RESUMEN
Airway inflammation and remodeling are characteristic features of asthma, with both contributing to airway hyperresponsiveness (AHR) and lung function limitation. Airway smooth muscle (ASM) accumulation and extracellular matrix deposition are characteristic features of airway remodeling, which may contribute to persistent AHR. Laminins containing the α2-chain contribute to characteristics of ASM remodeling in vitro and AHR in animal models of asthma. The role of other laminin chains, including the laminin α4 and α5 chains, which contribute to leukocyte migration in other diseases, is currently unknown. The aim of the current study was to investigate the role of these laminin chains in ASM function and in AHR, remodeling, and inflammation in asthma. Expression of both laminin α4 and α5 was observed in the human and mouse ASM bundle. In vitro, laminin α4 was found to promote a pro-proliferative, pro-contractile, and pro-fibrotic ASM cell phenotype. In line with this, treatment with laminin α4 and α5 function-blocking antibodies reduced allergen-induced increases in ASM mass in a mouse model of allergen-induced asthma. Moreover, eosinophilic inflammation was reduced by the laminin α4 function-blocking antibody as well. Using airway biopsies from healthy subjects and asthmatic patients, we found inverse correlations between ASM α4-chain expression and lung function and AHR, whereas eosinophil numbers correlated positively with expression of laminin α4 in the ASM bundle. This study, for the first time, indicates a prominent role for laminin α4 in ASM function and in inflammation, AHR, and remodeling in asthma, whereas the role of laminin α5 is more subtle.
Asunto(s)
Remodelación de las Vías Aéreas (Respiratorias) , Asma/complicaciones , Eosinófilos/patología , Inflamación/etiología , Laminina/metabolismo , Adolescente , Adulto , Anciano , Animales , Asma/metabolismo , Asma/patología , Eosinófilos/metabolismo , Femenino , Humanos , Inflamación/metabolismo , Inflamación/patología , Laminina/genética , Masculino , Ratones , Ratones Endogámicos BALB C , Persona de Mediana Edad , Contracción Muscular , Adulto JovenRESUMEN
Combining voriconazole and flucloxacillin is indicated in patient cohorts experiencing both invasive aspergillosis and Gram-positive infections (e.g., patients with chronic granulomatous disease or postinfluenza pulmonary aspergillosis). We report a highly relevant interaction between voriconazole and flucloxacillin, resulting in subtherapeutic plasma voriconazole concentrations in more than 50% of patients, that poses a severe threat if not managed properly.
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Antifúngicos/sangre , Antifúngicos/uso terapéutico , Floxacilina/uso terapéutico , Voriconazol/sangre , Voriconazol/uso terapéutico , Adolescente , Adulto , Anciano , Aspergillus/efectos de los fármacos , Niño , Preescolar , Interacciones Farmacológicas , Femenino , Enfermedad Granulomatosa Crónica/sangre , Enfermedad Granulomatosa Crónica/tratamiento farmacológico , Enfermedad Granulomatosa Crónica/microbiología , Humanos , Infecciones Fúngicas Invasoras/sangre , Infecciones Fúngicas Invasoras/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Aspergilosis Pulmonar/sangre , Aspergilosis Pulmonar/tratamiento farmacológico , Adulto JovenRESUMEN
Haloperidol decanoate is a typical antipsychotic drug used as maintenance therapy for schizophrenia and mood disorders formulated as an ester for intramuscular injection. Cases of oral haloperidol decanoate intoxications have not been described in literature. In this report, we present for the first time a case of an oral ingestion of haloperidol decanoate of a young woman who presented to the emergency department following an intentional oral ingestion of 1 ampoule of haloperidol decanoate 100mg. At presentation, she had a bilateral rest tremor of both hands and mild hypothermia. No other obvious signs of an intoxication were observed. She was treated with a single dose of activated charcoal and laxative and was admitted to the intensive care for rhythm monitoring and observation. During the night the QTc interval increased to 453ms, but stayed within the normal range. Haloperidol plasma levels increased as well, but also stayed within therapeutic ranges. These findings indicate that treatment with oral activated charcoal was sufficient to prevent any serious events.
