RESUMEN
BACKGROUND: Lung fibrosis is a major concern in severe COVID-19 patients undergoing mechanical ventilation (MV). Lung fibrosis frequency in post-COVID syndrome is highly variable and even if the risk is proportionally small, many patients could be affected. However, there is still no data on lung extracellular matrix (ECM) composition in severe COVID-19 and whether it is different from other aetiologies of ARDS. METHODS: We have quantified different ECM elements and TGF-ß expression in lung tissue of 28 fatal COVID-19 cases and compared to 27 patients that died of other causes of ARDS, divided according to MV duration (up to six days or seven days or more). In COVID-19 cases, ECM elements were correlated with lung transcriptomics and cytokines profile. RESULTS: We observed that COVID-19 cases presented significant increased deposition of collagen, fibronectin, versican, and TGF-ß, and decreased decorin density when compared to non-COVID-19 cases of similar MV duration. TGF-ß was precociously increased in COVID-19 patients with MV duration up to six days. Lung collagen was higher in women with COVID-19, with a transition of upregulated genes related to fibrillogenesis to collagen production and ECM disassembly along the MV course. CONCLUSIONS: Fatal COVID-19 is associated with an early TGF-ß expression lung environment after the MV onset, followed by a disordered ECM assembly. This uncontrolled process resulted in a prominent collagen deposition when compared to other causes of ARDS. Our data provides pathological substrates to better understand the high prevalence of pulmonary abnormalities in patients surviving COVID-19.
Asunto(s)
COVID-19 , Fibrosis Pulmonar , Síndrome de Dificultad Respiratoria , Humanos , Femenino , Fibrosis Pulmonar/metabolismo , COVID-19/metabolismo , Matriz Extracelular/metabolismo , Colágeno/metabolismo , Pulmón/metabolismo , Factor de Crecimiento Transformador beta/farmacología , Síndrome de Dificultad Respiratoria/metabolismoRESUMEN
Acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) is a critical respiratory syndrome with limited effective interventions. Lung macrophages play a critical role in the pathogenesis of abnormal inflammatory response in the syndrome. Recently, impaired fatty acid oxidation (FAO), one of the key lipid metabolic signalings, was found to participate in the onset and development of various lung diseases, including ALI/ARDS. Lipid/fatty acid contents within mouse lungs were quantified using the Oil Red O staining. The protective effect of FAO activator L-carnitine (Lca, 50, 500, or 5 mg/mL) was evaluated by cell counting kit 8 (CCK-8) assay, real-time quantitative PCR (qPCR), ELISA, immunoblotting, fluorescence imaging, and fluorescence plate reader detection in lipopolysaccharide (LPS) (100 ng/mL)-stimulated THP-1-derived macrophages. The in vivo efficacy of Lca (300 mg/kg) was determined in a 10 mg/kg LPS-induced ALI mouse model. We found for the first time that lipid accumulation in pulmonary macrophages was significantly increased in a classical ALI murine model, which indicated disrupted FAO induced by LPS. Lca showed potent anti-inflammatory and antioxidative effects on THP-1 derived macrophages upon LPS stimulation. Mechanistically, Lca was able to maintain FAO, mitochondrial activity, and ameliorate mitochondrial dynamics. In the LPS-induced ALI mouse model, we further discovered that Lca inhibited neutrophilic inflammation and decreased diffuse damage, which might be due to the preservation of mitochondrial homeostasis. These results broadened our understanding of ALI/ARDS pathogenesis and provided a promising drug candidate for this syndrome.
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Lesión Pulmonar Aguda , Síndrome de Dificultad Respiratoria , Ratones , Animales , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/patología , Lipopolisacáridos , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/inducido químicamente , Inflamación/metabolismo , Síndrome de Dificultad Respiratoria/metabolismo , Síndrome de Dificultad Respiratoria/patología , Mitocondrias/metabolismo , Mitocondrias/patología , Ácidos Grasos , Pulmón/patologíaRESUMEN
PURPOSE: Although mechanical ventilation is an essential support for acute respiratory distress syndrome (ARDS), ventilation also leads to ventilator-induced lung injury (VILI). This study aimed to estimate the effect and mechanism of Annexin A1 peptide (Ac2-26) on VILI in ARDS rats. METHODS: Thirty-two rats were randomized into the sham (S), mechanical ventilation (V), mechanical ventilation/Ac2-26 (VA), and mechanical ventilation/Ac2-26/L-NIO (VAL) groups. The S group only received anesthesia, and the other three groups received endotoxin and then ventilation for 4 h. Rats in the V, VA and VAL groups received saline, Ac2-26, and A c2-26/N5-(1-iminoethyl)-l-ornithine (L-NIO), respectively. RESULTS: All indexes deteriorated in the V, VA and VAL groups compared with the S group. Compared with V group, the PaO2/FiO2 ratio was increased, but the wet-to-dry weight ratio and protein levels in bronchoalveolar lavage fluid were decreased in the VA group. The inflammatory cells and proinflammatory factors were reduced by Ac2-26. The oxidative stress response, lung injury and apoptosis were also decreased by Ac2-26 compared to V group. All improvements of Ac2-26 were partly reversed by L-NIO. CONCLUSIONS: Ac2-26 mitigates VILI in ARDS rats and partly depended on the endothelial nitric oxide synthase pathway.
