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1.
Lung ; 202(3): 299-315, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38684519

RESUMO

PURPOSE: Acute respiratory distress syndrome (ARDS) is a major cause of hypoxemic respiratory failure in adults. In ARDS extensive inflammation and leakage of fluid into the alveoli lead to dysregulation of pulmonary surfactant metabolism and function. Altered surfactant synthesis, secretion, and breakdown contribute to the clinical features of decreased lung compliance and alveolar collapse. Lung function in ARDS could potentially be restored with surfactant replacement therapy, and synthetic surfactants with modified peptide analogues may better withstand inactivation in ARDS alveoli than natural surfactants. METHODS: This study aimed to investigate the activity in vitro and the bolus effect (200 mg phospholipids/kg) of synthetic surfactant CHF5633 with analogues of SP-B and SP-C, or natural surfactant Poractant alfa (Curosurf®, both preparations Chiesi Farmaceutici S.p.A.) in a severe ARDS model (the ratio of partial pressure arterial oxygen and fraction of inspired oxygen, P/F ratio ≤ 13.3 kPa) induced by hydrochloric acid instillation followed by injurious ventilation in adult New Zealand rabbits. The animals were ventilated for 4 h after surfactant treatment and the respiratory parameters, histological appearance of lung parenchyma and levels of inflammation, oxidative stress, surfactant dysfunction, and endothelial damage were evaluated. RESULTS: Both surfactant preparations yielded comparable improvements in lung function parameters, reductions in lung injury score, pro-inflammatory cytokines levels, and lung edema formation compared to untreated controls. CONCLUSIONS: This study indicates that surfactant replacement therapy with CHF5633 improves lung function and lung architecture, and attenuates inflammation in severe ARDS in adult rabbits similarly to Poractant alfa. Clinical trials have so far not yielded conclusive results, but exogenous surfactant may be a valid supportive treatment for patients with ARDS given its anti-inflammatory and lung-protective effects.


Assuntos
Produtos Biológicos , Modelos Animais de Doenças , Pulmão , Estresse Oxidativo , Fosfolipídeos , Proteína B Associada a Surfactante Pulmonar , Proteína C Associada a Surfactante Pulmonar , Surfactantes Pulmonares , Síndrome do Desconforto Respiratório , Animais , Coelhos , Síndrome do Desconforto Respiratório/tratamento farmacológico , Síndrome do Desconforto Respiratório/fisiopatologia , Surfactantes Pulmonares/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/fisiopatologia , Pulmão/metabolismo , Fosfolipídeos/farmacologia , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Proteína B Associada a Surfactante Pulmonar/farmacologia , Proteína B Associada a Surfactante Pulmonar/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Proteína C Associada a Surfactante Pulmonar/farmacologia , Masculino , Líquido da Lavagem Broncoalveolar , Fragmentos de Peptídeos , Fosfatidilcolinas
2.
Respir Physiol Neurobiol ; 316: 104138, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37579929

RESUMO

Accumulation of reactive oxygen species during hyperoxia together with secondary bacteria-induced inflammation leads to lung damage in ventilated critically ill patients. Antioxidant N-acetylcysteine (NAC) in combination with surfactant may improve lung function. We compared the efficacy of NAC combined with surfactant in the double-hit model of lung injury. Bacterial lipopolysaccharide (LPS) instilled intratracheally and hyperoxia were used to induce lung injury in Wistar rats. Animals were mechanically ventilated and treated intravenously with NAC alone or in combination with intratracheal surfactant (poractant alfa; PSUR+NAC). Control received saline. Lung functions, inflammatory markers, oxidative damage, total white blood cell (WBC) count and lung oedema were evaluated during 4 hrs. Administration of NAC increased total antioxidant capacity (TAC) and decreased IL-6. This effect was potentiated by the combined administration of surfactant and NAC. In addition, PSUR+NAC reduced the levels of TNFα, IL-1ß, and TAC compared to NAC only and improved lung injury score. The combination of exogenous surfactant with NAC suppresses lung inflammation and oxidative stress in the experimental double-hit model of lung injury.


Assuntos
Hiperóxia , Lesão Pulmonar , Surfactantes Pulmonares , Síndrome do Desconforto Respiratório , Ratos , Animais , Acetilcisteína/farmacologia , Acetilcisteína/uso terapêutico , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Tensoativos , Roedores , Ratos Wistar , Pulmão , Surfactantes Pulmonares/farmacologia
3.
Int J Mol Sci ; 24(14)2023 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-37511170