Asunto(s)
Antipsicóticos/envenenamiento , Carbón Orgánico/uso terapéutico , Haloperidol/análogos & derivados , Laxativos/uso terapéutico , Esquizofrenia/tratamiento farmacológico , Administración Oral , Arritmias Cardíacas/inducido químicamente , Electrocardiografía , Femenino , Haloperidol/envenenamiento , Humanos , Masculino , Adulto JovenRESUMEN
Hypothyroidism may reduce, whereas hyperthyroidism may aggravate, asthma symptoms. The mechanisms underlying this relationship are largely unknown. Since thyroid hormones have central roles in cell growth and differentiation, we hypothesized that airway remodeling, in particular increased airway smooth muscle (ASM) mass, may be involved. To address this hypothesis, we investigated the effects of triiodothyronine (T3) and l-thyroxine (T4) in the absence and presence of the profibrotic transforming growth factor (TGF)-ß1 on human ASM cell phenotype switching. T3 (1-100 nM) and T4 (1-100 nM) did not affect basal ASM proliferation. However, when combined with TGF-ß1 (2 ng/ml), T4 synergistically increased the proliferative response, whereas only a minor effect was observed for T3. In line with a switch from a contractile to a proliferative ASM phenotype, T4 reduced the TGF-ß1-induced contractile protein expression by â¼50%. Cotreatment with T3 reduced TGF-ß1-induced contractile protein expression by â¼25%. The synergistic increase in proliferation was almost fully inhibited by the integrin αvß3 antagonist tetrac (100 nM), whereas no significant effects of the thyroid receptor antagonist 1-850 (3 µM) were observed. Inhibition of MEK1/2, downstream of the integrin αvß3, also inhibited the T4- and TGF-ß1-induced proliferative responses. Collectively, the results indicate that T4, and to a lesser extent T3, promotes a proliferative ASM phenotype in the presence of TGF-ß1, which is predominantly mediated by the membrane-bound T4 receptor αvß3. These results indicate that thyroid hormones may enhance ASM remodeling in asthma, which could be of relevance for hyperthyroid patients with this disease.
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Miocitos del Músculo Liso/fisiología , Tiroxina/fisiología , Factor de Crecimiento Transformador beta1/fisiología , Remodelación de las Vías Aéreas (Respiratorias) , Bronquios/patología , Línea Celular , Proliferación Celular , Regulación hacia Abajo , Expresión Génica , Humanos , Integrina alfaVbeta3/metabolismo , Sistema de Señalización de MAP Quinasas , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Fenotipo , Triyodotironina/fisiologíaRESUMEN
INTRODUCTION: Amanita phalloides poisoning is a serious health problem with a mortality rate of 10-40%. Poisonings are characterized by severe liver and kidney toxicity. The effect of Amanita phalloides poisonings on hematological parameters has not been systematically evaluated thus far. METHODS: Patients with suspected Amanita phalloides poisonings were retrospectively selected from the hospital database of the University Medical Center Groningen (UMCG). Medical data-including demographics; liver, kidney, and blood parameters; treatment; and outcomes-were collected. The severity of the poisoning was scored using the poison severity score. RESULTS: Twenty-eight patients were identified who were admitted to the UMCG with suspected Amanita phalloides poisoning between 1994 and 2022. A time-dependent decrease was observed for hemoglobin and hematocrit concentrations, leukocytes, and platelets. Six out of twenty-eight patients developed acute liver failure (ALF). Patients with ALF showed a higher increase in liver enzymes, international normalized ratios, and PSS compared to patients without ALF. Conversely, hemoglobin and platelet numbers were decreased even further in these patients. Three out of six patients with ALF died and one patient received a liver transplant. CONCLUSION: Our study shows that Amanita phalloides poisonings may be associated with hematotoxicity in patients. The quantification of hematological parameters is of relevance in intoxicated patients, especially in those with ALF.
Asunto(s)
Amanita , Fallo Hepático Agudo , Intoxicación por Setas , Humanos , Estudios Retrospectivos , Fallo Hepático Agudo/inducido químicamente , Hemoglobinas , Intoxicación por Setas/terapiaRESUMEN
BACKGROUND: Interruption of the enterohepatic circulation is regarded as an effective way to treat patients with amatoxin poisoning. Nonetheless, its effectiveness has not yet been systematically evaluated. Therefore, we performed a systematic review to investigate the role of enterohepatic circulation on patient outcome and clinical laboratory values. We specifically sought to evaluate the effect of activated charcoal, which absorbs drugs and toxins in the gastrointestinal tract. METHODS: A previously established database with data extracted from case reports and series from literature, supplemented with recent publications, was used. Patient characteristics, outcome, and laboratory values were evaluated. RESULTS: We included 133 publications describing a total of 1,119 unique cases. Survival was 75 per cent in the control group (n = 452), whereas in the group treated with single or multiple doses of activated charcoal (n = 667) survival was 83 per cent (P < 0.001, odds ratio 1.89 [95 per cent confidence interval 1.40-2.56]). Furthermore, no difference in peak values of alanine aminotransferase and aspartate aminotransferase activities were observed, whereas peak values of total serum bilirubin concentration and international normalized ratio were statistically significantly reduced in patients treated with activated charcoal. DISCUSSION: The ability of activated charcoal to enhance the elimination of amatoxin through interruption of the enterohepatic circulation offers a potentially safe and inexpensive therapy for patients in the post-absorptive phase. LIMITATIONS: Limitations include the potential for publication bias, the lack of universal confirmation of amatoxin concentrations, and the inability to directly measure enterohepatic circulation of amatoxin. CONCLUSION: Treatment with activated charcoal in patients with amatoxin poisoning was associated with a greater chance of a successful outcome. Additionally, activated charcoal was associated with a reduction in markers of liver function, but not markers of liver injury.