Asunto(s)
Anexina A1 , Síndrome de Dificultad Respiratoria , Lesión Pulmonar Inducida por Ventilación Mecánica , Ratas , Animales , Anexina A1/farmacología , Anexina A1/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Pulmón/metabolismo , Lesión Pulmonar Inducida por Ventilación Mecánica/tratamiento farmacológico , Líquido del Lavado Bronquioalveolar , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Síndrome de Dificultad Respiratoria/metabolismo , Péptidos/farmacología , Péptidos/uso terapéutico , Péptidos/metabolismoRESUMEN
Many individuals infected with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) develop no or only mild symptoms, but some can go on onto develop a spectrum of pathologies including pneumonia, acute respiratory distress syndrome, respiratory failure, systemic inflammation, and multiorgan failure. Many pathogens, viral and non-viral, can elicit these pathologies, which justifies reconsidering whether the target of therapeutic approaches to fight pathogen infections should be (a) the pathogen itself, (b) the pathologies elicited by the pathogen interaction with the human host, or (c) a combination of both. While little is known about the immunopathology of SARS-CoV-2, it is well-established that the above-mentioned pathologies are associated with hyper-inflammation, tissue damage, and the perturbation of target organ metabolism. Mounting evidence has shown that these processes are regulated by endoproteinases (particularly, matrix metalloproteinases (MMPs)). Here, we review what is known about the roles played by MMPs in the development of COVID-19 and postulate a mechanism by which MMPs could influence energy metabolism in target organs, such as the lung. Finally, we discuss the suitability of MMPs as therapeutic targets to increase the metabolic tolerance of the host to damage inflicted by the pathogen infection, with a focus on SARS-CoV-2.
Asunto(s)
COVID-19/metabolismo , Pulmón/fisiopatología , Metaloproteinasas de la Matriz/metabolismo , Proteínas Quinasas/metabolismo , Síndrome de Dificultad Respiratoria/metabolismo , Quinasas de la Proteína-Quinasa Activada por el AMP , COVID-19/enzimología , COVID-19/fisiopatología , COVID-19/virología , Comorbilidad , Citocinas/metabolismo , Humanos , Inflamación/tratamiento farmacológico , Inflamación/enzimología , Inflamación/metabolismo , Inflamación/patología , Pulmón/enzimología , Pulmón/metabolismo , Pulmón/virología , Inhibidores de la Metaloproteinasa de la Matriz/farmacología , Síndrome de Dificultad Respiratoria/enzimología , Síndrome de Dificultad Respiratoria/fisiopatología , Síndrome de Dificultad Respiratoria/virología , SARS-CoV-2/patogenicidad , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genéticaRESUMEN
BACKGROUND: The ARDS (Acute Respiratory Distress Syndrome) is a severe respiratory syndrome that was recently associated as the main death cause in the COVID-19 pandemic outbreak. Hence, in order to prevent ARDS, the pulmonary function maintenance has been the target of several pharmacological approaches. However, there is a lack of reports regarding the use of effective pharmaceutical active natural products (PANPs) for early treatment and prevention of COVID-19-related ARDS. Therefore, the aim of this work was to conduct a systematic review regarding the PANPs that could be further studied as alternatives to prevent ARDS. Consequently, this work can pave the way to spread the use of PANPs on the prevention of ARDS in COVID-19-confirmed or -suspected patients. METHODS: The search strategy included scientific studies published in English from 2015 to 2020 that promoted the elucidation of anti-inflammatory pathways targeting ARDS by in vitro and/or in vivo experiments using PANPs. Then, 74 studies regarding PANPs, able to maintain or improve the pulmonary function, were reported. CONCLUSIONS: The PANPs may present different pulmonary anti-inflammatory pathways, wherein (i) reduction/attenuation of pro-inflammatory cytokines, (ii) increase of the anti-inflammatory mediators' levels, (iii) pulmonary edema inhibition and (iv) attenuation of lung injury were the most observed biological effects of such products in in vitro experiments or in clinical studies. Finally, this work highlighted the PANPs with promising potential to be used on respiratory syndromes, allowing their possible use as alternative treatment at the prevention of ARDS in COVID-19-infected or -suspected patients.
