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1.
Oxid Med Cell Longev ; 2021: 6646923, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33628371

RESUMEN

Inflammatory lung disease results in a high global burden of death and disability. There are no effective treatments for the most severe forms of many inflammatory lung diseases, such as chronic obstructive pulmonary disease, emphysema, corticosteroid-resistant asthma, and coronavirus disease 2019; hence, new treatment options are required. Here, we review the role of oxidative imbalance in the development of difficult-to-treat inflammatory lung diseases. The inflammation-induced overproduction of reactive oxygen species (ROS) means that endogenous antioxidants may not be sufficient to prevent oxidative damage, resulting in an oxidative imbalance in the lung. In turn, intracellular signaling events trigger the production of proinflammatory mediators that perpetuate and aggravate the inflammatory response and may lead to tissue damage. The production of high levels of ROS in inflammatory lung diseases can induce the phosphorylation of mitogen-activated protein kinases, the inactivation of phosphoinositide 3-kinase (PI3K) signaling and histone deacetylase 2, a decrease in glucocorticoid binding to its receptor, and thus resistance to glucocorticoid treatment. Hence, antioxidant treatment might be a therapeutic option for inflammatory lung diseases. Preclinical studies have shown that antioxidants (alone or combined with anti-inflammatory drugs) are effective in the treatment of inflammatory lung diseases, although the clinical evidence of efficacy is weaker. Despite the high level of evidence for the efficacy of antioxidants in the treatment of inflammatory lung diseases, the discovery and clinical investigation of safer, more efficacious compounds are now a priority.


Asunto(s)
Antioxidantes/uso terapéutico , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Enfermedades Pulmonares/tratamiento farmacológico , Enfermedades Pulmonares/metabolismo , Animales , Humanos , Inflamación/inmunología , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Enfermedades Pulmonares/inmunología , Oxidación-Reducción/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Enfermedad Pulmonar Obstructiva Crónica/inmunología , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Especies Reactivas de Oxígeno/metabolismo
2.
Ecotoxicol Environ Saf ; 210: 111871, 2021 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-33422840

RESUMEN

AIM: Ambient fine particulate matter (PM2.5) consists of various components, and their respective contributions to the toxicity of PM2.5 remains to be determined. To provide specific recommendations for preventing adverse effects due to PM2.5 pollution, we determined whether the induction of pulmonary inflammation, the putative pathogenesis for the morbidity and mortality due to PM2.5 exposure, was fractioned through solubility-dependent fractioning. METHODS: In the present study, the water and heptane solubilities-dependent serial fractioning of diesel exhaust particulate matter (DEP), a prominent source of urban PM2.5 pollution, was performed. The pro-inflammatory actions of these resultant fractions were then determined using both an intratracheal instillation mouse model and cultured BEAS-2B cells, a human bronchial epithelial cell line. RESULTS: Instillation of the water-insoluble, but not -soluble fraction elicited significant pulmonary inflammatory and acute phase responses, comparable to those induced by instillation of DEP. The water-insoluble fraction was further fractioned using heptane, a polar organic solvent, and instillation of heptane-insoluble, but not -soluble fraction elicited significant pulmonary inflammation and acute phase responses. Furthermore, we showed that DEP and water-insoluble DEP, but not water-soluble DEP, activated pro-inflammatory signaling in cultured BEAS-2B cells, ruling out the possibility that the solubility impacts the in vivo distribution and thus the pulmonary inflammatory response.


Asunto(s)
Reacción de Fase Aguda/inducido químicamente , Contaminantes Atmosféricos/toxicidad , Inflamación/inducido químicamente , Pulmón/efectos de los fármacos , Material Particulado/toxicidad , Emisiones de Vehículos/toxicidad , Reacción de Fase Aguda/patología , Animales , Bronquios/citología , Línea Celular , Células Epiteliales/efectos de los fármacos , Humanos , Inflamación/patología , Pulmón/patología , Masculino , Ratones Endogámicos C57BL
3.
Ecotoxicol Environ Saf ; 210: 111870, 2021 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-33440271

RESUMEN

Ammonia is the main harmful gas in livestock houses. However, the toxic mechanism of ammonia is still unclear. Therefore, we examined the effects of ammonia exposure on different tissues of fattening pigs by histological analysis and transcriptome techniques in this study. The results showed that there were varying degrees of pathological changes in liver, kidney, hypothalamus, jejunum, lungs, spleen, heart and trachea of fattening pigs under ammonia exposure. Notably, the extent of damage in liver, kidney, jejunum, lungs, hypothalamus and trachea was more severe than that in heart and spleen. Transcriptome results showed that ammonia exposure caused changes in 349, 335, 340, 229, 120, 578, 407 and 115 differentially expressed genes in liver, kidney, spleen, lung, trachea, hypothalamus, jejunum and heart, respectively. Interestingly, the changes in solute vector (SLC) family genes were found in all 8 tissues, and the verified gene results (SLC11A1, SLC17A7, SLC17A6, SLC6A4, SLC22A7, SLC25A3, SLC28A3, SLC7A2, SLC6A6, SLC38A5, SLC22A12, SLC34A1, SLC26A1, SLC26A6, SLC27A5, SLC22A8 and SLC44A4) were consistent with qRT-PCR results. In conclusion, ammonia exposure can cause pathological changes in many tissues and organs of fattening pigs and changes in the SCL family gene network. Importantly, the SCL family is involved in the toxic mechanism of ammonia. Our findings will provide a new insight for better assessing the mechanism of ammonia toxicity.