Asunto(s)
Carbón Orgánico , Intoxicación por Setas , Humanos , Amanitinas , Carbón Orgánico/uso terapéutico , Circulación Enterohepática , Hígado , Intoxicación por Setas/diagnóstico , Intoxicación por Setas/tratamiento farmacológicoRESUMEN
Amanita phalloides poisonings account for the majority of fatal mushroom poisonings. Recently, we identified hematotoxicity as a relevant aspect of Amanita poisonings. In this study, we investigated the effects of the main toxins of Amanita phalloides, α- and ß-amanitin, on hematopoietic cell viability in vitro. Hematopoietic cell lines were exposed to α-amanitin or ß-amanitin for up to 72 h with or without the pan-caspase inhibitor Z-VAD(OH)-FMK, antidotes N-acetylcysteine, silibinin, and benzylpenicillin, and organic anion-transporting polypeptide 1B3 (OATP1B3) inhibitors rifampicin and cyclosporin. Cell viability was established by trypan blue exclusion, annexin V staining, and a MTS assay. Caspase-3/7 activity was determined with Caspase-Glo assay, and cleaved caspase-3 was quantified by Western analysis. Cell number and colony-forming units were quantified after exposure to α-amanitin in primary CD34+ hematopoietic stem cells. In all cell lines, α-amanitin concentration-dependently decreased viability and mitochondrial activity. ß-Amanitin was less toxic, but still significantly reduced viability. α-Amanitin increased caspase-3/7 activity by 2.8-fold and cleaved caspase-3 by 2.3-fold. Z-VAD(OH)-FMK significantly reduced α-amanitin-induced toxicity. In CD34+ stem cells, α-amanitin decreased the number of colonies and cells. The antidotes and OATP1B3 inhibitors did not reverse α-amanitin-induced toxicity. In conclusion, α-amanitin induces apoptosis in hematopoietic cells via a caspase-dependent mechanism.
Asunto(s)
Alfa-Amanitina , Intoxicación por Setas , Humanos , Alfa-Amanitina/toxicidad , Caspasa 3 , Antídotos/farmacología , AmanitaRESUMEN
Transforming growth factor-ß1 (TGF-ß1) is a central mediator in tissue remodeling processes, including fibrosis and airway smooth muscle (ASM) hyperplasia, as observed in asthma. The mechanisms underlying this response, however, remain unclear because TGF-ß1 exerts only weak mitogenic effects on ASM cells. In this study, we hypothesized that the mitogenic effect of TGF-ß1 on ASM is indirect and requires prolonged exposure to allow for extracellular matrix (ECM) deposition. To address this hypothesis, we investigated the effects of acute and prolonged treatment with TGF-ß1, alone and in combination with the muscarinic receptor agonist methacholine, on human ASM cell proliferation. Acutely, TGF-ß1 exerted no mitogenic effect. However, prolonged treatment (for 7 d) with TGF-ß1 increased ASM cell proliferation and potentiated the platelet-derived growth factor-induced mitogenic response. Muscarinic receptor stimulation with methacholine synergistically enhanced the effect of TGF-ß1. Interestingly, the integrin-blocking peptide Arg-Gly-Asp-Ser, as well as integrin α5ß1 function-blocking antibodies, inhibited the effects of TGF-ß1 and its combination with methacholine on cell proliferation. Accordingly, prolonged treatment with TGF-ß1 increased fibronectin expression, which was also synergistically enhanced by methacholine. The synergistic effects of methacholine on TGF-ß1-induced proliferation were reduced by the long-acting muscarinic receptor antagonist tiotropium and the M2 receptor subtype-selective antagonist gallamine, but not the M3-selective antagonist DAU5884. In line with these findings, the irreversible Gi protein inhibitor pertussis toxin also prevented the potentiation of TGF-ß1-induced proliferation by methacholine. We conclude that prolonged exposure to TGF-ß1 enhances ASM cell proliferation, which is mediated by extracellular matrix-integrin interactions, and which can be enhanced by muscarinic M2 receptor stimulation.