Asunto(s)
Antiinflamatorios/uso terapéutico , Productos Biológicos/uso terapéutico , Tratamiento Farmacológico de COVID-19 , Mediadores de Inflamación/antagonistas & inhibidores , Síndrome de Dificultad Respiratoria/prevención & control , Animales , Antiinflamatorios/farmacología , Productos Biológicos/farmacología , COVID-19/diagnóstico , COVID-19/metabolismo , Humanos , Mediadores de Inflamación/metabolismo , Síndrome de Dificultad Respiratoria/diagnóstico , Síndrome de Dificultad Respiratoria/metabolismoRESUMEN
Evidence regarding the impact of air pollution on acute respiratory distress syndrome (ARDS) is limited, and most studies focus on ARDS onset. Our study aimed to evaluate whether exposure to fine particulate matter interferes with lung recovery and remodeling in a murine model of acute lung injury. Forty-eight mice received nebulized LPS or the vehicle (controls). Blood, BALF, lungs and spleen were collected after 5 weeks of exposure to either PM2.5 (PM and LPS + PM group) or filtered air (control and LPS5w groups). Inflammatory cells and cytokines were assessed in the blood, BALF, lungs and spleen. Stereological analyses and remodeling assessments were performed by histology. The LPS + PM group showed increased BALF leukocytes, characterized by increased macrophages, increased IL-1ß and IL-6 levels, anemia and thrombocytopenia. Moreover, we also observed septal thickening, decreased alveolar air space total volume and, septa surface density. Finally, regarding tissue remodeling, we observed elastosis of the lung parenchyma, and unlike in the LPS5w group, we did not observe fibrosis in the LPS + PM group. In conclusion, the delayed inflammation resolution due to subchronic exposure to PM2.5 could be influenced by low systemic and local lymphocyte counts, which lead to impaired lung injury recovery and tissue remodeling.
Asunto(s)
Lesión Pulmonar Aguda/patología , Contaminación del Aire/efectos adversos , Síndrome de Dificultad Respiratoria/metabolismo , Síndrome de Dificultad Respiratoria/patología , Lesión Pulmonar Aguda/metabolismo , Animales , Líquido del Lavado Bronquioalveolar , Citocinas/metabolismo , Modelos Animales de Enfermedad , Inflamación/metabolismo , Inflamación/patología , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Pulmón/metabolismo , Pulmón/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Material Particulado/efectos adversosRESUMEN
The COVID-19 pandemic has reached most of the countries worldwide causing death, which often results from an inflammatory storm associated with severe acute respiratory syndrome (SARS). This has prompted researchers to seek specific novel and definitive treatments urgently. In this context, it is interesting to evaluate the preventive and therapeutic effects of existing pharmacological agents that could be useful. In this regard, vitamin D supplementation, particularly in individuals likely to be deficient, may be a promising option. Vitamin D is a hormone that modulates many of the same inflammatory and oxidative signaling pathways triggered during COVID-19. For example, vitamin D suppresses the actions of the renin-angiotensin system, which has a determining role in the pathophysiology of the inflammatory response related to COVID-19. This paper analyzes the evidence that vitamin D supplementation might be a valuable preventive/therapeutic measure in groups at risk for or infected with COVID-19. It also discusses how clinical studies could be best designed to evaluate the possible advantages of vitamin D supplementation for the benefit of public health during the pandemic.
Asunto(s)
COVID-19/prevención & control , Suplementos Dietéticos , Pandemias/prevención & control , Síndrome de Dificultad Respiratoria/prevención & control , SARS-CoV-2/metabolismo , Vitamina D/uso terapéutico , Animales , COVID-19/epidemiología , COVID-19/metabolismo , COVID-19/patología , Humanos , Estrés Oxidativo/efectos de los fármacos , Sistema Renina-Angiotensina/efectos de los fármacos , Síndrome de Dificultad Respiratoria/epidemiología , Síndrome de Dificultad Respiratoria/metabolismo , Síndrome de Dificultad Respiratoria/patologíaRESUMEN
The acute respiratory distress syndrome (ARDS) is a multifaceted lung disorder in which no specific therapeutic intervention is able to effectively improve clinical outcomes. Despite an improved understanding of molecular mechanisms and advances in supportive care strategies, ARDS remains associated with high mortality, and survivors usually face long-term morbidity. In recent years, preclinical studies have provided mounting evidence of the potential of mesenchymal stem cell (MSC)-based therapies in lung diseases and critical illnesses. In several models of ARDS, MSCs have been demonstrated to induce anti-inflammatory and anti-apoptotic effects, improve epithelial and endothelial cell recovery, and enhance microbial and alveolar fluid clearance, thus resulting in improved lung and distal organ function and survival. Early-stage clinical trials have also demonstrated the safety of MSC administration in patients with ARDS, but further, large-scale investigations are required to assess the safety and efficacy profile of these therapies. In this review, we summarize the main mechanisms whereby MSCs have been shown to exert therapeutic effects in experimental ARDS. We also highlight questions that need to be further elucidated and barriers that must be overcome in order to efficiently translate MSC research into clinical practice.