Asunto(s)
Amoníaco/toxicidad , Proteínas de Transporte de Membrana/genética , Animales , Femenino , Redes Reguladoras de Genes/efectos de los fármacos , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Hipotálamo/patología , Yeyuno/efectos de los fármacos , Yeyuno/metabolismo , Yeyuno/patología , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/patología , Miocardio/patología , Bazo/efectos de los fármacos , Bazo/metabolismo , Bazo/patología , Porcinos , Tráquea/efectos de los fármacos , Tráquea/metabolismo , Tráquea/patología , Transcriptoma/efectos de los fármacos
4.
J Cell Mol Med ; 25(4): 2279-2284, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33421348

RESUMEN

Obesity increases the morbidity and severity of asthma, with poor sensitivity to corticosteroid treatment. Metformin has potential effects on improving asthma airway inflammation. Regulatory T cells (Tregs) play a key role in suppressing the immunoreaction to allergens. We built an obese asthmatic mouse model by administering a high-fat diet (HFD) and ovalbumin (OVA) sensitization, with daily metformin treatment. We measured the body weight and airway inflammatory status by histological analysis, qRT-PCR, and ELISA. The percentage of Tregs was measured by flow cytometry. Obese asthmatic mice displayed more severe airway inflammation and more significant changes in inflammatory cytokines. Metformin reversed the obese situation and alleviated the airway inflammation and remodelling with increased Tregs and related transcript factors. The anti-inflammatory function of metformin may be mediated by increasing Tregs.


Asunto(s)
Antiinflamatorios/farmacología , Asma/tratamiento farmacológico , Hipoglucemiantes/farmacología , Metformina/farmacología , Obesidad/tratamiento farmacológico , Linfocitos T Reguladores/efectos de los fármacos , Animales , Asma/inmunología , Asma/patología , Peso Corporal/efectos de los fármacos , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/inmunología , Recuento de Linfocito CD4 , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Humanos , Inflamación , Interleucina-4/antagonistas & inhibidores , Interleucina-4/inmunología , Interleucina-4/metabolismo , Pulmón/efectos de los fármacos , Pulmón/inmunología , Pulmón/patología , Ratones , Obesidad/inmunología , Obesidad/patología , Ovalbúmina/administración & dosificación , Bazo/efectos de los fármacos , Bazo/inmunología , Bazo/patología , Linfocitos T Reguladores/inmunología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/inmunología , Factor de Necrosis Tumoral alfa/metabolismo
5.
PLoS One ; 16(1): e0245924, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33481950

RESUMEN

SARS-CoV-2 is a single stranded RNA (ssRNA) virus and contains GU-rich sequences distributed abundantly in the genome. In COVID-19, the infection and immune hyperactivation causes accumulation of inflammatory immune cells, blood clots, and protein aggregates in lung fluid, increased lung alveolar wall thickness, and upregulation of serum cytokine levels. A serum protein called serum amyloid P (SAP) has a calming effect on the innate immune system and shows efficacy as a therapeutic for fibrosis in animal models and clinical trials. Here we show that aspiration of the GU-rich ssRNA oligonucleotide ORN06 into mouse lungs induces all of the above COVID-19-like symptoms. Men tend to have more severe COVID-19 symptoms than women, and in the aspirated ORN06 model, male mice tended to have more severe symptoms than female mice. Intraperitoneal injections of SAP starting from day 1 post ORN06 aspiration attenuated the ORN06-induced increase in the number of inflammatory cells and formation of clot-like aggregates in the mouse lung fluid, reduced ORN06-increased alveolar wall thickness and accumulation of exudates in the alveolar airspace, and attenuated an ORN06-induced upregulation of the inflammatory cytokines IL-1ß, IL-6, IL-12p70, IL-23, and IL-27 in serum. SAP also reduced D-dimer levels in the lung fluid. In human peripheral blood mononuclear cells, SAP attenuated ORN06-induced extracellular accumulation of IL-6. Together, these results suggest that aspiration of ORN06 is a simple model for both COVID-19 as well as cytokine storm in general, and that SAP is a potential therapeutic for diseases with COVID-19-like symptoms and/or a cytokine storm.


Asunto(s)
/tratamiento farmacológico , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Neumonía/tratamiento farmacológico , Componente Amiloide P Sérico/uso terapéutico , Animales , /patología , Síndrome de Liberación de Citoquinas/complicaciones , Síndrome de Liberación de Citoquinas/patología , Modelos Animales de Enfermedad , Femenino , Humanos , Pulmón/efectos de los fármacos , Pulmón/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Neumonía/complicaciones , Neumonía/patología , Componente Amiloide P Sérico/administración & dosificación
6.
Respir Res ; 22(1): 20, 2021 Jan 18.
Artículo en Inglés | MEDLINE | ID: mdl-33461535

RESUMEN

BACKGROUND: COVID-19 causes acute respiratory distress syndrome (ARDS) and depletes the lungs of surfactant, leading to prolonged mechanical ventilation and death. The feasibility and safety of surfactant delivery in COVID-19 ARDS patients have not been established. METHODS: We performed retrospective analyses of data from patients receiving off-label use of exogenous natural surfactant during the COVID-19 pandemic. Seven COVID-19 PCR positive ARDS patients received liquid Curosurf (720 mg) in 150 ml normal saline, divided into five 30 ml aliquots) and delivered via a bronchoscope into second-generation bronchi. Patients were matched with 14 comparable subjects receiving supportive care for ARDS during the same time period. Feasibility and safety were examined as well as the duration of mechanical ventilation and mortality. RESULTS: Patients showed no evidence of acute decompensation following surfactant installation into minor bronchi. Cox regression showed a reduction of 28-days mortality within the surfactant group, though not significant. The surfactant did not increase the duration of ventilation, and health care providers did not convert to COVID-19 positive. CONCLUSIONS: Surfactant delivery through bronchoscopy at a dose of 720 mg in 150 ml normal saline is feasible and safe for COVID-19 ARDS patients and health care providers during the pandemic. Surfactant administration did not cause acute decompensation, may reduce mortality and mechanical ventilation duration in COVID-19 ARDS patients. This study supports the future performance of randomized clinical trials evaluating the efficacy of meticulous sub-bronchial lavage with surfactant as treatment for patients with COVID-19 ARDS.