RESUMO

Acute respiratory distress syndrome (ARDS) is a life-threatening condition characterized by the rapid onset of lung inflammation Therefore, monitoring the spatial distribution of the drug directly administered to heterogeneously damaged lungs is desirable. In this work, we focus on optimizing the drug N-acetylcysteine (NAC) adsorption on poly-l-lysine-modified magnetic nanoparticles (PLLMNPs) to monitor the drug spatial distribution in the lungs using magnetic resonance imaging (MRI) techniques. The physicochemical characterizations of the samples were conducted in terms of morphology, particle size distributions, surface charge, and magnetic properties followed by the thermogravimetric quantification of NAC coating and cytotoxicity experiments. The sample with the theoretical NAC loading concentration of 0.25 mg/mL was selected as an optimum due to the hydrodynamic nanoparticle size of 154 nm, the surface charge of +32 mV, good stability, and no cytotoxicity. Finally, MRI relaxometry confirmed the suitability of the sample to study the spatial distribution of the drug in vivo using MRI protocols. We showed the prevailing transverse relaxation with high transverse relaxivity values and a high r2(*)/r1 ratio, causing visible hypointensity in the final MRI signal. Furthermore, NAC adsorption significantly affects the relaxation properties of PLLMNPs, which can help monitor drug release in vitro/in vivo.


Assuntos
Nanopartículas de Magnetita , Nanopartículas , Nanopartículas de Magnetita/química , Meios de Contraste/química , Acetilcisteína/farmacologia , Imageamento por Ressonância Magnética/métodos , Nanopartículas/química , Adsorção
4.
Transl Res ; 262: 60-74, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37499744

RESUMO

Respiratory distress syndrome (RDS) in premature infants is caused by insufficient amounts of endogenous lung surfactant and is efficiently treated with replacement therapy using animal-derived surfactant preparations. On the other hand, adult/acute RDS (ARDS) occurs secondary to for example, sepsis, aspiration of gastric contents, and multitrauma and is caused by alveolar endothelial damage, leakage of plasma components into the airspaces and inhibition of surfactant activity. Instillation of surfactant preparations in ARDS has so far resulted in very limited treatment effects, partly due to inactivation of the delivered surfactants in the airspace. Here, we develop a combined surfactant protein B (SP-B) and SP-C peptide analogue (Combo) that can be efficiently expressed and purified from Escherichia coli without any solubility or purification tag. NMR spectroscopy shows that Combo peptide forms α-helices both in organic solvents and in lipid micelles, which coincide with the helical regions described for the isolated SP-B and SP-C parts. Artificial Combo surfactant composed of synthetic dipalmitoylphosphatidylcholine:palmitoyloleoylphosphatidylglycerol, 1:1, mixed with 3 weights % relative to total phospholipids of Combo peptide efficiently improves tidal volumes and lung gas volumes at end-expiration in a premature rabbit fetus model of RDS. Combo surfactant also improves oxygenation and respiratory parameters and lowers cytokine release in an acid instillation-induced ARDS adult rabbit model. Combo surfactant is markedly more resistant to inhibition by albumin and fibrinogen than a natural-derived surfactant in clinical use for the treatment of RDS. These features of Combo surfactant make it attractive for the development of novel therapies against human ARDS.


Assuntos
Surfactantes Pulmonares , Síndrome do Desconforto Respiratório do Recém-Nascido , Síndrome do Desconforto Respiratório , Recém-Nascido , Animais , Feminino , Coelhos , Adulto , Humanos , Síndrome do Desconforto Respiratório do Recém-Nascido/tratamento farmacológico , Surfactantes Pulmonares/farmacologia , Surfactantes Pulmonares/uso terapêutico , Surfactantes Pulmonares/química , Tensoativos/uso terapêutico , Síndrome do Desconforto Respiratório/tratamento farmacológico , Síndrome do Desconforto Respiratório/metabolismo , Peptídeos/farmacologia , Peptídeos/química
5.
J Inflamm (Lond) ; 20(1): 10, 2023 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-36927675

RESUMO

Acute respiratory distress syndrome (ARDS) is a common complication of critical illness characterized by lung inflammation, epithelial and endothelial dysfunction, alveolar-capillary leakage, and worsening respiratory failure. The present study aimed to investigate the anti-inflammatory effects of non-selective phosphodiesterase (PDE) inhibitor aminophylline. New Zealand white rabbits were randomly divided into 3 groups: animals with respiratory failure defined as PaO2/FiO2 ratio (P/F) below < 26.7 kPa, and induced by saline lung lavage (ARDS), animals with ARDS treated with intravenous aminophylline (1 mg/kg; ARDS/AMINO), and healthy ventilated controls (Control). All animals were oxygen ventilated for an additional 4 h and respiratory parameters were recorded regularly. Post mortem, the lung tissue was evaluated for oedema formation, markers of inflammation (tumor necrosis factor, TNFα, interleukin (IL)-1ß, -6, -8, -10, -13, -18), markers of epithelial damage (receptor for advanced glycation end products, RAGE) and endothelial injury (sphingosine 1-phosphate, S1P), oxidative damage (thiobarbituric acid reactive substances, TBARS, 3-nitrotyrosine, 3NT, total antioxidant capacity, TAC). Aminophylline therapy decreased the levels of pro-inflammatory cytokines, markers of epithelial and endothelial injury, oxidative modifications in lung tissue, reduced lung oedema, and improved lung function parameters compared to untreated ARDS animals. In conclusion, non-selective PDE inhibitor aminophylline showed a significant anti-inflammatory activity suggesting a potential of this drug to be a valuable component of ARDS therapy.

