RESUMO
BACKGROUND: Hyperinflation (HI) is performed following open endotracheal suctioning (OES), whose goals include: to stimulate a cough, recover oxygenation and improve compliance. However, it may also induce unintended consequences, including: lung stress and strain, failure to maintain high distending pressure, and subsequently cycling recruitment and derecruitment. Here, our aim was to investigate the effects of hyperinflation after repeated OES on sequential alteration of arterial oxygenation and lung injury profile using a saline lavage-induced surfactant depleted ARDS rabbit model. METHODS: Briefly, 30 Japanese White Rabbits were anesthetized and ventilated in pressure-controlled setting with a tidal volume of 6-8 ml/kg. Animals were divided into four groups, i.e.; Control, ARDS, OES, and HI. Saline-lavage-induced lung injury was induced except for Control group. Thereafter, rabbits were ventilated with positive-end expiratory pressure (PEEP) at 10 cm H2O. The ARDS group received ventilation with the same PEEP without derecruitment. As intervention, OES and HI were performed in ARDS animals. OES was performed for 15 seconds at 150 mm Hg, whereas HI was performed with PEEP at 0 cm H2O and peak inspiratory pressure at +5 cm H2O for a minute. Total duration of the experiment was for 3 hours. OES and HI were performed every 15 minutes from beginning of the protocol. RESULTS: PaO2 was maintained at about 400 mm Hg in both control and ARDS groups for the duration of this study, while in both OES and HI groups, PaO2 decreased continuously up to 3 hours, dropped to a mean (±SD) of 226 ± 28.9 and 97.0 ± 30.7 mmHg at 3 h, respectively. HI group had the lowest PaO2 in the present investigation. Histological lung injury score was the highest in HI group than other three groups. Pulmonary TNF-α and IL-8 levels were the highest in HI group compared to other groups, but without significant alterations at circulatory level in all the experimental groups. CONCLUSIONS: We show in the present study that hyperinflation following repeated OES deteriorate arterial oxygenation and the severity of lung injury in a rabbit model of ARDS undergoing mechanical ventilation.
Assuntos
Lesão Pulmonar/etiologia , Respiração com Pressão Positiva/efeitos adversos , Síndrome do Desconforto Respiratório/terapia , Análise de Variância , Animais , Dióxido de Carbono/sangue , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Interleucina-8/metabolismo , Masculino , Oxigênio/sangue , Pressão Parcial , Coelhos , Distribuição Aleatória , Sucção/efeitos adversos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: Although endotracheal suctioning induces alveolar derecruitment during mechanical ventilation, it is not clear whether repeated endotracheal suctioning exacerbates lung injuries. The present study aimed to determine whether repeated open endotracheal suctioning (OS) exacerbates lung injury compared to closed endotracheal suctioning (CS) during mechanical ventilation in an animal model of acute respiratory distress syndrome (ARDS). METHODS: Briefly, thirty six Japanese white rabbits were initially ventilated in pressure-controlled mode with a constant tidal volume (6 mL/kg). Then, lung injury was induced by repeated saline lavage. The rabbits were divided into four groups, namely: a) OS; b) CS; c) control with ARDS only; d) and healthy control (HC) without ARDS. Animals in all the groups were then ventilated with positive end expiratory pressure (PEEP) at 10 cm H2O. CS was performed using 6 French-closed suctioning catheters connected to endotracheal tube under the following conditions: a) a suctioning time and pressure of 10 sec and 140 mm Hg, respectively; and b) a suction depth of 2 cm (length of adapter) plus tracheal tube. OS was performed using the same conditions described for CS, except the ventilator was disconnected from the animals. Each endotracheal suctioning was performed at an interval of 30 min. RESULTS: PaO2/FIO2 (P/F) ratio for CS, control and HC groups remained at >400 for 6 hours, whereas that of the OS group progressively declined to 300 (p < 0.05), with each suctioning. However, no difference was observed either in lung injury score (histology) or in the expression pattern of inflammatory cytokines (tumor necrosis factor-α and interleukin-6) after 6 hours between the OS and CS groups in the circulatory as well as the pulmonary tissues. CONCLUSIONS: Progressive arterial desaturation under conditions of repeated endotracheal suctioning is greater in OS than in CS time-dependently. However, OS does not exacerbate lung injury during mechanical ventilation when observed over a longer time span (6 hours) of repeated endotracheal suctioning, based on morphological and molecular analysis.