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Células Madre Mesenquimatosas/fisiología , Síndrome de Dificultad Respiratoria/metabolismo , Síndrome de Dificultad Respiratoria/fisiopatología , Lesión Pulmonar Aguda/metabolismo , Animales , Modelos Animales de Enfermedad , Células Endoteliales/metabolismo , Humanos , Pulmón/citología , Trasplante de Células Madre Mesenquimatosas/tendencias , Células Madre Mesenquimatosas/metabolismoRESUMEN
The severity of Plasmodium falciparum malaria is associated with parasite cytoadherence, but there is limited knowledge about the effect of parasite cytoadherence in malaria-associated acute respiratory distress syndrome (ARDS). Our objective was to evaluate the cytoadherence of infected red blood cells (iRBCs) in a murine model of ARDS and to appraise a potential function of endothelial protein C receptor (EPCR) in ARDS pathogenesis. DBA/2 mice infected with P. berghei ANKA were classified as ARDS- or hyperparasitemia- (HP-) developing mice according to respiratory parameters and parasitemia. Lungs, blood, and bronchoalveolar lavage were collected for gene expression or protein analyses. Primary cultures of microvascular lung endothelial cells from DBA/2 mice were analyzed for iRBC interactions. Lungs from ARDS-developing mice showed evidence of iRBC accumulation along with an increase in EPCR and TNF concentrations. Furthermore, TNF increased iRBC adherence in vitro. Dexamethasone-treated infected mice showed low levels of TNF and EPCR mRNA expression and, finally, decreased vascular permeability, thus protecting mice from ARDS. In conclusion, we identified that increased iRBC cytoadherence in the lungs underlies malaria-associated ARDS in DBA/2-infected mice and that inflammation increased cytoadherence capacity, suggesting a participation of EPCR and a conceivable target for drug development.
Asunto(s)
Susceptibilidad a Enfermedades , Receptor de Proteína C Endotelial/metabolismo , Malaria/complicaciones , Malaria/parasitología , Síndrome de Dificultad Respiratoria/etiología , Síndrome de Dificultad Respiratoria/metabolismo , Animales , Biomarcadores , Citocinas/metabolismo , Modelos Animales de Enfermedad , Expresión Génica , Inmunohistoquímica , Macrófagos Peritoneales/inmunología , Macrófagos Peritoneales/metabolismo , Masculino , Ratones , Plasmodium berghei , Plasmodium falciparum , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Síndrome de Dificultad Respiratoria/patologíaRESUMEN
The innate immune response plays an important role in the pathophysiology of acute respiratory distress syndrome (ARDS). Glutamine (Gln) decreases lung inflammation in experimental ARDS, but its impact on the formation of extracellular traps (ETs) in the lung is unknown. In a mouse model of endotoxin-induced pulmonary ARDS, the effects of Gln treatment on leukocyte counts and ET content in bronchoalveolar lavage fluid (BALF), inflammatory profile in lung tissue, and lung morphofunction were evaluated in vivo. Furthermore, ET formation, reactive oxygen species (ROS) production, glutathione peroxidase (GPx), and glutathione reductase (GR) activities were tested in vitro. Our in vivo results demonstrated that Gln treatment reduced ET release (as indicated by cell-free-DNA content and myeloperoxidase activity), decreased lung inflammation (reductions in interferon-γ and increases in interleukin-10 levels), and improved lung morpho-function (decreased static lung elastance and alveolar collapse) in comparison with ARDS animals treated with saline. Moreover, Gln reduced ET and ROS formation in BALF cells stimulated with lipopolysaccharide in vitro, but it did not alter GPx or GR activity. In this model of endotoxin-induced pulmonary ARDS, treatment with Gln reduced pulmonary functional and morphological impairment, inflammation, and ET release in the lung.