6.
Int J Mol Sci ; 24(3)2023 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-36768179

RESUMO

Inhalation of silica particles causes inflammatory changes leading to fibrotizing silicosis. Considering a lack of effective therapy, and a growing information on the wide actions of green tea polyphenols, particularly epigallocatechin-3-gallate (EGCG), the aim of this study was to evaluate the early effects of EGCG on markers of inflammation and lung fibrosis in silicotic rats. The silicosis model was induced by a single transoral intratracheal instillation of silica (50 mg/mL/animal), while controls received an equivalent volume of saline. The treatment with intraperitoneal EGCG (20 mg/kg, or saline in controls) was initiated the next day after silica instillation and was given twice a week. Animals were euthanized 14 or 28 days after the treatment onset, and the total and differential counts of leukocytes in the blood and bronchoalveolar lavage fluid (BALF), wet/dry lung weight ratio, and markers of inflammation, oxidative stress, and fibrosis in the lung were determined. The presence of collagen and smooth muscle mass in the walls of bronchioles and lung vessels was investigated immunohistochemically. Early treatment with EGCG showed some potential to alleviate inflammation, and a trend to decrease oxidative stress-induced changes, including apoptosis, and a prevention of fibrotic changes in the bronchioles and pulmonary vessels. However, further investigations should be undertaken to elucidate the effects of EGCG in the lung silicosis model in more detail. In addition, because of insufficient data from EGCG delivery in silicosis, the positive and eventual adverse effects of this herbal compound should be carefully studied before any preventive use or therapy with EGCG may be recommended.


Assuntos
Catequina , Silicose , Ratos , Animais , Polifenóis/farmacologia , Polifenóis/uso terapêutico , Chá/química , Pulmão/patologia , Silicose/tratamento farmacológico , Silicose/patologia , Fibrose , Inflamação/tratamento farmacológico , Inflamação/patologia , Catequina/farmacologia , Catequina/uso terapêutico , Dióxido de Silício
7.
Antioxidants (Basel) ; 12(1)2022 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-36670899

RESUMO

Aspirated meconium into a newborn's airways induces the transcription of pro-oxidative mediators that cooperate in the pathogenesis of inflammatory changes and may negatively affect the commonly used exogenous surfactant therapy. However, inflammation is not treated at present, nor is the time dependence of oxidative damage known. The aim of our study was to describe the time course of oxidative stress marker production during meconium aspiration syndrome (MAS) and its relationship to leukocyte infiltration. New Zealand rabbits were instilled with saline or meconium suspension and ventilated for 5.5 h. Respiratory parameters were recorded and blood samples were taken before meconium application and in time intervals of 15 and 30 min, 1.0, 1.5, 3.5 and 5.5 h after application to evaluate oxidative markers and differential leukocytes count. Meconium aspiration led to a worsening of respiratory parameters and a decrease in leukocytes in the first 15 min. Changes in leukocytes were correlated both with nitrotyrosine (3NT) levels and thiobarbituric acid reactive substance (TBARS) levels, with the latter also related to changes in neutrophil count. The production of 3NT and TBARS increased in 1.5 and 3.5 h, respectively, in different ways, suggesting more than one source of oxidative agents and a potential risk of exogenous surfactant inactivation in a short time. We observed that MAS triggered neutrophil migration to the alveolar space and activation, as shown by the increased expression of pro-inflammatory cytokines and generation of indicators of oxidative damage to proteins and lipids during the time period when iNOS and NO metabolites were released.

8.
Pharmaceutics ; 13(12)2021 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-34959373

RESUMO

Acute respiratory distress syndrome (ARDS) is a common complication of critical illness and remains a major source of morbidity and mortality in the intensive care unit (ICU). ARDS is characterised by diffuse lung inflammation, epithelial and endothelial deterioration, alveolar-capillary leak and oedema formation, and worsening respiratory failure. The present study aimed to investigate the anti-inflammatory activity of nitric-oxide-releasing dexamethasone derivative NCX-1005 as a potential novel drug for ARDS. Adult rabbits with lavage-induced ARDS were treated with dexamethasone i.v. (0.5 mg/kg; DEX) and nitro-dexamethasone i.v. (0.5 mg/kg, NCX-1005) or were untreated (ARDS). Controls represented healthy ventilated animals. The animals were subsequently oxygen-ventilated for an additional 4 h and respiratory parameters were recorded. Lung oedema, inflammatory cell profile in blood and bronchoalveolar lavage, levels of the cytokines (IL-1ß, IL-6, IL-8, TNF-α), and oxidative damage (TBARS, 3NT) in the plasma and lung were evaluated. Nitric oxide-releasing dexamethasone derivative NCX-1005 improved lung function, reduced levels of cytokines, oxidative modifications, and lung oedema formation to similar degrees as dexamethasone. Only NCX-1005 prevented the migration of neutrophils into the lungs compared to dexamethasone. In conclusion, the nitric oxide-releasing dexamethasone derivative NCX-1005 has the potential to be effective drug with anti-inflammatory effect in experimental ARDS.