Asunto(s)
Productos Biológicos/administración & dosificación , Pulmón/efectos de los fármacos , Fosfolípidos/administración & dosificación , Surfactantes Pulmonares/administración & dosificación , Anciano , Productos Biológicos/efectos adversos , Broncoscopía , /mortalidad , Estudios de Factibilidad , Femenino , Humanos , Pulmón/fisiopatología , Masculino , Persona de Mediana Edad , Fosfolípidos/efectos adversos , Proyectos Piloto , Surfactantes Pulmonares/efectos adversos , Respiración Artificial , Estudios Retrospectivos , Factores de Tiempo , Resultado del Tratamiento
7.
Free Radic Biol Med ; 163: 153-162, 2021 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-33347987

RESUMEN

Nitric oxide (NO) is a free radical playing an important pathophysiological role in cardiovascular and immune systems. Recent studies reported that NO levels were significantly lower in patients with COVID-19, which was suggested to be closely related to vascular dysfunction and immune inflammation among them. In this review, we examine the potential role of NO during SARS-CoV-2 infection from the perspective of the unique physical, chemical and biological properties and potential mechanisms of NO in COVID-19, as well as possible therapeutic strategies using inhaled NO. We also discuss the limits of NO treatment, and the future application of this approach in prevention and therapy of COVID-19.


Asunto(s)
Antiinflamatorios/uso terapéutico , Anticoagulantes/uso terapéutico , Antivirales/uso terapéutico , Pulmón/efectos de los fármacos , Óxido Nítrico/uso terapéutico , Administración por Inhalación , Antiinflamatorios/sangre , Anticoagulantes/sangre , Antivirales/sangre , /patología , Células Endoteliales/efectos de los fármacos , Células Endoteliales/patología , Células Endoteliales/virología , Humanos , Inflamación , Pulmón/irrigación sanguínea , Pulmón/virología , Mitocondrias/efectos de los fármacos , Mitocondrias/virología , Óxido Nítrico/sangre , /patogenicidad , Índice de Severidad de la Enfermedad , Vasodilatación/efectos de los fármacos
8.
Phytomedicine ; 80: 153392, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33113503

RESUMEN

BACKGROUND: Acacetin 7-O-ß-D-glucoside (tilianin) is a major constituent of Agastache rugosa, a traditional medicine that has long been used for the treatment of gastrointestinal disorders. Tilianin has a wide variety of pharmacological properties such as cardioprotective, neuroprotective, and anti-atherogenic activities. We recently discovered that tilianin has the ability to suppress MUC5AC expression in vitro. In addition, we have established an in vivo model of allergic asthma using house dust mite (HDM) that can be applied to tilianin. PURPOSE: We investigated the effects of tilianin on airway inflammation in a HDM-induced asthma mouse model and associated mechanisms. METHODS: Tilianin was treated in splenocytes cultured in Th0 condition and HDM-stimulated bone marrow-derived dendritic cells (BMDCs), and their mRNA expression and cytokines production were determined by quantitative real-time PCR and ELISA. To evaluate the effects of tilianin in an allergic asthma model, mice were sensitized and challenged with HDM. Tilianin was administered prior to challenge by oral gavage and airway hyper-reactivity (AHR) to methacholine, inflammatory cell infiltration, cytokine levels, and airway remodeling were assessed. RESULTS: Tilianin inhibited the production of Th2-related cytokines in splenocytes, which play pivotal roles in allergic airway inflammation. When treated in HDM-stimulated BMDCs, tilianin decreased Th2-skewing cytokine IL-33 and transcription factor IRF4. On the contrary, tilianin increased Th1-skewing regulators, IL-12 and IRF1. In an HDM-induced asthmatic mouse model, tilianin attenuated AHR and airway inflammation. Tilianin suppressed the expression of Th2-related cytokines, IL-13 and IL-33 in lung tissues. As seen in HDM-stimulated BMDCs, tilianin also downregulated the expression of the transcription factor IRF4 but not IRF1. CONCLUSION: Taken together, these results suggest that tilianin attenuates HDM-induced allergic airway inflammation by inhibiting Th2-mediated inflammation through the selective inhibition of the IRF4-IL-33 axis in dendritic cells.


Asunto(s)
Antiasmáticos/farmacología , Asma/tratamiento farmacológico , Flavonoides/farmacología , Glicósidos/farmacología , Factores Reguladores del Interferón/metabolismo , Células Th2/efectos de los fármacos , Remodelación de las Vías Aéreas (Respiratorias) , Animales , Asma/inmunología , Asma/metabolismo , Citocinas/metabolismo , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Modelos Animales de Enfermedad , Regulación hacia Abajo/efectos de los fármacos , Femenino , Hipersensibilidad/tratamiento farmacológico , Hipersensibilidad/etiología , Factores Reguladores del Interferón/inmunología , Interleucina-33/metabolismo , Pulmón/efectos de los fármacos , Pulmón/inmunología , Pulmón/metabolismo , Ratones Endogámicos BALB C , Pyroglyphidae/patogenicidad , Células Th2/inmunología , Células Th2/metabolismo
9.
Chemosphere ; 262: 128330, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33182093