Asunto(s)
Trampas Extracelulares/metabolismo , Glutamina/uso terapéutico , Inflamación/tratamiento farmacológico , Pulmón/efectos de los fármacos , Neumonía/tratamiento farmacológico , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Animales , ADN , Modelos Animales de Enfermedad , Endotoxinas , Femenino , Glutamina/farmacología , Glutatión Peroxidasa/metabolismo , Glutatión Reductasa/metabolismo , Inflamación/etiología , Interferón gamma/metabolismo , Interleucina-10/metabolismo , Recuento de Leucocitos , Pulmón/metabolismo , Pulmón/patología , Masculino , Ratones Endogámicos BALB C , Peroxidasa/metabolismo , Neumonía/etiología , Alveolos Pulmonares , Especies Reactivas de Oxígeno/metabolismo , Síndrome de Dificultad Respiratoria/metabolismo , Síndrome de Dificultad Respiratoria/patologíaRESUMEN
INTRODUCTION: Molecular imaging of the earliest events related to the development of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) could facilitate therapeutic development and patient management. We previously reported that 18F-fluoro-2-deoxyglucose (18F-FDG) PET identifies ALI/ARDS prior to radiographic abnormalities. The purpose of this study was to establish the time courses of 18F-FDG uptake, edema and neutrophil recruitment in an endotoxin-induced acute lung injury model and to examine molecular events required for 14C-2DG uptake in activated neutrophils. METHODS: Lung uptake of 18F-FDG was measured by PET in control male Sprague Dawley rats and at 2, 6 and 24h following the intraperitoneal injection of 10mg/kg LPS. Lung edema (attenuation) was measured by microCT. Neutrophil influx into the lungs was measured by myeloperoxidase assay. Control and activated human donor neutrophils were compared for uptake of 14C-2DG, transcription and content of hexokinase and GLUT isoforms and for hexokinase (HK) activity. RESULTS: Significant uptake of 18F-FDG occurred by 2h following LPS, and progressively increased to 24h. Lung uptake of 18F-FDG preceded increased CT attenuation (lung edema). Myeloperoxidase activity in the lungs, supporting neutrophil influx, paralleled 18F-FDG uptake. Activation of isolated human neutrophils resulted in increased uptake of 14C-2DG, expression of GLUT 3 and GLUT 4 and expression and increased HK1 activity. CONCLUSION: Systemic endotoxin-induced ALI results in very early and progressive uptake of 18F-FDG, parallels neutrophil accumulation and occurs earlier than lung injury edema. Activated neutrophils show increased uptake of 14C-2DG, expression of specific GLUT3, GLUT4 and HK1 protein and HK activity. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: 18F-FDG pulmonary uptake is an early biomarker of neutrophil recruitment in ALI and is associated with specific molecular events that mediate 14C-2DG uptake in activated neutrophils. 18F-FDG PET may provide a potential mechanism for early diagnosis and therapeutic assessment of ALI/ARDS.
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Lesión Pulmonar Aguda/diagnóstico por imagen , Lesión Pulmonar Aguda/inmunología , Fluorodesoxiglucosa F18 , Lipopolisacáridos/farmacología , Activación Neutrófila/efectos de los fármacos , Neutrófilos/efectos de los fármacos , Tomografía de Emisión de Positrones , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/metabolismo , Animales , Transporte Biológico/efectos de los fármacos , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Citosol/efectos de los fármacos , Citosol/metabolismo , Fluorodesoxiglucosa F18/metabolismo , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Proteínas Facilitadoras del Transporte de la Glucosa/metabolismo , Hexoquinasa/metabolismo , Pulmón/diagnóstico por imagen , Pulmón/efectos de los fármacos , Pulmón/inmunología , Pulmón/patología , Masculino , Neutrófilos/citología , Neutrófilos/inmunología , Ratas , Ratas Sprague-Dawley , Síndrome de Dificultad Respiratoria/inducido químicamente , Síndrome de Dificultad Respiratoria/diagnóstico por imagen , Síndrome de Dificultad Respiratoria/inmunología , Síndrome de Dificultad Respiratoria/metabolismoRESUMEN
Malaria is a serious disease, caused by the parasite of the genus Plasmodium, which was responsible for 440,000 deaths in 2015. Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is one of the main clinical complications in severe malaria. The murine model DBA/2 reproduces the clinical signs of ALI/ARDS in humans, when infected with Plasmodium berghei ANKA. High levels of HO-1 were reported in cases of severe malaria. Our data indicated that the HO-1 mRNA and protein expression are increased in mice that develop malaria-associated ALI/ARDS (MA-ALI/ARDS). Additionally, the hemin, a HO-1 inducing drug, prevented mice from developing MA-ALI/ARDS when administered prior to the development of MA-ALI/ARDS in this model. Also, hemin treatment showed an amelioration of respiratory parameters in mice, high VEGF levels in the sera, and a decrease in vascular permeability in the lung, which are signs of ALI/ARDS. Therefore, the induction of HO-1 before the development of MA-ALI/ARDS could be protective. However, the increased expression of HO-1 on the onset of MA-ALI/ARDS development may represent an effort to revert the phenotype of this syndrome by the host. We therefore confirm that HO-1 inducing drugs could be used for prevention of MA-ALI/ARDS in humans.