9.
Biomedicines ; 9(12)2021 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-34944701

RESUMO

Treatment of acute respiratory distress syndrome (ARDS) is challenging due to its multifactorial aetiology. The benefit of antioxidant therapy was not consistently demonstrated by previous studies. We evaluated the effect of two different doses of intravenous (i.v.) N-acetylcysteine (NAC) on oxidative stress, inflammation and lung functions in the animal model of severe LPS-induced lung injury requiring mechanical ventilation. Adult Wistar rats with LPS (500 µg/kg; 2.2 mL/kg) were treated with i.v. NAC 10 mg/kg (NAC10) or 20 mg/kg (NAC20). Controls received saline. Lung functions, lung oedema, total white blood cell (WBC) count and neutrophils count in blood and bronchoalveolar lavage fluid, and tissue damage in homogenized lung were evaluated. NAC significantly improved ventilatory parameters and oxygenation, reduced lung oedema, WBC migration and alleviated oxidative stress and inflammation. NAC20 in comparison to NAC10 was more effective in reduction of oxidative damage of lipids and proteins, and inflammation almost to the baseline. In conclusion, LPS-instilled and mechanically ventilated rats may be a suitable model of ARDS to test the treatment effects at organ, systemic, cellular and molecular levels. The results together with literary data support the potential of NAC in ARDS.

10.
Physiol Rep ; 9(1): e14700, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33403805

RESUMO

Acute respiratory distress syndrome (ARDS) is associated with diffuse inflammation, alveolar epithelial damage, and leakage of plasma proteins into the alveolar space, which together contribute to inactivation of pulmonary surfactant and respiratory failure. Exogenous surfactant delivery is therefore considered to hold potential for ARDS treatment, but clinical trials with natural derived surfactant or synthetic surfactant containing a surfactant protein C (SP-C) analogue have been negative. Synthetic surfactant CHF5633, containing analogues of SP-B and SP-C, may be effective against ARDS. The aim here was to compare treatment effects of CHF5633 and animal-derived surfactant poractant alfa in animal model of ARDS. ARDS was induced in adult New Zealand rabbits by mild lung lavages followed by injurious ventilation until respiratory failure (P/F ratio <26.7 kPa). The animals were then treated with intratracheal bolus of 200 mg/kg CHF5633 or poractant alfa (Curosurf® ), or air as control. The animals were subsequently ventilated for an additional 4 hr and respiratory parameters were recorded regularly. Postmortem, histological analysis, degree of lung edema, and levels of the cytokines TNFα, IL-6, and IL-8 in lung homogenates were evaluated. Both surfactant preparations improved lung function, reduced the levels of pro-inflammatory cytokines, and degree of lung edema to very similar degrees versus the controls. No significant differences in any of the analyzed parameters were observed between the CHF5633- and poractant alfa-treated groups. This study indicates that single dose of CHF5633 improves lung function and attenuates inflammation as effectively as poractant alfa in experimental ARDS caused by injurious ventilation.


Assuntos
Produtos Biológicos/farmacologia , Inflamação/tratamento farmacológico , Pulmão/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Fosfatidilcolinas/farmacologia , Fosfolipídeos/farmacologia , Proteína B Associada a Surfactante Pulmonar/metabolismo , Proteína C Associada a Surfactante Pulmonar/metabolismo , Síndrome do Desconforto Respiratório/tratamento farmacológico , Animais , Modelos Animais de Doenças , Inflamação/patologia , Pulmão/patologia , Proteína B Associada a Surfactante Pulmonar/farmacologia , Proteína C Associada a Surfactante Pulmonar/farmacologia , Surfactantes Pulmonares/farmacologia , Coelhos , Síndrome do Desconforto Respiratório/metabolismo , Síndrome do Desconforto Respiratório/patologia
11.
Molecules ; 25(19)2020 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-32977392

RESUMO

The study aimed to prove the hypothesis that exogenous surfactant and an antibiotic polymyxin B (PxB) can more effectively reduce lipopolysaccharide (LPS)-induced acute lung injury (ALI) than surfactant treatment alone, and to evaluate the effect of this treatment on the gene expression of surfactant proteins (SPs). Anesthetized rats were intratracheally instilled with different doses of LPS to induce ALI. Animals with LPS 500 µg/kg have been treated with exogenous surfactant (poractant alfa, Curosurf®, 50 mg PL/kg b.w.) or surfactant with PxB 1% w.w. (PSUR + PxB) and mechanically ventilated for 5 hrs. LPS at 500 µg/kg increased lung edema, oxidative stress, and the levels of proinflammatory mediators in lung tissue and bronchoalveolar lavage fluid (BALF). PSUR reduced lung edema and oxidative stress in the lungs and IL-6 in BALF. This effect was further potentiated by PxB added to PSUR. Exogenous surfactant enhanced the gene expression of SP-A, SP-B, and SP-C, however, gene expression for all SPs was reduced after treatment with PSUR + PxB. In mechanically ventilated rats with LPS-induced ALI, the positive effect of exogenous surfactant on inflammation and oxidative stress was potentiated with PxB. Due to the tendency for reduced SPs gene expression after surfactant/PxB treatment topical use of PxB should be considered with caution.