Asunto(s)
Proliferación Celular , Miocitos del Músculo Liso/efectos de los fármacos , Receptor Cross-Talk , Receptor Muscarínico M2/metabolismo , Factor de Crecimiento Transformador beta1/farmacología , Línea Celular Transformada , Medio de Cultivo Libre de Suero , Replicación del ADN , Sinergismo Farmacológico , Matriz Extracelular/metabolismo , Fibronectinas/metabolismo , Trietyoduro de Galamina/farmacología , Humanos , Integrina alfa5beta1/metabolismo , Cloruro de Metacolina/farmacología , Mitógenos/farmacología , Miocitos del Músculo Liso/metabolismo , Oligopéptidos/farmacología , Toxina del Pertussis/farmacología , Receptor Muscarínico M2/agonistas , Sistema Respiratorio/citología , Factores de TiempoRESUMEN
Increased extracellular matrix (ECM) deposition and airway smooth muscle (ASM) mass are major contributors to airway remodeling in asthma. Recently, we demonstrated that the ECM protein collagen I, which is increased surrounding asthmatic ASM, induces a proliferative, hypocontractile ASM phenotype. Little is known, however, about the signaling pathways involved. Using bovine tracheal smooth muscle, we investigated the role of focal adhesion kinase (FAK) and downstream signaling pathways in collagen I-induced ASM phenotype modulation. Phosphorylation of FAK was increased during adhesion to both uncoated and collagen I-coated culture dishes, without differences between these matrices. Nor were any differences found in cellular adhesion. Inhibition of FAK activity by overexpression of the FAK deletion mutants FAT (focal adhesion targeting domain) and FRNK (FAK-related nonkinase) attenuated adhesion. After attachment, FAK phosphorylation increased in a time-dependent manner in cells cultured on collagen I, whereas no activation was found on an uncoated plastic matrix. In addition, collagen I increased in a time- and concentration-dependent manner the cell proliferation, which was fully inhibited by FAT and FRNK. Similarly, the specific pharmacologic FAK inhibitor PF-573228 [6-((4-((3-(methanesulfonyl)benzyl)amino)-5-trifluoromethylpyrimidin-2-yl) amino)-3,4-dihydro-1H-quinolin-2-one] as well as specific inhibitors of p38 mitogen-activated protein kinase (MAPK) and Src also fully inhibited collagen I-induced proliferation, whereas partial inhibition was observed by inhibition of phosphatidylinositol-3-kinase (PI3-kinase) and mitogen-activated protein kinase kinase (MEK). The inhibition of cell proliferation by these inhibitors was associated with attenuation of the collagen I-induced hypocontractility. Collectively, the results indicate that induction of a proliferative, hypocontractile ASM phenotype by collagen I is mediated by FAK and downstream signaling pathways.
Asunto(s)
Remodelación de las Vías Aéreas (Respiratorias) , Asma/metabolismo , Colágeno Tipo I/metabolismo , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Sistema de Señalización de MAP Quinasas , Contracción Muscular , Músculo Liso/metabolismo , Remodelación de las Vías Aéreas (Respiratorias)/efectos de los fármacos , Animales , Asma/tratamiento farmacológico , Bovinos , Adhesión Celular , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Colágeno Tipo I/antagonistas & inhibidores , Activación Enzimática , Proteína-Tirosina Quinasas de Adhesión Focal/antagonistas & inhibidores , Proteína-Tirosina Quinasas de Adhesión Focal/química , Proteína-Tirosina Quinasas de Adhesión Focal/genética , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Terapia Molecular Dirigida , Contracción Muscular/efectos de los fármacos , Músculo Liso/citología , Músculo Liso/efectos de los fármacos , Proteínas Mutantes/química , Proteínas Mutantes/metabolismo , Fosforilación , Dominios y Motivos de Interacción de Proteínas , Inhibidores de Proteínas Quinasas/farmacología , Procesamiento Proteico-Postraduccional , Proteínas Tirosina Quinasas/biosíntesis , Proteínas Tirosina Quinasas/genética , Proteínas Tirosina Quinasas/metabolismo , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes de Fusión/metabolismo , Técnicas de Cultivo de Tejidos , Tráquea/citología , Tráquea/metabolismoRESUMEN
Since ancient times, anticholinergics have been used as a bronchodilator therapy for obstructive lung diseases. Targets of these drugs are G-protein-coupled muscarinic M(1), M(2) and M(3) receptors in the airways, which have long been recognized to regulate vagally-induced airway smooth muscle contraction and mucus secretion. However, recent studies have revealed that acetylcholine also exerts pro-inflammatory, pro-proliferative and pro-fibrotic actions in the airways, which may involve muscarinic receptor stimulation on mesenchymal, epithelial and inflammatory cells. Moreover, acetylcholine in the airways may not only be derived from vagal nerves, but also from non-neuronal cells, including epithelial and inflammatory cells. Airway smooth muscle cells seem to play a major role in the effects of acetylcholine on airway function. It has become apparent that these cells are multipotent cells that may reversibly adopt (hyper)contractile, proliferative and synthetic phenotypes, which are all under control of muscarinic receptors and differentially involved in bronchoconstriction, airway remodeling and inflammation. Cholinergic contractile tone is increased by airway inflammation associated with asthma and COPD, resulting from exaggerated acetylcholine release as well as increased expression of contraction related proteins in airway smooth muscle. Moreover, muscarinic receptor stimulation promotes proliferation of airway smooth muscle cells as well as fibroblasts, and regulates cytokine, chemokine and extracellular matrix production by these cells, which may contribute to airway smooth muscle growth, airway fibrosis and inflammation. In line, animal models of chronic allergic asthma and COPD have recently demonstrated that tiotropium may potently inhibit airway inflammation and remodeling. These observations indicate that muscarinic receptors have a much larger role in the pathophysiology of obstructive airway diseases than previously thought, which may have important therapeutic implications.