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Lesión Pulmonar Aguda/metabolismo , Hemo-Oxigenasa 1/metabolismo , Pulmón/metabolismo , Malaria/metabolismo , Proteínas de la Membrana/metabolismo , Síndrome de Dificultad Respiratoria/metabolismo , Lesión Pulmonar Aguda/complicaciones , Animales , Permeabilidad Capilar , Citocinas/metabolismo , Modelos Animales de Enfermedad , Hemina/metabolismo , Pulmón/irrigación sanguínea , Malaria/complicaciones , Masculino , Ratones , Ratones Endogámicos DBA , Permeabilidad , Fenotipo , Plasmodium berghei , Síndrome de Dificultad Respiratoria/complicacionesRESUMEN
Abnormalities in lungs caused by emphysema might alter their response to sepsis and the occurrence of acute lung injury (ALI). This study compared the extension of ALI in response to intraperitoneal lipopolysaccharide (LPS) injection in Wistar rats with and without emphysema induced by elastase. Adult male Wistar rats were randomized into four groups: control, emphysema without sepsis, normal lung with sepsis and emphysema with sepsis. Sepsis was induced, and 24 h later the rats were euthanised. The following analysis was performed: blood gas measurements, bronchoalveolar lavage (BAL), lung permeability and histology. Animals that received LPS showed significant increase in a lung injury scoring system, inflammatory cells in bronchoalveolar lavage (BAL) and IL-6, TNF-α and CXCL2 mRNA expression in lung tissue. Animals with emphysema and sepsis showed increased alveolocapillary membrane permeability, demonstrated by higher BAL/serum albumin ratio. In conclusion, the presence of emphysema induced by elastase increases the inflammatory response in the lungs to a systemic stimulus, represented in this model by the intraperitoneal injection of LPS.
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Lesión Pulmonar Aguda/patología , Elastasa Pancreática/efectos adversos , Enfisema Pulmonar/patología , Síndrome de Dificultad Respiratoria/patología , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/metabolismo , Animales , Líquido del Lavado Bronquioalveolar , Quimiocina CXCL2/genética , Quimiocina CXCL2/metabolismo , Modelos Animales de Enfermedad , Inflamación/inducido químicamente , Inflamación/metabolismo , Inflamación/patología , Inyecciones Intraperitoneales , Interleucina-6/genética , Interleucina-6/metabolismo , Lipopolisacáridos/efectos adversos , Pulmón/metabolismo , Pulmón/patología , Masculino , Enfisema Pulmonar/inducido químicamente , Enfisema Pulmonar/metabolismo , Ratas , Ratas Wistar , Síndrome de Dificultad Respiratoria/inducido químicamente , Síndrome de Dificultad Respiratoria/metabolismo , Sepsis/inducido químicamente , Sepsis/metabolismo , Sepsis/patología , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Extracellular vesicles (EVs) are plasma membrane-bound fragments released from several cell types, including mesenchymal stromal cells (MSCs), constitutively or under stimulation. EVs derived from MSCs and other cell types transfer molecules (such as DNA, proteins/peptides, mRNA, microRNA, and lipids) and/or organelles with reparative and anti-inflammatory properties to recipient cells. The paracrine anti-inflammatory effects promoted by MSC-derived EVs have attracted significant interest in the regenerative medicine field, including for potential use in lung injuries. In the present review, we describe the characteristics, biological activities, and mechanisms of action of MSC-derived EVs. We also review the therapeutic potential of EVs as reported in relevant preclinical models of acute and chronic respiratory diseases, such as pneumonia, acute respiratory distress syndrome, asthma, and pulmonary arterial hypertension. Finally, we discuss possible approaches for potentiating the therapeutic effects of MSC-derived EVs so as to enable use of this therapy in clinical practice.