Assuntos
Homeostase/efeitos dos fármacos , Lipopolissacarídeos/efeitos adversos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Polimixina B/farmacologia , Respiração Artificial , Tensoativos/farmacologia , Animais , Antibacterianos/farmacologia , Biomarcadores/metabolismo , Citocinas/metabolismo , Interações Medicamentosas , Regulação da Expressão Gênica/efeitos dos fármacos , Contagem de Leucócitos , Pulmão/citologia , Pulmão/imunologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Suínos
12.
Int J Mol Sci ; 21(9)2020 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-32403267

RESUMO

This study aimed to investigate whether a selective phosphodiesterase-3 (PDE3) inhibitor olprinone can positively influence the inflammation, apoptosis, and respiratory parameters in animals with acute respiratory distress syndrome (ARDS) model induced by repetitive saline lung lavage. Adult rabbits were divided into 3 groups: ARDS without therapy (ARDS), ARDS treated with olprinone i.v. (1 mg/kg; ARDS/PDE3), and healthy ventilated controls (Control), and were oxygen-ventilated for the following 4 h. Dynamic lung-thorax compliance (Cdyn), mean airway pressure (MAP), arterial oxygen saturation (SaO2), alveolar-arterial gradient (AAG), ratio between partial pressure of oxygen in arterial blood to a fraction of inspired oxygen (PaO2/FiO2), oxygenation index (OI), and ventilation efficiency index (VEI) were evaluated every hour. Post mortem, inflammatory and oxidative markers (interleukin (IL)-6, IL-1ß, a receptor for advanced glycation end products (RAGE), IL-10, total antioxidant capacity (TAC), 3-nitrotyrosine (3NT), and malondialdehyde (MDA) and apoptosis (apoptotic index and caspase-3) were assessed in the lung tissue. Treatment with olprinone reduced the release of inflammatory mediators and markers of oxidative damage decreased apoptosis of epithelial cells and improved respiratory parameters. The results indicate a future potential of PDE3 inhibitors also in the therapy of ARDS.


Assuntos
Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Imidazóis/farmacologia , Inflamação/prevenção & controle , Inibidores da Fosfodiesterase 3/farmacologia , Piridonas/farmacologia , Síndrome do Desconforto Respiratório/prevenção & controle , Animais , Biomarcadores/metabolismo , Citocinas/metabolismo , Inflamação/metabolismo , Inflamação/fisiopatologia , Mediadores da Inflamação/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/fisiopatologia , Coelhos , Síndrome do Desconforto Respiratório/metabolismo , Síndrome do Desconforto Respiratório/fisiopatologia
13.
PLoS One ; 14(12): e0226072, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31800629

RESUMO

Pulmonary surfactant preparations extracted from natural sources have been used to treat millions of newborn babies with respiratory distress syndrome (RDS) and can possibly also be used to treat other lung diseases. Due to costly production and limited supply of animal-derived surfactants, synthetic alternatives are attractive. The water insolubility and aggregation-prone nature of the proteins present in animal-derived surfactant preparations have complicated development of artificial surfactant. A non-aggregating analog of lung surfactant protein C, SP-C33Leu is used in synthetic surfactant and we recently described an efficient method to produce rSP-C33Leu in bacteria. Here rSP-C33Leu obtained by salt precipitation of bacterial extracts was purified by two-step liquid gel chromatography and analyzed using mass spectrometry and RP-HPLC, showing that it is void of modifications and adducts. Premature New Zealand White rabbit fetuses instilled with 200mg/kg of 2% of rSP-C33Leu in phospholipids and ventilated with a positive end expiratory pressure showed increased tidal volumes and lung gas volumes compared to animals treated with phospholipids only. This shows that rSP-C33Leu can be purified from bacterial lipids and that rSP-C33Leu surfactant is active against experimental RDS.


