1 and 5 %. At 5 mg/ml Survanta was inhibited by 10 % RIF (p < 0.05), while γ(min) of Curosurf was low (<5 mN/m) in all mixtures. In conclusion, Curosurf and Survanta interfere with RIF in a concentration-dependent manner. At the appropriate phospholipid concentration, especially porcine-derived surfactant is able to retain good surface activity when mixed with antibiotics.