Asunto(s)
Asma/terapia , Vesículas Extracelulares/trasplante , Hipertensión Pulmonar/terapia , Lesión Pulmonar/terapia , Células Madre Mesenquimatosas/química , Neumonía Bacteriana/terapia , Síndrome de Dificultad Respiratoria/terapia , Asma/metabolismo , Asma/fisiopatología , ADN/uso terapéutico , Endocitosis , Vesículas Extracelulares/química , Humanos , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/fisiopatología , Lípidos/uso terapéutico , Lesión Pulmonar/metabolismo , Lesión Pulmonar/fisiopatología , Células Madre Mesenquimatosas/metabolismo , MicroARNs/uso terapéutico , Terapia Molecular Dirigida , Neumonía Bacteriana/metabolismo , Neumonía Bacteriana/fisiopatología , Proteínas/uso terapéutico , ARN Mensajero/uso terapéutico , Síndrome de Dificultad Respiratoria/metabolismo , Síndrome de Dificultad Respiratoria/fisiopatologíaRESUMEN
Several respiratory diseases feature increased inflammatory response and catabolic activity, which are associated with glutamine depletion; thus, the benefits of exogenous glutamine administration have been evaluated in clinical trials and models of different respiratory diseases. Recent reviews and meta-analyses have focused on the effects and mechanisms of action of glutamine in a general population of critical care patients or in different models of injury. However, little information is available about the role of glutamine in respiratory diseases. The aim of the present review is to discuss the evidence of glutamine depletion in cystic fibrosis (CF), asthma, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), and lung cancer, as well as the results of exogenous glutamine administration in experimental and clinical studies. Exogenous glutamine administration might be beneficial in ARDS, asthma, and during lung cancer treatment, thus representing a potential therapeutic tool in these conditions. Further experimental and large randomized clinical trials focusing on the development and progression of respiratory diseases are necessary to elucidate the effects and possible therapeutic role of glutamine in this setting.
Asunto(s)
Asma/tratamiento farmacológico , Fibrosis Quística/tratamiento farmacológico , Glutamina/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Pulmón/efectos de los fármacos , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Asma/metabolismo , Fibrosis Quística/metabolismo , Glutamina/metabolismo , Glutamina/farmacología , Humanos , Pulmón/metabolismo , Neoplasias Pulmonares/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Síndrome de Dificultad Respiratoria/metabolismoRESUMEN
The morbidity and mortality rates associated with acute respiratory distress syndrome (ARDS) remain high and the development of new therapeutic strategies is urgently required. Some pharmacological treatments, proposed or under evaluation for ARDS, seek to protect the endothelium and consequently mitigate fluid extravasation into the alveolar space. FG-4497 is a new compound which acts as a prolyl hydroxylase domain 2 inhibitor and mimics hypoxia in the activation of hypoxia-inducible factor-2α signaling, decreasing VE-cadherin phosphorylation and thus promoting integrity of adherens junctions. In this special report, we discuss the pharmacological characteristics of FG-4497, its effect on lung parenchyma and other organs and future perspectives in ARDS. In short, FG-4497 may be considered a novel pharmacological option targeting endothelial cell repair in lung diseases such as ARDS. Further experimental and clinical studies are warranted to better understand the mechanisms of action of FG-4497 in different types of lung injury.
Asunto(s)
Inhibidores Enzimáticos/uso terapéutico , Prolina Dioxigenasas del Factor Inducible por Hipoxia/antagonistas & inhibidores , Pulmón/efectos de los fármacos , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Inhibidores Enzimáticos/farmacología , Humanos , Pulmón/metabolismo , Fosforilación/efectos de los fármacos , Síndrome de Dificultad Respiratoria/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Acute respiratory distress syndrome (ARDS) is the most severe lung inflammatory manifestation and has no effective therapy nowadays. Sepsis is one of the main illnesses among ARDS causes. The use of fluid resuscitation is an important treatment for sepsis, but positive fluid balance may induce pulmonary injury. As an alternative, fluid resuscitation with hypertonic saline ((HS) NaCl 7.5%) has been described as a promising therapeutical agent in sepsis-induced ARDS by the diminished amount of fluid necessary. Thus, we evaluated the effect of hypertonic saline in the treatment of LPS-induced ARDS. We found that hypertonic saline (NaCl 7.5%) treatment in rat model of LPS-induced ARDS avoided pulmonary function worsening and inhibited type I collagen deposition. In addition, hypertonic saline prevented pulmonary injury by decreasing metalloproteinase 9 (MMP-9) activity in tissue. Focal adhesion kinase (FAK) activation was reduced in HS group as well as neutrophil infiltration, NOS2 expression and NO content. Our study shows that fluid resuscitation with hypertonic saline decreases the progression of LPS-induced ARDS due to inhibition of pulmonary remodeling that is observed when regular saline is used.