RESUMEN

Recently, there have been reports that many microplastics are found in the air, which has raised concerns about their toxicity. To date, however, only limited research has investigated the effects of micro(nano)plastics on human health, and even less the potential for inhalation toxicity. To fill this research gap, we investigated the potential inhalation toxicity of micro(nano)plastics using a modified OECD Guideline for Testing of Chemicals No. 412 '28-Day (subacute) inhalation toxicity study' using a whole-body inhalation system. Sprague-Dawley rats were exposed to three different exposure concentrations of polystyrene micro(nano)plastics (PSMPs), as well as control, for 14 days of inhalation exposure. After 14 days, alterations were observed on sevral endpoints in physiological, serum biochemical, hematological, and respiratory function markers measured on the samples exposed to PSMPs. However, no concentration-response relationships were observed, suggesting that these effects may not be definitively linked to exposure of PSMPs. On the other hand, the expression of inflammatory proteins (TGF-ß and TNF-α) increased in the lung tissue in an exposure concentration-dependent manner. The overall results indicate that 14-day inhalation exposure of PSMPs to rats has a more pronounced effect at the molecular level than at the organismal one. These results suggest that if the exposure sustained, alterations at the molecular level may lead to subsequent alterations at the higher levels, and consequently, the health risks of inhalation exposed micro(nano)plastics should not be neglected.


Asunto(s)
Exposición por Inhalación/efectos adversos , Pulmón/efectos de los fármacos , Microplásticos/toxicidad , Nanopartículas/toxicidad , Poliestirenos/toxicidad , Aerosoles , Animales , Femenino , Humanos , Pulmón/metabolismo , Pulmón/patología , Masculino , Microplásticos/farmacocinética , Nanopartículas/metabolismo , Organización para la Cooperación y el Desarrollo Económico , Tamaño de la Partícula , Poliestirenos/farmacocinética , Ratas , Ratas Sprague-Dawley , Pruebas de Función Respiratoria , Propiedades de Superficie
10.
Gene ; 766: 145153, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-32950633

RESUMEN

AIM: Acute lung injury (ALI) is the mild form of acute respiratory distress syndrome (ARDS) which is a common lung disease with a high incidence and mortality rate. Recent studies manifested that some circular RNAs were associated with ALI. In this study, we aimed to uncover the effect of circular RNA circ_0054633 on ALI initiation and progression and proposed a new mechanism related to ALI. METHODS: The lipopolysaccharides (LPS)-induced acute lung injury model were build both in vivo of rat and in vitro of primary murine pulmonary microvascular endothelial cells (MPVECs). Hematoxylin and eosin (H&E) was employed to observe the tissue morphology and estimate the degree of lung damage. We used real-time quantitative polymerase chain reaction (RT-qPCR) to measure the expression level of circ_0054633. The expression levels of inflammatory cytokines IL-17A and tumor necrosis factor-α (TNF-α) were detected by ELISA. The effects of circ_0054633 on MPVECs proliferation and apoptosis were detected with the help of CCK-8 and apoptosis assay, separately. The expression level of NF-κB p65 protein was measured by Western blot. RESULTS: circ_0054633, IL-17A, TNF-α and NF-κB p65 were all overexpressed in LPS-treated rat and MPVECs, and LPS enhanced the proliferation and apoptosis of MPVECs. While circ_0054633 silencing reversed the above promotion effects of LPS on IL-17A, TNF-α expression and MPVECs proliferation and apoptosis. CONCLUSIONS: Quietness of circ_0054633 alleviated LPS-induced ALI via NF-κB signaling pathway, implicating circ_0054633 may be a potential biomarker for diagnose and therapy of ALI.


Asunto(s)
Lesión Pulmonar Aguda/metabolismo , Proliferación Celular/fisiología , Células Endoteliales/metabolismo , Inflamación/metabolismo , FN-kappa B/metabolismo , ARN Circular/metabolismo , Lesión Pulmonar Aguda/inducido químicamente , Animales , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Inflamación/inducido químicamente , Interleucina-17/metabolismo , Lipopolisacáridos/farmacología , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Masculino , Ratones , Ratas , Ratas Sprague-Dawley , Factor de Transcripción ReIA/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo
11.
Exp Gerontol ; 145: 111197, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33310152

RESUMEN

Senior individuals are more susceptible to the irreversible outcomes of endothelial barrier dysfunction, the hallmark of Acute Respiratory Distress Syndrome (ARDS). The Severe Acute Respiratory Syndrome Coronovirus 2 (SARS-CoV-2) - inflicted ARDS delivers the devastating outcomes of the COVID-19 worldwide. Endothelial hyperpermeability has been associated with both the progression and establishment of the COVID-19 - related respiratory failure. In the present study we investigated the in vitro effects of Metformin in the permeability of bovine pulmonary artery endothelial cells. Our preliminary results suggest that moderate doses (0.1, 0.5, 1.0 mM) of this anti-diabetic agent enhance the vascular barrier integrity, since it produces an increase in the transendothelial resistance of endothelial monolayers. Thus, we speculate that Metformin may deliver a new therapeutic possibility in ARDS, alone or in combination with other barrier enhancers.


Asunto(s)
Metformina/uso terapéutico , /tratamiento farmacológico , Animales , Bovinos , Células Endoteliales/efectos de los fármacos , Humanos , Pulmón/efectos de los fármacos
12.
Biomed Pharmacother ; 133: 111083, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33378979

RESUMEN

Apo-A1 is correlated with conditions like hyperlipidemia, cardiovascular diseases, high altitude pulmonary edema and etc. where hypoxia constitutes an important facet.Hypoxia causes oxidative stress, vaso-destructive and inflammatory outcomes.Apo-A1 is reported to have vasoprotective, anti-oxidative, anti-apoptotic, and anti-inflammatory effects. However, effects of Apo-A1 augmentation during hypoxia exposure are unknown.In this study, we investigated the effects of exogenously supplementing Apo-A1-mimetic peptide on SD rats during hypoxia exposure. For easing the processes of delivery, absorption and bio-availability, Apo-A1 mimetic peptide D4F was used. The rats were given 10 mg/kg BW dose (i.p.) of D4F for 7 days and then exposed to hypoxia. D4F was observed to attenuate both oxidative stress and inflammation during hypoxic exposure. D4F improved energy homeostasis during hypoxic exposure. D4F did not affect HIF-1a levels during hypoxia but increased MnSOD levels while decreasing CRP and Apo-B levels. D4F showed promise as a prophylactic against hypoxia exposure.