Assuntos
Lipopeptídeos/química , Pulmão/efeitos dos fármacos , Surfactantes Pulmonares/farmacologia , Sequência de Aminoácidos , Animais , Animais Recém-Nascidos , Cromatografia Líquida , Feminino , Lipopeptídeos/genética , Lipopeptídeos/metabolismo , Pulmão/fisiologia , Espectrometria de Massas , Fosfatidilgliceróis/química , Fosfolipídeos/farmacologia , Respiração com Pressão Positiva , Gravidez , Surfactantes Pulmonares/química , Coelhos , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Proteínas Recombinantes/isolamento & purificação , Volume de Ventilação Pulmonar/efeitos dos fármacos
14.
Int J Mol Sci ; 20(19)2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31557974

RESUMO

Acute lung injury (ALI) represents a serious heterogenous pulmonary disorder with high mortality. Despite improved understanding of the pathophysiology, the efficacy of standard therapies such as lung-protective mechanical ventilation, prone positioning and administration of neuromuscular blocking agents is limited. Recent studies have shown some benefits of corticosteroids (CS). Prolonged use of CS can shorten duration of mechanical ventilation, duration of hospitalization or improve oxygenation, probably because of a wide spectrum of potentially desired actions including anti-inflammatory, antioxidant, pulmonary vasodilator and anti-oedematous effects. However, the results from experimental vs. clinical studies as well as among the clinical trials are often controversial, probably due to differences in the designs of the trials. Thus, before the use of CS in ARDS can be definitively confirmed or refused, the additional studies should be carried on to determine the most appropriate dosing, timing and choice of CS and to analyse the potential risks of CS administration in various groups of patients with ARDS.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Corticosteroides/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Lesão Pulmonar Aguda/diagnóstico , Lesão Pulmonar Aguda/epidemiologia , Lesão Pulmonar Aguda/etiologia , Corticosteroides/administração & dosagem , Corticosteroides/efeitos adversos , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/efeitos adversos , Estudos Clínicos como Assunto , Gerenciamento Clínico , Modelos Animais de Doenças , Suscetibilidade a Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Incidência , Síndrome do Desconforto Respiratório/diagnóstico , Síndrome do Desconforto Respiratório/etiologia , Síndrome do Desconforto Respiratório/terapia , Resultado do Tratamento
15.
Molecules ; 24(5)2019 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-30841517

RESUMO

This study aimed to evaluate the molecular background of N-acetylcysteine (NAC) and recombinant human superoxide dismutase (rhSOD) antioxidant action when combined with exogenous surfactant in the treatment of meconium aspiration syndrome (MAS), considering redox signalling a principal part of cell response to meconium. Young New Zealand rabbits were instilled with meconium suspension (Mec) and treated by surfactant alone (Surf) or surfactant in combination with i.v. NAC (Surf + NAC) or i.t. rhSOD (Surf + SOD), and oxygen-ventilated for 5 h. Dynamic lung-thorax compliance, mean airway pressure, PaO2/FiO2 and ventilation efficiency index were evaluated every hour; post mortem, inflammatory and oxidative markers (advanced oxidation protein products, total antioxidant capacity, hydroxynonenal (HNE), p38 mitogen activated protein kinase, caspase 3, thromboxane, endothelin-1 and secretory phospholipase A2) were assessed in pulmonary tissue homogenates. rhSOD addition to surfactant improved significantly, but transiently, gas exchange and reduced levels of inflammatory and oxidative molecules with higher impact; Surf + NAC had stronger effect only on HNE formation, and duration of treatment efficacy in respiratory parameters. In both antioxidants, it seems that targeting reactive oxygen species may be strong supporting factor in surfactant treatment of MAS due to redox sensitivity of many intracellular pathways triggered by meconium.


Assuntos
Acetilcisteína/farmacologia , Proteínas Recombinantes/farmacologia , Superóxido Dismutase/farmacologia , Tensoativos/farmacologia , Animais , Apoptose , Biomarcadores , Modelos Animais de Doenças , Humanos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/fisiopatologia , Complacência Pulmonar/efeitos dos fármacos , Síndrome de Aspiração de Mecônio/tratamento farmacológico , Síndrome de Aspiração de Mecônio/etiologia , Síndrome de Aspiração de Mecônio/metabolismo , Síndrome de Aspiração de Mecônio/fisiopatologia , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Coelhos , Espécies Reativas de Oxigênio/metabolismo , Testes de Função Respiratória
16.
Life Sci ; 203: 121-128, 2018 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-29684443

RESUMO

AIMS: Combination of exogenous surfactant with antioxidant enzyme recombinant human superoxide dismutase (rhSOD) was tested in the treatment of experimental meconium aspiration syndrome as oxidative processes play key role in its pathogenesis. MATERIAL AND METHODS: Young New Zealand rabbits were instilled by saline (Sal group) or by meconium suspension (Mec group). Some of meconium-instilled animals were treated by surfactant alone (Surf group) or surfactant in combination with rhSOD (Surf + SOD group) and oxygen-ventilated for 5 h. PaO2/FiO2, oxygenation index, oxygen saturation, PaCO2, ventilation efficiency index and alveolar-arterial gradient were evaluated every hour; post mortem, cells in bronchoalveolar lavage were counted, inflammatory and oxidative markers were assessed using ELISA in lung tissue homogenates. KEY FINDINGS: Exogenous surfactant combined with rhSOD improved oxygenation during the first hour after the treatment more than surfactant alone (p = 0.039 to 0.0001 vs. Mec and Surf group). Amelioration was also seen in CO2 elimination (p = 0.049 to 0.0096 vs. Mec group), alveolar-arterial gradient diminution (p = 0.024 to 0.0019 vs. Mec and Surf group), prevention of oxidative damage and cytokine production (p = 0.049 to 0.002 vs. Mec group). SIGNIFICANCE: It seems that inhibition of oxidative signalization may be strong supporting factor in surfactant treatment of MAS.