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Asma/tratamiento farmacológico , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Receptores Muscarínicos/metabolismo , Acetilcolina/metabolismo , Remodelación de las Vías Aéreas (Respiratorias) , Animales , Asma/fisiopatología , Modelos Animales de Enfermedad , Fibroblastos/metabolismo , Humanos , Inflamación/tratamiento farmacológico , Inflamación/patología , Terapia Molecular Dirigida , Contracción Muscular , Miocitos del Músculo Liso/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/fisiopatologíaRESUMEN
The biological responses of airway smooth muscle (ASM) are diverse, in part due to ASM phenotype plasticity. ASM phenotype plasticity refers to the ability of ASM cells to change the degree of a variety of functions, including contractility, proliferation, migration and secretion of inflammatory mediators. This plasticity occurs due to intrinsic or acquired abnormalities in ASM cells, and these abnormalities or predisposition of the ASM cell may alter the ASM response and in some cases recapitulate disease hallmarks of asthma. These phenotypic changes are ultimately determined by multiple stimuli and occur due to alterations in the intricate balance or reversible state that maintains ASM cells in either a contractile or synthetic state, through processes termed maturation or modulation, respectively. To elucidate the role of ASM phenotype in disease states, numerous in vitro studies have suggested a phenotypic switch in ASM primary cell cultures as an explanation for the plethora of responses mediated by ASM cells. Moreover, there is overwhelming evidence suggesting that the immunomodulatory response of ASM is due to the acquisition of a synthetic phenotype; however, whether this degree of plasticity is present in vivo as opposed to cell culture-based models remains speculative. Nonetheless, this review will give an overall scope of ASM phenotypic markers, triggers of ASM phenotype modulation and novel therapeutic approaches to control ASM phenotype plasticity.
Asunto(s)
Asma/fisiopatología , Músculo Liso/patología , Miocitos del Músculo Liso/patología , Animales , Movimiento Celular , Proliferación Celular , Humanos , Mediadores de Inflamación/metabolismo , Contracción Muscular/fisiología , Músculo Liso/citología , Músculo Liso/metabolismo , Miocitos del Músculo Liso/metabolismo , FenotipoRESUMEN
In asthma, the airway smooth muscle (ASM) cell plays a central role in disease pathogenesis through cellular changes which may impact on its microenvironment and alter ASM response and function. The answer to the long debated question of what makes a 'healthy' ASM cell become 'asthmatic' still remains speculative. What is known of an 'asthmatic' ASM cell, is its ability to contribute to the hallmarks of asthma such as bronchoconstriction (contractile phenotype), inflammation (synthetic phenotype) and ASM hyperplasia (proliferative phenotype). The phenotype of healthy or diseased ASM cells or tissue for the most part is determined by expression of key phenotypic markers. ASM is commonly accepted to have different phenotypes: the contractile (differentiated) state versus the synthetic (dedifferentiated) state (with the capacity to synthesize mediators, proliferate and migrate). There is now accumulating evidence that the synthetic functions of ASM in culture derived from asthmatic and non-asthmatic donors differ. Some of these differences include an altered profile and increased production of extracellular matrix proteins, pro-inflammatory mediators and adhesion receptors, collectively suggesting that ASM cells from asthmatic subjects have the capacity to alter their environment, actively participate in repair processes and functionally respond to changes in their microenvironment.