Asunto(s)
Antiinflamatorios/farmacología , Antioxidantes/farmacología , Apolipoproteína A-I/farmacología , Metabolismo Energético/efectos de los fármacos , Hipoxia/tratamiento farmacológico , Inflamación/prevención & control , Pulmón/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Animales , Apolipoproteínas B/sangre , Proteínas Portadoras/sangre , Modelos Animales de Enfermedad , Hipoxia/sangre , Hipoxia/complicaciones , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Inflamación/sangre , Inflamación/etiología , Pulmón/metabolismo , Masculino , Oxidación-Reducción , Ratas Sprague-Dawley , Superóxido Dismutasa/metabolismo
13.
Biomed Pharmacother ; 133: 110910, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33378990

RESUMEN

Pulmonary arterial hypertension (PAH) is a type of high morbidity and mortality disease. Currently, the intrinsic metabolic alteration and potential mechanism of PAH are still not fully uncovered. Previously, we have found that polyphenol resveratrol (Rev) reversed the remodeling of the pulmonary vasculature and decreased the number of mitochondria in pulmonary arterial smooth muscle cells (PASMCs) (Lei Yu et al. (2017)). However, potential effects of Rev on the changed metabolic molecules derived from lung tissue and serum have no fully elucidated. Thus, we conducted a systematic elaboration through the metabonomics method. Various of metabolites in different pathways including amino acid metabolism, tricarboxylic acid cycle (TCA), acetylcholine metabolism, fatty acid metabolism and biosynthesis in male Wistar rats' sera and lung tissues were explored in three groups (normal group, PAH group, PAH and Rev treatment group). We found that leucine and isoleucine degradation, valine, leucine and isoleucine biosynthesis, tryptophan metabolism and aminoacyl-tRNA biosynthesis were involved in the development of PAH. Hydroxyphenyllactic, isopalmitic acid and cytosine might be significant key metabolites. Further work in this area may inform personalized treatment approaches in clinical practice of PAH through elucidating pathophysiology mechanisms of experimental verification.


Asunto(s)
Metabolismo Energético/efectos de los fármacos , Pulmón/efectos de los fármacos , Metabolómica , Hipertensión Arterial Pulmonar/tratamiento farmacológico , Resveratrol/farmacología , Animales , Biomarcadores/sangre , Cromatografía Líquida de Alta Presión , Modelos Animales de Enfermedad , Hipoxia/complicaciones , Pulmón/metabolismo , Masculino , Hipertensión Arterial Pulmonar/sangre , Hipertensión Arterial Pulmonar/etiología , Ratas Wistar , Espectrometría de Masa por Ionización de Electrospray
14.
Biomed Pharmacother ; 133: 110998, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33378995

RESUMEN

OBJECTIVE: Mycoplasma pneumoniae (MP) is the only pathogen in the Mycoplasma family that can cause respiratory symptoms, including acute upper respiratory tract infection and bronchitis, which are often attributed to Mycoplasma pneumoniae pneumonia (MPP). MPP is one of the diseases that commonly affects the pediatric respiratory system, but its pathogenesis is unclear. This study investigated the therapeutic effects and mechanisms of Qingxuan Tongluo formula and its main component, curcumin, on MPP. METHODS: A mouse model of MPP was obtained by nasal drip of the MP strain. The effects of Qingxuan Tongluo formula and curcumin on the treatment of MPP were studied. The proteomic profiles of the alveolar lavage fluid of mice in the model group, Qingxuan Tongluo formula group and curcumin group were evaluated by LC-MS/MS. ELISA and immunohistochemistry were used to verify the possible presence of MP infection biomarkers and drug target proteins. RESULTS: Compared with the mice in the model group, the MPP mice in the Qingxuan Tongluo formula group had significantly reduced fever and cough and prolonged the cough incubation period. Moreover, the pulmonary pathology of the MPP mice was significantly improved, and the lung histopathological score was decreased. After treatment with Qingxuan Tongluo formula and curcumin, the functional and pathway abnormalities caused by MP were mainly inhibited. Levels of HSP90AA1, GRP94, ENO1 and PLG expression were verified by ELISA and immunohistochemistry. CONCLUSION: Qingxuan Tongluo formula significantly reduced fevers and cough and prolonged the cough incubation period of MPP mice. Qingxuan Tongluo formula and curcumin significantly improved the pathological changes in lung tissue caused by MP infection. Proteomics analyses indicated that Qingxuan Tongluo formula and curcumin may have therapeutic effects on MPP by regulating energy metabolism, relieving oxidative stress and activating the fibrinolytic system. ENO1 and PLG were found to be potential drug targets.


