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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. [ABSTRACT FROM AUTHOR]

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 salinelavaged 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. [ABSTRACT FROM AUTHOR]

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 (PaO2<26.7 kPa in FiO2 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 TNFa, 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. [ABSTRACT FROM AUTHOR]

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 (TNFα, IL-6 and IL-8) and markers of oxidation (3-nitrotyrosine, thiobarbituricacid 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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-κB (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. PaO2/FiO2, 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-1β, 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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-α 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. [ABSTRACT FROM AUTHOR]

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-1β, 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-1β (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. [ABSTRACT FROM AUTHOR]

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-1ß, 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-1β (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. [ABSTRACT FROM AUTHOR]

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 μg/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-α) 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 ms2, 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. [ABSTRACT FROM AUTHOR]

The study was designed to prove the hypothesis that lipopolysaccharide (LPS)-induced fever elicits the changes in surfactant specific proteins, potentially related to thermal tachypnea. In adult rats fever was induced by intraperitoneal administration of LPS at a dose 100 μg/kg of body weight; control group received saline. Respiratory parameters, arterial blood gases and pH and colonic body temperature (BT) were recorded. Five hours later, surfactant proteins (SP) A, B, C and D were evaluated in bronchoalveolar lavage fluid (BALF) and lung tissue (LT). LPS evoked monophasic thermic response (at 300 min 38.7±0.2 vs. 36.4±0.3 °C, P<0.05) and an increase in minute ventilation due to changes in breathing rate and tidal volume. LPS-instilled animals had higher levels of SP-A and SP-D in LT (P<0.05 and 0.01), and higher SP-D in BALF (P<0.01) than controls. SP-B increased in LT and SP-C in BALF of animals with LPS (both P<0.05 vs. controls). The changes in all surfactant specific proteins are present in LPS-induced fever. Alterations of proteins related to local immune mechanisms (SP-A, SP-D) are probably a part of general inflammatory response to pyrogen. Changes in proteins related to surface activity (SP-B and SP-C) might reflect the effort of the body to stabilize the lungs in thermal challenge. [ABSTRACT FROM AUTHOR]