RESUMO
AIMS: Endothelin-1 (ET-1) is a mediator of various physiological and pathological processes, including vascular inflammation, cell proliferation and vasoconstriction. Attenuation of ET action using ET-1 antagonists reduces pulmonary vascular leakage and inflammation in several models of lung injuries and experimental acute respiratory distress syndrome (ARDS). Based on these earlier reports, the current study investigates the patterns of ET-1 levels in circulation and pulmonary tissues in an experimental model of lavage-induced surfactant-depleted lung injury. Additionally, we also test the effects of open endotracheal suctioning (OES) and hyperinflation (HI) as recruitment maneuver following OES on ET-1 levels. MAIN METHODS: Briefly, 24 Japanese white rabbits were anesthetized and intubated. Normal saline was instilled into the lung and washed mildly. After instillation, rabbits were ventilated at definite settings at a total duration of 3 hours. OES and HI were performed every 15 minutes from the beginning of the protocol. KEY FINDINGS: Here, we show that both circulatory and pulmonary ET-1 levels increased in models with lung injury induced by saline lavage compared to healthy control group. No further aggravation in expression of pulmonary ET-1 was seen after OES and HI, although OES and HI worsened arterial hypoxygenation and severity of lung injury. In contrast, circulatory ET-1 levels significantly decreased after OES and HI but were not associated with blood pressure changes. SIGNIFICANCE: We conclude that in a saline lavage-induced lung injury model, both circulatory and pulmonary ET-1 levels increased. Further, OES and HI exerted differential effects on ET-1 expression at both circulatory and pulmonary levels.
Assuntos
Endotelina-1/sangue , Lesão Pulmonar/sangue , Lesão Pulmonar/cirurgia , Surfactantes Pulmonares/metabolismo , Sucção/métodos , Irrigação Terapêutica/métodos , Traqueia/cirurgia , Animais , Gasometria , Líquido da Lavagem Broncoalveolar , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Hemodinâmica , Lesão Pulmonar/patologia , Lesão Pulmonar/fisiopatologia , Troca Gasosa Pulmonar , Coelhos , Receptor de Endotelina B/metabolismo , Mecânica Respiratória , Traqueia/metabolismo , Traqueia/patologia , Traqueia/fisiopatologiaRESUMO
AIMS: Sepsis is a cluster of heterogeneous syndromes associated with progressive endotoxemic developments, ultimately leading to damage of multiple organs, including the heart. However, the pathogenesis of sepsis-induced myocardial dysfunction is still not fully understood. The present study is the first to examine alterations in expression of key angiogenic signaling system mediated by vascular endothelial growth factor (VEGF) in septic heart and the effects of endothelin dual blocker (ETDB) on it. MAIN METHODS: Normal Wistar rats were either administered with: a) vehicle only (control group), b) lipopolysaccharide only (LPS: 15 mg/kg) and then sacrificed at different time points (1 h, 3 h, 6 h and 10 h), and c) the last group was co-administered with LPS and ETDB (SB-209670, 1 mg/kg body weight) for 6 h and then sacrificed. KEY FINDINGS: Administration of LPS resulted in increases in levels of: a) serum tumor necrosis factor (TNF)-α, b) serum VEGF and c) serum endothelin (ET)-1 levels accompanied by up-regulation of cardiac VEGF and its downstream angiogenic signaling molecules. While cardiac TNF-α level was unchanged among experimental groups, cardiac ET-1 level was significantly higher in LPS-administered group. SIGNIFICANCE: We conclude that elevation in VEGF angiogenic signaling may be triggered by diminished oxygenation in the myocardium following LPS administration as a consequence of sepsis-induced microvascular dysfunction. Because of this cardiac dysfunction, oxygen supply may be inadequate at microregional level to support the normal heart metabolism and function. ETDB at 6 h further increased the elevated levels of VEGF angiogenic signaling in endotoxemic heart.
Assuntos
Antagonistas dos Receptores de Endotelina/farmacologia , Endotoxemia/metabolismo , Miocárdio/metabolismo , Neovascularização Fisiológica/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Gasometria , Modelos Animais de Doenças , Antagonistas dos Receptores de Endotelina/uso terapêutico , Endotelina-1/sangue , Endotoxemia/sangue , Endotoxemia/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Lipopolissacarídeos , Masculino , Miocárdio/patologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Ratos Wistar , Fator de Necrose Tumoral alfa/sangue , Fator A de Crescimento do Endotélio Vascular/sangueRESUMO
AIMS: Endothelin (ET)-1 is the best known potent vasoconstrictor and has been implicated in pathogenesis of sepsis-associated acute kidney injury (AKI) in human or lipopolysaccharide (LPS)-induced AKI in animal models. We have previously shown that ET-1 is highly up-regulated in renal tissues and in plasma after LPS administration. Here, we investigated whether landiolol hydrochloride, an ultra-short-acting beta-blocker, can play an important role in ameliorating levels of LPS-induced up-regulation of renal HIF-1α-ET-1 system and inflammatory cytokines in a rat model of endotoxemia. MAIN METHODS: Male Wistar rats at 8 weeks of age were either administered with: a) lipopolysaccharide (LPS) only for three hours (3 h) or b) LPS, followed by continuous administration of landiolol for 3 h; c) third group was only treated with vehicle. KEY FINDINGS: At 3 h after LPS administration there was: a) minimal injury in kidney tissues; b) circulatory levels of creatinine, blood urea nitrogen and NGAL increased and c) expression of inflammatory cytokines, such as TNF-α, IL-6 and iNOS increased at the level of both circulatory and renal tissues. In addition, LPS significantly induced renal expression of ET-1 and HIF-1α compared to control. Finally, treatment of LPS-administered rats with landiolol for 3 h normalized elevated serum markers of renal injury and up-regulated levels of renal HIF-1α-ET-1 system with normalization of TNF-α. SIGNIFICANCE: Taken together, these data led us to conclude that landiolol ameliorates the up-regulation of HIF-1α-ET-1 system in minimally morphologically-injured kidney and normalizes biomarkers of renal injury in early hours of endotoxemia of a rat model.