Asunto(s)
Curcumina/farmacología , Medicamentos Herbarios Chinos/farmacología , Pulmón/efectos de los fármacos , Mycoplasma pneumoniae/patogenicidad , Neumonía por Mycoplasma/tratamiento farmacológico , Proteómica , Animales , Líquido del Lavado Bronquioalveolar/química , Modelos Animales de Enfermedad , Proteínas HSP90 de Choque Térmico/metabolismo , Interacciones Huésped-Patógeno , Pulmón/metabolismo , Pulmón/microbiología , Pulmón/patología , Masculino , Glicoproteínas de Membrana/metabolismo , Ratones Endogámicos BALB C , Fosfopiruvato Hidratasa/metabolismo , Plasminógeno/metabolismo , Neumonía por Mycoplasma/metabolismo , Neumonía por Mycoplasma/microbiología , Neumonía por Mycoplasma/patología , Mapas de Interacción de Proteínas
15.
Diabetes ; 70(3): 759-771, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33310740

RESUMEN

The causes of the increased risk of severe coronavirus disease 2019 (COVID-19) in people with diabetes are unclear. It has been speculated that renin-angiotensin system (RAS) blockers may promote COVID-19 by increasing ACE2, which severe acute respiratory syndrome coronavirus 2 uses to enter host cells, along with the host protease TMPRSS2. Taking a reverse translational approach and by combining in situ hybridization, primary cell isolation, immunoblotting, quantitative RT-PCR, and liquid chromatography-tandem mass spectrometry, we studied lung and kidney ACE2 and TMPRSS2 in diabetic mice mimicking host factors linked to severe COVID-19. In healthy young mice, neither the ACE inhibitor ramipril nor the AT1 receptor blocker telmisartan affected lung or kidney ACE2 or TMPRSS2, except for a small increase in kidney ACE2 protein with ramipril. In contrast, mice with comorbid diabetes (aging, high-fat diet, and streptozotocin-induced diabetes) had heightened lung ACE2 and TMPRSS2 protein levels and increased lung ACE2 activity. None of these parameters were affected by RAS blockade. ACE2 was similarly upregulated in the kidneys of mice with comorbid diabetes compared with aged controls, whereas TMPRSS2 (primarily distal nephron) was highest in telmisartan-treated animals. Upregulation of lung ACE2 activity in comorbid diabetes may contribute to an increased risk of severe COVID-19. This upregulation is driven by comorbidity and not by RAS blockade.


Asunto(s)
/genética , Diabetes Mellitus Experimental/metabolismo , Dieta Alta en Grasa , Riñón/metabolismo , Pulmón/metabolismo , Serina Endopeptidasas/genética , Factores de Edad , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , /metabolismo , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Animales , Immunoblotting , Hibridación in Situ , Riñón/efectos de los fármacos , Pulmón/efectos de los fármacos , Masculino , Ratones , Ramipril/farmacología , /genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Serina Endopeptidasas/efectos de los fármacos , Serina Endopeptidasas/metabolismo , Telmisartán/farmacología
16.
Immunology ; 162(1): 30-43, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-32935333

RESUMEN

Coronavirus disease 2019 (COVID-19) is caused by SARS-CoV-2, a novel coronavirus strain. Some studies suggest that COVID-19 could be an immune-related disease, and failure of effective immune responses in initial stages of viral infection could contribute to systemic inflammation and tissue damage, leading to worse disease outcomes. T cells can act as a double-edge sword with both pro- and anti-roles in the progression of COVID-19. Thus, better understanding of their roles in immune responses to SARS-CoV-2 infection is crucial. T cells primarily react to the spike protein on the coronavirus to initiate antiviral immunity; however, T-cell responses can be suboptimal, impaired or excessive in severe COVID-19 patients. This review focuses on the multifaceted roles of T cells in COVID-19 pathogenesis and rationalizes their significance in eliciting appropriate antiviral immune responses in COVID-19 patients and unexposed individuals. In addition, we summarize the potential therapeutic approaches related to T cells to treat COVID-19 patients. These include adoptive T-cell therapies, vaccines activating T-cell responses, recombinant cytokines, Th1 activators and Th17 blockers, and potential utilization of immune checkpoint inhibitors alone or in combination with anti-inflammatory drugs to improve antiviral T-cell responses against SARS-CoV-2.


Asunto(s)
/inmunología , Inmunidad Celular , Inmunoterapia , Pulmón/inmunología , Linfocitos T/inmunología , Traslado Adoptivo , Animales , Antivirales/uso terapéutico , /virología , Interacciones Huésped-Patógeno , Humanos , Inmunidad Celular/efectos de los fármacos , Factores Inmunológicos/uso terapéutico , Pulmón/efectos de los fármacos , Pulmón/virología , /patogenicidad , Linfocitos T/efectos de los fármacos , Linfocitos T/trasplante , Linfocitos T/virología
17.
Int J Nanomedicine ; 15: 9939-9960, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33376320

RESUMEN

Background: Non-spherical titanium dioxide (TiO2) nanoparticles have been increasingly applied in various biomedical and technological fields. Their toxicological characterization is, however, less complete than that of roundish nanoparticles. Materials and Methods: Anatase form TiO2 nanorods, ca. 15x65 nm in size, were applied to cultured astrocytes in vitro and to the airways of young adult Wistar rats in vivo in 5, 10, and 8 mg/kg BW dose for altogether 28 days. Presence of nanorods and cellular damage was investigated in the astrocytes and in rat lungs and kidneys. Functional damage of the nervous system was studied by electrophysiological methods. Results: The treated astrocytes showed loss of viability without detectable apoptosis. In rats, TiO2 nanorods applied to the airways reached the blood and various organs including the lungs, kidneys, and the central nervous system. In lung and kidney samples, nanorods were observed within (partly damaged) phagolysosomes and attached to organelles, and apoptotic cell death was also detected. In cortical and peripheral electrophysiological activity, alterations corresponding to energy shortage (resulting possibly from mitochondrial damage) and astrocytic dysfunction were detected. Local titanium levels and relative weight of the investigated organs, apoptotic cell death in the lungs and kidneys, and changes in the central and peripheral nervous activity were mostly proportional to the applied doses, and viability loss of the cultured astrocytes was also dose-dependent, suggesting causal relationship of treatments and effects. Conclusion: Based on localization of the visualized nanorods, on neuro-functional changes, and on literature data, the toxic mechanism involved mitochondrial damage, oxidative stress, and apoptotic cell death. These indicate potential human toxicity and occupational risk in case of exposure to rod-shaped TiO2 nanoparticles.