Asunto(s)
Asma/fisiopatología , Inflamación/patología , Miocitos del Músculo Liso/patología , Animales , Broncoconstricción , Microambiente Celular , Humanos , Hiperplasia/patología , Contracción Muscular , Miocitos del Músculo Liso/metabolismo , FenotipoRESUMEN
Airway remodeling, including increased airway smooth muscle (ASM) mass and contractility, contributes to increased airway narrowing in asthma. Increased ASM mass may be caused by exposure to mitogens, including platelet-derived growth factor (PDGF) and collagen type I, which induce a proliferative, hypocontractile ASM phenotype. In contrast, prolonged exposure to insulin induces a hypercontractile phenotype. Glucocorticosteroids and ß2-adrenoceptor agonists synergize to increase glucocorticosteroid receptor translocation in ASM cells; however, the impact of this synergism on phenotype modulation is unknown. Using bovine tracheal smooth muscle, we investigated the effects of the glucocorticosteroids fluticasone (10 nM), budesonide (30 nM), and dexamethasone (0.1-1 µM) and the combination of low concentrations of fluticasone (3-100 pM) and fenoterol (10 nM) on ASM phenotype switching in response to PDGF (10 ng/ml), collagen type I (50 µg/ml), and insulin (1 µM). All glucocorticosteroids inhibited PDGF- and collagen I-induced proliferation and hypocontractility, with the effects of collagen I being less susceptible to glucocorticosteroid action. At 100-fold lower concentrations, fluticasone (100 pM) synergized with fenoterol to prevent PDGF- and collagen I-induced phenotype switching. This inhibition of ASM phenotype switching was associated with a normalization of the PDGF-induced decrease in the cell cycle inhibitors p21(WAF1/CIP1) and p57(KIP2). At this concentration, fluticasone also prevented the insulin-induced hypercontractile phenotype. At even lower concentrations, fluticasone (3 pM) synergized with fenoterol to inhibit this phenotype switch. Collectively, these findings indicate that glucocorticosteroids and ß2-agonists synergistically inhibit ASM phenotype switching, which may contribute to the increased effectiveness of combined treatment with glucocorticosteroids and ß2-agonists in asthma.
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Agonistas de Receptores Adrenérgicos beta 2/farmacología , Remodelación de las Vías Aéreas (Respiratorias)/efectos de los fármacos , Glucocorticoides/farmacología , Músculo Liso/efectos de los fármacos , Remodelación de las Vías Aéreas (Respiratorias)/fisiología , Androstadienos/farmacología , Animales , Budesonida/farmacología , Bovinos , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Colágeno Tipo I/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/metabolismo , Dexametasona/farmacología , Sinergismo Farmacológico , Fenoterol/farmacología , Fluticasona , Insulina/metabolismo , Mitógenos/farmacología , Contracción Muscular/efectos de los fármacos , Músculo Liso/metabolismo , Músculo Liso/fisiología , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/fisiología , Fenotipo , Factor de Crecimiento Derivado de Plaquetas/metabolismo , Sistema Respiratorio/efectos de los fármacos , Sistema Respiratorio/metabolismo , Tráquea/efectos de los fármacos , Tráquea/metabolismo , Tráquea/fisiologíaRESUMEN
INTRODUCTION: Nicotine is an addictive and poisonous agent. The recent development of e-cigarettes has caused a new demand for highly concentrated nicotine-containing solutions. These concentrated nicotine solutions have also increased the risk of nicotine overdoses. AREAS COVERED: Essential factors for nicotine exposure are the concentration of the nicotine-containing e-liquid solution and its pharmacokinetics. Liquid nicotine refills contain nicotine in varying concentrations, which vary widely between and within products. The pharmacokinetics of nicotine are dependent on the route of administration, renal/hepatic clearance and urinary pH. The dose is another essential determinant of nicotine exposure. There is a considerable discrepancy between the generally accepted lethal dose and symptoms reported in case studies. Ingested doses correlate poorly to clinical symptoms. Symptoms of liquid nicotine toxicity vary from mild to severe between patients and are the result of overstimulation of nicotinic acetylcholine receptors, which may lead to fatal respiratory failure and cardiovascular collapse. EXPERT OPINION: The literature on nicotine-containing e-liquid intoxications originating from vaping device refills are mainly case reports. Based on these case reports, we propose a treatment plan which is primarily symptomatic. Research should focus on providing insight on its toxicity, based on oral and transdermal pharmacokinetics and on toxicodynamics.