Assuntos
Antioxidantes/farmacologia , Modelos Animais de Doenças , Síndrome de Aspiração de Mecônio/terapia , Pneumonia/terapia , Surfactantes Pulmonares/química , Superóxido Dismutase/administração & dosagem , Animais , Lavagem Broncoalveolar , Feminino , Humanos , Masculino , Síndrome de Aspiração de Mecônio/enzimologia , Síndrome de Aspiração de Mecônio/patologia , Pneumonia/enzimologia , Pneumonia/patologia , Coelhos , Suínos
17.
Exp Lung Res ; 44(1): 40-50, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29324051

RESUMO

AIM: Meconium aspiration syndrome (MAS) is life-threatening respiratory failure of newborns which can be treated by exogenous surfactant. In response to meconium, increased levels of chemokine IL-8 (CXCL8) stimulate massive neutrophil infiltration of the lungs. Local accumulation and activation of neutrophils, on-going inflammation, lung edema, and oxidative damage contribute to inactivation of endogenous and therapeutically given surfactants. Therefore, we have hypothesized that addition of monoclonal anti-IL-8 antibody into exogenous surfactant can mitigate the neutrophil-induced local injury and the secondary surfactant inactivation and may finally result in improvement of respiratory functions. METHODS: New Zealand rabbits with intratracheal meconium-induced respiratory failure (meconium 25 mg/ml, 4 ml/kg) were divided into three groups: untreated (M), surfactant-treated (M + S), and treated with combination of surfactant and anti-IL-8 antibody (M + S + anti-IL-8). Surfactant therapy consisted of two lung lavages with diluted porcine surfactant Curosurf (10 ml/kg, 5 mg phospholipids (PL)/ml) followed by undiluted Curosurf (100 mg PL/kg) delivered by means of asymmetric high-frequency jet ventilation (f. 300/min, Ti 20%). In M + S + anti-IL-8 group, anti-IL-8 antibody (100 µg/kg) was added directly to Curosurf dose. Animals were oxygen-ventilated for additional 5 h, respiratory parameters were measured regularly. Subsequently, cell counts in bronchoalveolar lavage fluid (BAL), lung edema formation, oxidative damage, levels of interleukins (IL)-1ß and IL-6 in the lung homogenate were evaluated. RESULTS: Surfactant instillation significantly improved lung function. Addition of anti-IL-8 to surfactant further improved gas exchange and ventilation efficiency and had longer-lasting effect than surfactant-only therapy. Combined treatment showed the trend to reduce neutrophil count in BAL fluid, local oxidative damage, and levels of IL-1ß and IL-6 more effectively than surfactant-alone, however, these differences were not significant. CONCLUSION: Addition of anti-IL-8 antibody to surfactant could potentiate the efficacy of Curosurf on the gas exchange in experimental model of MAS.


Assuntos
Anticorpos/farmacologia , Interleucina-8/imunologia , Síndrome de Aspiração de Mecônio/tratamento farmacológico , Surfactantes Pulmonares/uso terapêutico , Insuficiência Respiratória/etiologia , Animais , Anticorpos/uso terapêutico , Sinergismo Farmacológico , Troca Gasosa Pulmonar/efeitos dos fármacos , Surfactantes Pulmonares/farmacologia , Coelhos
18.
Exp Lung Res ; 43(9-10): 407-416, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29220595