Asunto(s)
Astrocitos/efectos de los fármacos , Sistema Nervioso Central/efectos de los fármacos , Riñón/efectos de los fármacos , Pulmón/efectos de los fármacos , Nanotubos/química , Titanio/química , Titanio/toxicidad , Animales , Apoptosis/efectos de los fármacos , Astrocitos/citología , Astrocitos/metabolismo , Células Cultivadas , Sistema Nervioso Central/metabolismo , Humanos , Riñón/metabolismo , Pulmón/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Wistar
18.
PLoS One ; 15(12): e0242945, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33370348

RESUMEN

BACKGROUND: Emerging data suggests a possible role for cysteamine as an adjunct treatment for pulmonary exacerbations of cystic fibrosis (CF) that continue to be a major clinical challenge. There are no studies investigating the use of cysteamine in pulmonary exacerbations of CF. This exploratory randomized clinical trial was conducted to answer the question: In future pivotal trials of cysteamine as an adjunct treatment in pulmonary exacerbations of CF, which candidate cysteamine dosing regimens should be tested and which are the most appropriate, clinically meaningful outcome measures to employ as endpoints? METHODS AND FINDINGS: Multicentre double-blind randomized clinical trial. Adults experiencing a pulmonary exacerbation of CF being treated with standard care that included aminoglycoside therapy were randomized equally to a concomitant 14-day course of placebo, or one of 5 dosing regimens of cysteamine. Outcomes were recorded on days 0, 7, 14 and 21 and included sputum bacterial load and the patient reported outcome measures (PROMs): Chronic Respiratory Infection Symptom Score (CRISS), the Cystic Fibrosis Questionnaire-Revised (CFQ-R); FEV1, blood leukocyte count, and inflammatory markers. Eighty nine participants in fifteen US and EU centres were randomized, 78 completed the 14-day treatment period. Cysteamine had no significant effect on sputum bacterial load, however technical difficulties limited interpretation. The most consistent findings were for cysteamine 450mg twice daily that had effects additional to that observed with placebo, with improved symptoms, CRISS additional 9.85 points (95% CI 0.02, 19.7) p = 0.05, reduced blood leukocyte count by 2.46x109 /l (95% CI 0.11, 4.80), p = 0.041 and reduced CRP by geometric mean 2.57 nmol/l (95% CI 0.15, 0.99), p = 0.049. CONCLUSION: In this exploratory study cysteamine appeared to be safe and well-tolerated. Future pivotal trials investigating the utility of cysteamine in pulmonary exacerbations of CF need to include the cysteamine 450mg doses and CRISS and blood leukocyte count as outcome measures. CLINICAL TRIAL REGISTRATION: NCT03000348; www.clinicaltrials.gov.


Asunto(s)
Cisteamina/administración & dosificación , Cisteamina/uso terapéutico , Fibrosis Quística/tratamiento farmacológico , Pulmón/efectos de los fármacos , Administración Oral , Adulto , Cisteamina/efectos adversos , Femenino , Humanos , Masculino , Cumplimiento de la Medicación , Seguridad
19.
Biomed Res Int ; 2020: 2909673, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33376717

RESUMEN

Difficulties have risen while managing Acute Respiratory Distress Syndrome (ARDS) caused by COVID-19, although it meets the Berlin definition. Severe hypoxemia with near-normal compliance was noted along with coagulopathy. Understanding the precise pathophysiology of this atypical ARDS will assist researchers and physicians in improving their therapeutic approach. Previous work is limited to postmortem studies, while our report addresses patients under protective lung mechanical ventilation. An open-lung minithoracotomy was performed in 3 patients who developed ARDS related to COVID-19 and were admitted to the intensive care unit to carry out a pathological and microbiological analysis on lung tissue biopsy. Diffused alveolar damage with hyaline membranes was found, as well as plurifocal fibrin microthrombi and vascular congestion in all patients' specimens. Microbiological cultures were negative, whereas qualitative Reversed Transcriptase Polymerase Chain Reaction (RT-PCR) detected SARS-CoV-2 in the pulmonary parenchyma and pleural fluid in two patients. COVID-19 causes progressive ARDS with onset of severe hypoxemia, underlying a dual mechanism: shunt effect through diffused alveolar damage and dead space effect through thrombotic injuries in microvascular beds. It seems reasonable to manage this ventilation-perfusion ratio mismatch using a high dose of anticoagulant combined with glucocorticoids.


Asunto(s)
/tratamiento farmacológico , Pulmón/efectos de los fármacos , Pulmón/patología , /tratamiento farmacológico , Anciano , Anticoagulantes/uso terapéutico , Biopsia/métodos , Glucocorticoides/uso terapéutico , Humanos , Pulmón/virología , Masculino , Respiración Artificial , /efectos de los fármacos
20.
Cochrane Database Syst Rev ; 12: CD004454, 2020 12 25.
Artículo en Inglés | MEDLINE | ID: mdl-33368142