Asunto(s)
Lesión Pulmonar Aguda/prevención & control , Remodelación de las Vías Aéreas (Respiratorias) , Fluidoterapia/métodos , Lipopolisacáridos , Pulmón , Síndrome de Dificultad Respiratoria/terapia , Solución Salina Hipertónica/administración & dosificación , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/fisiopatología , Resistencia de las Vías Respiratorias , Animales , Colágeno Tipo I/metabolismo , Modelos Animales de Enfermedad , Quinasa 1 de Adhesión Focal/metabolismo , Pulmón/metabolismo , Pulmón/patología , Pulmón/fisiopatología , Masculino , Metaloproteinasa 9 de la Matriz/metabolismo , Infiltración Neutrófila , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Edema Pulmonar/inducido químicamente , Edema Pulmonar/prevención & control , Ratas Wistar , Síndrome de Dificultad Respiratoria/inducido químicamente , Síndrome de Dificultad Respiratoria/metabolismo , Síndrome de Dificultad Respiratoria/fisiopatología , Factores de TiempoAsunto(s)
Animales , Masculino , Ratas , FN-kappa B/metabolismo , Poli(ADP-Ribosa) Polimerasas/metabolismo , Surfactantes Pulmonares/farmacología , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , /farmacología , /uso terapéutico , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/citología , Citrulina/metabolismo , Combinación de Medicamentos , Activación Enzimática , Alcoholes Grasos/farmacología , Alcoholes Grasos/uso terapéutico , Concentración de Iones de Hidrógeno , Quinasa I-kappa B/metabolismo , Lipopolisacáridos , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/patología , FN-kappa B/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo II/metabolismo , Nitritos/metabolismo , Células Epiteliales Alveolares/efectos de los fármacos , Células Epiteliales Alveolares/metabolismo , Poli(ADP-Ribosa) Polimerasas/antagonistas & inhibidores , Polietilenglicoles/farmacología , Polietilenglicoles/uso terapéutico , Surfactantes Pulmonares/uso terapéutico , Ratas Sprague-Dawley , Síndrome de Dificultad Respiratoria/inducido químicamente , Síndrome de Dificultad Respiratoria/metabolismo , PorcinosRESUMEN
BACKGROUND: The obesity has been shown to increase the severity of A/H1N1 infection and the development of acute respiratory distress syndrome (ARDS) and organ involvement. METHODS: Circulating levels of C-peptide, insulin, glucagon, leptin, acute phase reactants (procalcitonin, C-reactive protein, tissue plasminogen activator, and serum amyloids A and P), were measured in samples from 32 critically ill patients with A/H1N1 virus infection, 17 of whom had ARDS complicated by acute kidney injury (AKI) and 15 of whom had ARDS but did not develop AKI. RESULTS: Patients with ARDS and AKI (ARDS/AKI) had higher BMI and higher levels of C-peptide, insulin, leptin, procalcitonin and serum amyloid A compared to those ARDS patient who did not develop AKI. Adjusting for confounding variables using logistic regression analysis, higher levels of C-peptide (>0.75 ng/mL) (OR=64.8, 95% CI = 2.1-1980, p = 0.0006) and BMI>30 Kg/m(2) (OR = 42.0, 95% CI = 1.2-1478, p = 0.04) were significantly associated with the development of AKI in ARDS patients. CONCLUSION: High levels of C-peptide and BMI>30 kg/m(2) were associated with the development of AKI in ARDS patients due to A/H1N1 infection. These metabolic/obesity indicators, together with the profiles of pro-inflammatory acute phase proteins, may be important links between obesity and poor outcomes in A/H1N1 09 infection.
Asunto(s)
Lesión Renal Aguda/virología , Gripe Humana/complicaciones , Obesidad/complicaciones , Síndrome de Dificultad Respiratoria/virología , Lesión Renal Aguda/metabolismo , Adulto , Enfermedad Crítica , Femenino , Humanos , Inflamación/metabolismo , Subtipo H1N1 del Virus de la Influenza A , Gripe Humana/metabolismo , Masculino , Persona de Mediana Edad , Síndrome de Dificultad Respiratoria/metabolismoRESUMEN
Acute respiratory distress syndrome (ARDS) continues to be a major healthcare problem, affecting >190,000 people in the USA annually, with a mortality of 27-45%, depending on the severity of the illness and comorbidities. Despite advances in clinical care, particularly lung protective strategies of mechanical ventilation, most survivors experience impaired health-related quality of life for years after the acute illness. While most patients survive the acute illness, a subset of ARDS survivors develops a fibroproliferative response characterised by fibroblast accumulation and deposition of collagen and other extracellular matrix components in the lung. Historically, the development of severe fibroproliferative lung disease has been associated with a poor prognosis with high mortality and/or prolonged ventilator dependence. More recent studies also support a relationship between the magnitude of the fibroproliferative response and long-term health-related quality of life. The factors that determine which patients develop fibroproliferative ARDS and the cellular mechanisms responsible for this pathological response are not well understood. This article reviews our current understanding of the contribution of pulmonary dysfunction to mortality and to quality of life in survivors of ARDS, the mechanisms driving pathological fibroproliferation and potential therapeutic approaches to prevent or attenuate fibroproliferative lung disease.