Assuntos
Endotelina-1/metabolismo , Endotoxemia/tratamento farmacológico , Endotoxemia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Rim/metabolismo , Morfolinas/uso terapêutico , Regulação para Cima , Ureia/análogos & derivados , Animais , Biomarcadores/sangue , Gasometria , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Endotoxemia/sangue , Endotoxemia/patologia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Mediadores da Inflamação/metabolismo , Rim/efeitos dos fármacos , Rim/patologia , Lipopolissacarídeos , Masculino , Morfolinas/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Wistar , Regulação para Cima/efeitos dos fármacos , Ureia/farmacologia , Ureia/uso terapêuticoRESUMO
AIMS: Landiolol hydrochloride, an ultra-short-acting highly cardio-selective ß-1 blocker, has become useful for various medical problems. Recent studies have demonstrated that co-treatment with landiolol protects against acute lung injury and cardiac dysfunction in rats of lipopolysaccharide (LPS)-induced systemic inflammation, and was also associated with a significant reduction in serum levels of the inflammation mediator HMGB-1 and histological lung damage. Endothelin (ET)-1, a potent vasoconstrictor, has been implicated in pathogenesis of sepsis and sepsis-induced multiple organ dysfunction syndrome. Here, we investigated whether landiolol hydrochloride can play important roles in ameliorating LPS-induced alterations in cardiac ET system of septic rats. MAIN METHODS: Eight-week-old male Wistar rats were administered LPS only for 3 h and the rest were treated with LPS as well as with landiolol non-stop for 3 h. KEY FINDINGS: At 3 h after LPS (only) administration, circulatory tumor necrosis factor (TNF)-α level, blood lactate concentration and percentage of fractional shortening of heart were significantly increased. In addition, LPS induced a significant expression of various components of cardiac ET-1 system compared to control. Finally, treatment of LPS-administered rats with landiolol for 3 h normalized LPS-induced blood lactate levels and cardiac functional compensatory events, without altering levels of plasma TNF-α and ET-1. Most strikingly, landiolol treatment significantly normalized various components of cardiac ET-1 signaling system in septic rat. SIGNIFICANCE: Taken together, these data led us to conclude that landiolol may be cardio-protective in septic rats by normalizing the expression of cardiac vasoactive peptide such as ET, without altering the circulatory levels of inflammatory cytokines.
Assuntos
Endotelina-1/metabolismo , Morfolinas/uso terapêutico , Miocárdio/metabolismo , Sepse/tratamento farmacológico , Regulação para Cima/efeitos dos fármacos , Ureia/análogos & derivados , Animais , Gasometria , Modelos Animais de Doenças , Endotelina-1/sangue , Hemodinâmica/efeitos dos fármacos , Interleucina-6/sangue , Masculino , Morfolinas/farmacologia , Miocárdio/patologia , Ratos Wistar , Receptores de Endotelina/genética , Receptores de Endotelina/metabolismo , Sepse/sangue , Sepse/diagnóstico por imagem , Sepse/fisiopatologia , Fator de Necrose Tumoral alfa/sangue , Ultrassonografia , Ureia/farmacologia , Ureia/uso terapêuticoRESUMO
AIMS: The aim was to study the differences in the effectiveness of two types of endothelin (ET) receptor antagonists (selective ET-A or dual ET-A/B antagonists) on the hearts of streptozotocin (STZ)-induced diabetic rats (type I diabetes) at functional and biochemical/molecular levels. MAIN METHODS: Citrate saline (vehicle) or STZ was injected into rats. The ET-A/B dual receptor antagonist (SB209670, 1mg/kg/day) and the ET-A receptor antagonist (TA-0201, 1mg/kg/day) were then administered to these rats. One week after injection, the animals were separated into those receiving SB209670, TA-0201 or vehicle by 4-week osmotic mini-pump. KEY FINDINGS: The VEGF level and percent fractional shortening in the diabetic heart were significantly decreased compared to the non-diabetic heart, whereas SB209670 and TA-0201 treatments greatly and comparably prevented this decrease. SB209670 treatment was more effective in reversing decreased expressions of KDR and phosphorylated AKT, downstream of VEGF angiogenic signaling, than TA-0201 treatment. The eNOS levels in hearts were significantly higher in diabetic rats than in healthy rats, and this increase was significantly reduced by TA-0210 but not by SB209670 treatment. SIGNIFICANCE: Improvement of KDR mRNA and pAKT levels by SB209670 but not TA-0201 suggests that dual ET-A/-B blockade may be effective in improving intracellular systems of these components in the diabetic rat heart. However, the present study also showed that TA-0201 or SB209670 improved percent fractional shortening and VEGF levels of the diabetic hearts to a similar extent, suggesting that ET-A blockade and dual ET-A/-B blockade are similarly effective in improving cardiac dysfunction in the diabetic rats.