Asunto(s)
Sistemas Electrónicos de Liberación de Nicotina , Vapeo , Relación Dosis-Respuesta a Droga , Humanos , Nicotina/efectos adversosRESUMEN
BACKGROUND AND AIMS: Amanita phalloides poisoning causes severe liver damage which may be potentially fatal. Several treatments are available, but their effectiveness has not been systematically evaluated. We performed a systematic review to investigate the effect of the most commonly used therapies: N-acetylcysteine (NAC), benzylpenicillin (PEN), and silibinin (SIL) on patient outcomes. In addition, other factors contributing to patient outcomes are identified. METHODS: We searched MEDLINE and Embase for case series and case reports that described patient outcomes after poisoning with amanitin-containing Amanita mushrooms. We extracted clinical characteristics, treatment details, and outcomes. We used the liver item from the Poisoning Severity Score (PSS) to categorize intoxication severity. RESULTS: We included 131 publications describing a total of 877 unique cases. The overall survival rate of all patients was 84%. Patients receiving only supportive care had a survival rate of 59%. The use of SIL or PEN was associated with a 90% (OR 6.40 [3.14-13.04]) and 89% (OR 5.24 [2.87-9.56]) survival rate, respectively. NAC/SIL combination therapy was associated with 85% survival rate (OR 3.85 [2.04, 7.25]). NAC/PEN/SIL treatment group had a survival rate of 76% (OR 2.11 [1.25, 3.57]). Due to the limited number of cases, the use of NAC alone could not be evaluated. Additional analyses in 'proven cases' (amanitin detected), 'probable cases' (mushroom identified by mycologist), and 'possible cases' (neither amanitin detected nor mushroom identified) showed comparable results, but the results did not reach statistical significance. Transplantation-free survivors had significantly lower peak values of aspartate aminotransferase (AST), alanine aminotransferase (ALT), total serum bilirubin (TSB), and international normalized ratio (INR) compared to liver transplantation survivors and patients with fatal outcomes. Higher peak PSS was associated with increased mortality. CONCLUSION: Based on data available, no statistical differences could be observed for the effects of NAC, PEN or SIL in proven poisonings with amanitin-containing mushrooms. However, monotherapy with SIL or PEN and combination therapy with NAC/SIL appear to be associated with higher survival rates compared to supportive care alone. AST, ALT, TSB, and INR values are possible predictors of potentially fatal outcomes.
Asunto(s)
Amanitinas , Intoxicación por Setas , Humanos , Intoxicación por Setas/tratamiento farmacológico , Intoxicación por Setas/complicaciones , Amanita , Alanina Transaminasa , Acetilcisteína/uso terapéutico , Silibina/uso terapéutico , Penicilina G/uso terapéuticoRESUMEN
RATIONALE: Airway remodeling, including increased airway smooth muscle (ASM) mass and contractility, contributes to airway hyperresponsiveness in asthma. The mechanisms driving these changes are, however, incompletely understood. Recently, an important role for extracellular matrix proteins in regulating ASM proliferation and contractility has been found, suggesting that matrix proteins and their integrins actively modulate airway remodeling. OBJECTIVES: To investigate the role of RGD (Arg-Gly-Asp)-binding integrins in airway remodeling in an animal model of allergic asthma. METHODS: Using a guinea pig model of allergic asthma, the effects of topical application of the integrin-blocking peptide RGDS (Arg-Gly-Asp-Ser) and its negative control GRADSP (Gly-Arg-Ala-Asp-Ser-Pro) were assessed on markers of ASM remodeling, fibrosis, and inflammation induced by repeated allergen challenge. In addition, effects of these peptides on human ASM proliferation and maturation were investigated in vitro. MEASUREMENTS AND MAIN RESULTS: RGDS attenuated allergen-induced ASM hyperplasia and hypercontractility as well as increased pulmonary expression of smooth muscle myosin heavy chain and the proliferative marker proliferating cell nuclear antigen (PCNA). No effects were observed for GRADSP. The RGDS effects were ASM selective, as allergen-induced eosinophil and neutrophil infiltration as well as fibrosis were unaffected. In cultured human ASM cells, we demonstrated that proliferation induced by collagen I, fibronectin, serum, and platelet-derived growth factor requires signaling via RGD-binding integrins, particularly of the alpha(5)beta(1) subtype. In addition, RGDS inhibited smooth muscle alpha-actin accumulation in serum-deprived ASM cells. CONCLUSIONS: This is the first study indicating that integrins modulate ASM remodeling in an animal model of allergic asthma, which can be inhibited by a small peptide containing the RGD motif.
Asunto(s)
Remodelación de las Vías Aéreas (Respiratorias)/efectos de los fármacos , Asma/fisiopatología , Músculo Liso/efectos de los fármacos , Oligopéptidos/farmacología , Inhibidores de Agregación Plaquetaria/farmacología , Administración Tópica , Remodelación de las Vías Aéreas (Respiratorias)/inmunología , Animales , Anticuerpos/inmunología , Asma/inmunología , Biomarcadores , Western Blotting , Técnicas de Cultivo de Célula , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Fibrosis/inmunología , Cobayas , Humanos , Inflamación/inmunología , Masculino , Contracción Muscular/efectos de los fármacos , Músculo Liso/inmunología , Oligopéptidos/inmunología , Inhibidores de Agregación Plaquetaria/inmunología , Antígeno Nuclear de Célula en Proliferación/efectos de los fármacos , Antígeno Nuclear de Célula en Proliferación/inmunologíaRESUMEN
Increased and changed deposition of extracellular matrix proteins is a key feature of airway wall remodeling in obstructive pulmonary diseases, including asthma and chronic obstructive pulmonary disease. Studies have highlighted that the deposition of various basement membrane proteins in the lung tissue is altered and that these changes reflect tissue compartment specificity. Inflammatory responses in both diseases may result in the deregulation of production and degradation of these proteins. In addition to their role in tissue development and integrity, emerging evidence indicates that basement membrane proteins also actively modulate cellular processes in obstructive airway diseases, contributing to disease development, progression and maintenance. In this review, we summarize the changes in basement membrane composition in airway remodeling in obstructive airway diseases and explore their potential application as innovative targets for treatment development.