RESUMEN

BACKGROUND: Respiratory morbidity including respiratory distress syndrome (RDS) is a serious complication of preterm birth and the primary cause of early neonatal mortality and disability. Despite early evidence indicating a beneficial effect of antenatal corticosteroids on fetal lung maturation and widespread recommendations to use this treatment in women at risk of preterm delivery, some uncertainty remains about their effectiveness particularly with regard to their use in lower-resource settings, different gestational ages and high-risk obstetric groups such as women with hypertension or multiple pregnancies. This updated review (which supersedes an earlier review Crowley 1996) was first published in 2006 and subsequently updated in 2017. OBJECTIVES: To assess the effects of administering a course of corticosteroids to women prior to anticipated preterm birth (before 37 weeks of pregnancy) on fetal and neonatal morbidity and mortality, maternal mortality and morbidity, and on the child in later life. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (3 September 2020), ClinicalTrials.gov, the databases that contribute to the WHO International Clinical Trials Registry Platform (ICTRP) (3 September 2020), and reference lists of the retrieved studies. SELECTION CRITERIA: We considered all randomised controlled comparisons of antenatal corticosteroid administration with placebo, or with no treatment, given to women with a singleton or multiple pregnancy, prior to anticipated preterm delivery (elective, or following rupture of membranes or spontaneous labour), regardless of other co-morbidity, for inclusion in this review. DATA COLLECTION AND ANALYSIS: We used standard Cochrane Pregnancy and Childbirth methods for data collection and analysis. Two review authors independently assessed trials for inclusion, assessed risk of bias, evaluated trustworthiness based on predefined criteria developed by Cochrane Pregnancy and Childbirth, extracted data and checked them for accuracy, and assessed the certainty of the evidence using the GRADE approach. Primary outcomes included perinatal death, neonatal death, RDS, intraventricular haemorrhage (IVH), birthweight, developmental delay in childhood and maternal death. MAIN RESULTS: We included 27 studies (11,272 randomised women and 11,925 neonates) from 20 countries. Ten trials (4422 randomised women) took place in lower- or middle-resource settings. We removed six trials from the analysis that were included in the previous version of the review; this review only includes trials that meet our pre-defined trustworthiness criteria. In 19 trials the women received a single course of steroids. In the remaining eight trials repeated courses may have been prescribed. Fifteen trials were judged to be at low risk of bias, two had a high risk of bias in two or more domains and we ten trials had a high risk of bias due to lack of blinding (placebo was not used in the control arm. Overall, the certainty of evidence was moderate to high, but it was downgraded for IVH due to indirectness; for developmental delay due to risk of bias and for maternal adverse outcomes (death, chorioamnionitis and endometritis) due to imprecision. Neonatal/child outcomes Antenatal corticosteroids reduce the risk of: - perinatal death (risk ratio (RR) 0.85, 95% confidence interval (CI) 0.77 to 0.93; 9833 infants; 14 studies; high-certainty evidence; 2.3% fewer, 95% CI 1.1% to 3.6% fewer), - neonatal death (RR 0.78, 95% CI 0.70 to 0.87; 10,609 infants; 22 studies; high-certainty evidence; 2.6% fewer, 95% CI 1.5% to 3.6% fewer), - respiratory distress syndrome (RR 0.71, 95% CI 0.65 to 0.78; 11,183 infants; studies = 26; high-certainty evidence; 4.3% fewer, 95% CI 3.2% to 5.2% fewer). Antenatal corticosteroids probably reduce the risk of IVH (RR 0.58, 95% CI 0.45 to 0.75; 8475 infants; 12 studies; moderate-certainty evidence; 1.4% fewer, 95% CI 0.8% to1.8% fewer), and probably have little to no effect on birthweight (mean difference (MD) -14.02 g, 95% CI -33.79 to 5.76; 9551 infants; 19 studies; high-certainty evidence). Antenatal corticosteroids probably lead to a reduction in developmental delay in childhood (RR 0.51, 95% CI 0.27 to 0.97; 600 children; 3 studies; moderate-certainty evidence; 3.8% fewer, 95% CI 0.2% to 5.7% fewer). Maternal outcomes Antenatal corticosteroids probably result in little to no difference in maternal death (RR 1.19, 95% CI 0.36 to 3.89; 6244 women; 6 studies; moderate-certainty evidence; 0.0% fewer, 95% CI 0.1% fewer to 0.5% more), chorioamnionitis (RR 0.86, 95% CI 0.69 to 1.08; 8374 women; 15 studies; moderate-certainty evidence; 0.5% fewer, 95% CI 1.1% fewer to 0.3% more), and endometritis (RR 1.14, 95% CI 0.82 to 1.58; 6764 women; 10 studies; moderate-certainty; 0.3% more, 95% CI 0.3% fewer to 1.1% more) The wide 95% CIs in all of these outcomes include possible benefit and possible harm. AUTHORS' CONCLUSIONS: Evidence from this updated review supports the continued use of a single course of antenatal corticosteroids to accelerate fetal lung maturation in women at risk of preterm birth. Treatment with antenatal corticosteroids reduces the risk of perinatal death, neonatal death and RDS and probably reduces the risk of IVH. This evidence is robust, regardless of resource setting (high, middle or low). Further research should focus on variations in the treatment regimen, effectiveness of the intervention in specific understudied subgroups such as multiple pregnancies and other high-risk obstetric groups, and the risks and benefits in the very early or very late preterm periods. Additionally, outcomes from existing trials with follow-up into childhood and adulthood are needed in order to investigate any longer-term effects of antenatal corticosteroids. We encourage authors of previous studies to provide further information which may answer any remaining questions about the use of antenatal corticosteroids without the need for further randomised controlled trials. Individual patient data meta-analyses from published trials are likely to provide answers for most of the remaining clinical uncertainties.


Asunto(s)
Corticoesteroides/administración & dosificación , Madurez de los Órganos Fetales/efectos de los fármacos , Pulmón/embriología , Nacimiento Prematuro , Atención Prenatal/métodos , Síndrome de Dificultad Respiratoria del Recién Nacido/prevención & control , Betametasona/administración & dosificación , Sesgo , Hemorragia Cerebral Intraventricular/prevención & control , Discapacidades del Desarrollo/epidemiología , Dexametasona/administración & dosificación , Femenino , Humanos , Hidrocortisona/administración & dosificación , Recién Nacido , Pulmón/efectos de los fármacos , Muerte Materna , Muerte Perinatal , Embarazo , Ensayos Clínicos Controlados Aleatorios como Asunto
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