RESUMO

INTRODUCTION: Chronic obstructive diseases of airways associated with cough and/or airway smooth muscle hyperresponsiveness are usually treated with bronchodilating and anti-inflammatory drugs. Recently, selective phosphodiesterase (PDE) 4 inhibitors have been introduced into the therapy of chronic obstructive pulmonary disease. Several studies have demonstrated their ability to influence the airway reactivity and eosinophilic inflammation by increasing the intracellular cAMP concentrations also in bronchial asthma. Furthermore, the expression of PDE5 in several immune cells suggests perspectives of PDE5 inhibitors in the therapy of inflammation, as well. PURPOSE: The aim of this study was to assess the dose-dependent effects of PDE4 and PDE5 inhibitors in allergic inflammation. Therefore, the effects of 7-days administration of PDE4 inhibitor roflumilast and PDE5 inhibitor tadalafil at two different doses in experimentally-induced allergic inflammation were evaluated. MATERIALS AND METHODS: In the study, male adult guinea pigs were used. Control group was non-sensitized. Other animals were sensitized with ovalbumin over two weeks and thereafter treated intraperitoneally for 7 days with roflumilast or tadalafil (daily dose 0.5 mg/kg or 1.0 mg/kg b.w.), or with vehicle. RESULTS: Both roflumilast and tadalafil reduced specific airway resistance after nebulization of histamine (marker of in vivo airway reactivity) at both doses used. The in vitro airway reactivity to cumulative doses of acetylcholine was significantly reduced for roflumilast at higher dose, predominantly in the lung tissue strips. Histamine-induced contractile responses were significantly influenced in both lung and tracheal tissue strips, predominantly at the higher doses. Tadalafil led to a decrease in contractile responses induced by both acetylcholine and histamine, with more significant effects in the lung tissue strips. These changes were associated with decreased numbers of circulating leukocytes and eosinophils and concentrations of interleukin (IL)-4, IL-5 and TNF-α in the lung homogenate. CONCLUSIONS: The selective PDE4 and PDE5 inhibitors alleviated allergic airway inflammation, with more significant effects at the higher doses.


Assuntos
Aminopiridinas/farmacologia , Benzamidas/farmacologia , Hipersensibilidade Respiratória/tratamento farmacológico , Tadalafila/farmacologia , Resistência das Vias Respiratórias/efeitos dos fármacos , Aminopiridinas/uso terapêutico , Animais , Benzamidas/uso terapêutico , Ciclopropanos/farmacologia , Ciclopropanos/uso terapêutico , Relação Dose-Resposta a Droga , Cobaias , Histamina/efeitos adversos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Masculino , Ovalbumina/efeitos adversos , Inibidores da Fosfodiesterase 4/uso terapêutico , Inibidores da Fosfodiesterase 5/uso terapêutico , Tadalafila/uso terapêutico
19.
Sci Rep ; 6: 24647, 2016 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-27097888

RESUMO

Systems biology provides opportunities to fully understand the genes and pathways in disease pathogenesis. We used literature knowledge and unbiased multiple data meta-analysis paradigms to analyze microarray datasets across different mouse strains and acute allergic asthma models. Our combined gene-driven and pathway-driven strategies generated a stringent signature list totaling 933 genes with 41% (440) asthma-annotated genes and 59% (493) ignorome genes, not previously associated with asthma. Within the list, we identified inflammation, circadian rhythm, lung-specific insult response, stem cell proliferation domains, hubs, peripheral genes, and super-connectors that link the biological domains (Il6, Il1ß, Cd4, Cd44, Stat1, Traf6, Rela, Cadm1, Nr3c1, Prkcd, Vwf, Erbb2). In conclusion, this novel bioinformatics approach will be a powerful strategy for clinical and across species data analysis that allows for the validation of experimental models and might lead to the discovery of novel mechanistic insights in asthma.


Assuntos
Asma/genética , Asma/metabolismo , Redes Reguladoras de Genes , Transdução de Sinais , Doença Aguda , Análise por Conglomerados , Biologia Computacional/métodos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos
20.
Gen Physiol Biophys ; 32(2): 251-9, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23682025

RESUMO

The best-studied store-operated Ca2+ channels (SOCs), Ca2+ release activated Ca2+ (CRAC) channels, are activated by depleting endoplasmic reticulum Ca2+ pool and mediate Ca2+ influx vitally important for Ca2+ restoration and many cellular function. CRAC channels were identified on immune and airway smooth muscle (ASM) cells. Emerging evidence points to its involvement in allergic airways diseases. This article evaluated therapeutic potency of CRAC antagonist in experimental animal model of allergic asthma. Allergic asthma, induced by repetitive exposure of guinea pigs to ovalbumine, was followed by 14 days therapy by CRAC antagonist (3-fluoropyridine-4-carboxylic acid, FPCA). In vivo changes of specific airways resistance (sRaw) evaluated bronchodilatory effect of FPCA and salbutamol. The method of citric acid-induced cough reflex assessed antitussive activity of FPCA and codeine. The measurement of exhaled NO (ENO), expression of inducible NO-synthase (iNOS) by RT-PCR and immunohistochemical staining of airways tissue verified anti-inflammatory effect of FPCA. Long-term administration of FPCA resulted in significant cough suppression and bronchodilation, both comparable to the effect of control drugs. FPCA significantly decreased ENO and iNOS expression, which together with immunohistochemical analysis validated its anti-inflammatory effect. Presented data confirmed CRAC channels as a promising target for treatment of respiratory diseases associated with allergic inflammation.


Assuntos
Anti-Inflamatórios/administração & dosagem , Antitussígenos/administração & dosagem , Asma/tratamento farmacológico , Asma/fisiopatologia , Broncodilatadores/administração & dosagem , Bloqueadores dos Canais de Cálcio/administração & dosagem , Pulmão/fisiopatologia , Animais , Cobaias , Estudos Longitudinais , Pulmão/efeitos dos fármacos , Resultado do Tratamento
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