RESUMEN
BACKGROUND: Fibroproliferative airway remodelling, including increased airway smooth muscle (ASM) mass and contractility, contributes to airway hyperresponsiveness in asthma. In vitro studies have shown that maturation of ASM cells to a (hyper)contractile phenotype is dependent on laminin, which can be inhibited by the laminin-competing peptide Tyr-Ile-Gly-Ser-Arg (YIGSR). The role of laminins in ASM remodelling in chronic asthma in vivo, however, has not yet been established. METHODS: Using an established guinea pig model of allergic asthma, we investigated the effects of topical treatment of the airways with YIGSR on features of airway remodelling induced by repeated allergen challenge, including ASM hyperplasia and hypercontractility, inflammation and fibrosis. Human ASM cells were used to investigate the direct effects of YIGSR on ASM proliferation in vitro. RESULTS: Topical administration of YIGSR attenuated allergen-induced ASM hyperplasia and pulmonary expression of the proliferative marker proliferating cell nuclear antigen (PCNA). Treatment with YIGSR also increased both the expression of sm-MHC and ASM contractility in saline- and allergen-challenged animals; this suggests that treatment with the laminin-competing peptide YIGSR mimics rather than inhibits laminin function in vivo. In addition, treatment with YIGSR increased allergen-induced fibrosis and submucosal eosinophilia. Immobilized YIGSR concentration-dependently reduced PDGF-induced proliferation of cultured ASM to a similar extent as laminin-coated culture plates. Notably, the effects of both immobilized YIGSR and laminin were antagonized by soluble YIGSR. CONCLUSION: These results indicate that the laminin-competing peptide YIGSR promotes a contractile, hypoproliferative ASM phenotype in vivo, an effect that appears to be linked to the microenvironment in which the cells are exposed to the peptide.
Asunto(s)
Remodelación de las Vías Aéreas (Respiratorias)/efectos de los fármacos , Asma/metabolismo , Laminina/metabolismo , Pulmón/fisiopatología , Contracción Muscular/efectos de los fármacos , Músculo Liso/fisiopatología , Oligopéptidos/administración & dosificación , Administración Tópica , Animales , Modelos Animales de Enfermedad , Cobayas , Humanos , Laminina/antagonistas & inhibidores , Pulmón/efectos de los fármacos , Músculo Liso/efectos de los fármacos , FenotipoRESUMEN
Airway smooth muscle (ASM) plays a key role in the development of airway hyperresponsiveness and remodeling in asthma, which may involve maturation of ASM cells to a hypercontractile phenotype. In vitro studies have indicated that long-term exposure of bovine tracheal smooth muscle (BTSM) to insulin induces a functional hypercontractile, hypoproliferative phenotype. Similarly, the extracellular matrix protein laminin has been found to be involved in both the induction and maintenance of a contractile ASM phenotype. Using BTSM, we now investigated the role of laminins in the insulin-induced hypercontractile, hypoproliferative ASM phenotype. The results demonstrate that insulin-induced hypercontractility after 8 days of tissue culture was fully prevented by combined treatment of BTSM-strips with the laminin competing peptides Tyr-Ile-Gly-Ser-Arg (YIGSR) and Arg-Gly-Asp-Ser (RGDS). YIGSR also prevented insulin-induced increases in sm-myosin expression and abrogated the suppressive effects of prolonged insulin treatment on platelet-derived growth factor-induced DNA synthesis in cultured cells. In addition, insulin time-dependently increased laminin alpha2, beta1, and gamma1 chain protein, but not mRNA abundance in BTSM strips. Moreover, as previously found for contractile protein accumulation, signaling through PI3-kinase- and Rho kinase-dependent pathways was required for the insulin-induced increase in laminin abundance and contractility. Collectively, our results indicate a critical role for beta1-containing laminins, likely laminin-211, in the induction of a hypercontractile, hypoproliferative ASM phenotype by prolonged insulin exposure. Increased laminin production by ASM could be involved in the increased ASM contractility and contractile protein expression in asthma. Moreover, the results may be of interest for the use of inhaled insulin administrations by diabetics.