RESUMEN
The involvement of neutrophils in the lungs during the recovery phase of coronavirus disease 2019 (COVID-19) is not well defined mainly due to the limited accessibility of lung tissues from COVID-19 survivors. The lack of an appropriate small animal model has affected the development of effective therapeutic strategies. We here developed a long COVID mouse model to study changes in neutrophil phenotype and association with lung injury. Our data shows persistent neutrophil recruitment and neutrophil extracellular trap formation in the lungs for up to 30 days post-infection which correlates with lung fibrosis and inflammation.
Asunto(s)
COVID-19 , Modelos Animales de Enfermedad , Trampas Extracelulares , Pulmón , Neutrófilos , SARS-CoV-2 , Animales , Trampas Extracelulares/inmunología , COVID-19/inmunología , COVID-19/complicaciones , Ratones , Neutrófilos/inmunología , SARS-CoV-2/inmunología , SARS-CoV-2/fisiología , Pulmón/patología , Pulmón/inmunología , Pulmón/virología , Lesión Pulmonar/inmunología , Lesión Pulmonar/virología , Lesión Pulmonar/patología , Lesión Pulmonar/etiología , Enzima Convertidora de Angiotensina 2/metabolismo , Enzima Convertidora de Angiotensina 2/genética , Infiltración Neutrófila/inmunología , Humanos , Fibrosis Pulmonar/inmunología , Fibrosis Pulmonar/patología , Fibrosis Pulmonar/etiologíaRESUMEN
Varicellovirus bovinealpha 1 (BoAHV-1) is a significant pathogen responsible for respiratory disease in cattle, capable of inducing lung damage independently or co-infection with bacteria. The widespread spread of BoAHV-1 in cattle herds has caused substantial economic losses to the cattle industry. The pathogenic mechanisms of BoAHV-1 are often relevant to robust inflammatory responses, increased oxidative burden, and the initiation of apoptosis. Glycyrrhizin (GLY) is a small-molecule triterpenoid saponin compound obtained from the herb liquorice, which has a broad spectrum of pharmacological properties such as antiviral, anti-inflammatory, and antioxidant effects. Furthermore, GLY regulates lung physiology by modulating oxidative stress, inflammatory response, and cell apoptosis through interference with the NF-κB/NLRP3 and Nrf2/HO-1 Signaling pathways. However, the potential of GLY to mitigate lung injury induced by BoAHV-1 and its underlying mechanism remains unclear. Therefore, in this study, we investigated the protective effect of GLY against pulmonary injury induced by BoAHV-1 in a guinea pig model by reducing viral load and suppressing the inflammatory response, oxidative stress, and apoptosis. The results of this study demonstrated that GLY exerted a protective effect against BoAHV-1-induced lung injury in guinea pigs. Specifically, GLY reduced the levels of pro-inflammatory cytokines interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, and interleukin (IL)-8 in guinea pig tissues while suppressing the expression of Caspase-1. Additionally, GLY reduced BoAHV-1 load and the number of TUNEL-positive lung cells in guinea pig lungs while inhibiting Caspase 3 protein expression. Furthermore, GLY significantly enhanced lung antioxidant capacity by increasing superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activity while simultaneously reducing malondialdehyde (MDA) levels. Lung histological observation and score further validated the protective effect of GLY on BoAHV-1-induced lung injury. Furthermore, we observed that the expression of phosphorylated NF-κB p65 (p-NF-κB p65) and NLRP3 proteins in the lung tissue of BoAHV-1-infected guinea pigs decreased after GLY treatment while the expression of Nrf2 and HO-1 proteins increased. These results indicated that GLY inhibited the NF-κB/NLRP3 Signaling pathway and activated the Nrf2/HO-1 Signaling pathway during BoAHV-1 infection. Ultimately, our findings demonstrated that GLY alleviates BoAHV-1-induced inflammation response, oxidative stress, and cell apoptosis by inhibiting the NF-κB/NLRP3 Signaling pathway and activating the Nrf2/HO-1 Signaling pathway to protect guinea pigs from lung injury caused by BoAHV-1. Ultimately, our findings demonstrated that GLY alleviates BoAHV-1-induced inflammation response, oxidative stress, and cell apoptosis by inhibiting the NF-κB/NLRP3 Signaling pathway and activating the Nrf2/HO-1 Signaling pathway to protect guinea pigs from lung injury caused by BoAHV-1. Importantly, this study provides a compelling argument for the GLY in combating respiratory disease in cattle caused by BoAHV-1.
Asunto(s)
Ácido Glicirrínico , Factor 2 Relacionado con NF-E2 , FN-kappa B , Proteína con Dominio Pirina 3 de la Familia NLR , Transducción de Señal , Animales , Transducción de Señal/efectos de los fármacos , Cobayas , Factor 2 Relacionado con NF-E2/metabolismo , Factor 2 Relacionado con NF-E2/genética , FN-kappa B/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Ácido Glicirrínico/farmacología , Ácido Glicirrínico/uso terapéutico , Lesión Pulmonar/tratamiento farmacológico , Lesión Pulmonar/veterinaria , Lesión Pulmonar/virología , Hemo-Oxigenasa 1/metabolismo , Hemo-Oxigenasa 1/genética , MasculinoRESUMEN
AIM: To study the clinical and histological profile of lung tissue in patients with persistent pulmonary disease, respiratory symptoms and CT findings after SARS-CoV-2 infection. MATERIALS AND METHODS: The study included 15 patients (7 females and 8 males) with a mean age of 57.7 years. All patients underwent laboratory tests, chest computed tomography, echocardiography, and pulmonary function tests. Pulmonary tissue and bronchoalveolar lavage samples were obtained by fibrobronchoscopy, transbronchial forceps (2 patients), and lung cryobiopsy (11 patients); open biopsy was performed in 2 patients. Cellular composition, herpesvirus DNA, SARS-CoV-2, Mycobacterium tuberculosis complex, galactomannan optical density index, and bacterial and fungal microflora growth were determined in bronchoalveolar lavage. SARS-CoV-2 was also identified in samples from the nasal mucosa, throat and feces using a polymerase chain reaction. RESULTS: The results showed no true pulmonary fibrosis in patients recovered from SARS-CoV-2 infection with persistent respiratory symptoms, functional impairment, and CT findings after SARS-CoV-2 infection. The observed changes comply with the current and/or resolving infection and inflammatory process. CONCLUSION: Thus, no true pulmonary fibrosis was found in patients after SARS-CoV-2 infection with persistent respiratory symptoms, functional impairment, and CT findings. The observed changes comply with the current and/or resolving infection and inflammatory process.
Asunto(s)
COVID-19 , SARS-CoV-2 , Tomografía Computarizada por Rayos X , Humanos , COVID-19/diagnóstico , COVID-19/complicaciones , Masculino , Femenino , Persona de Mediana Edad , Tomografía Computarizada por Rayos X/métodos , Pulmón/diagnóstico por imagen , Pulmón/patología , Lesión Pulmonar/virología , Lesión Pulmonar/etiología , Lesión Pulmonar/diagnóstico , Pruebas de Función Respiratoria/métodosRESUMEN
SARS-CoV-2 infection causes severe pulmonary manifestations, with poorly understood mechanisms and limited treatment options. Hyperferritinemia and disrupted lung iron homeostasis in COVID-19 patients imply that ferroptosis, an iron-dependent cell death, may occur. Immunostaining and lipidomic analysis in COVID-19 lung autopsies reveal increases in ferroptosis markers, including transferrin receptor 1 and malondialdehyde accumulation in fatal cases. COVID-19 lungs display dysregulation of lipids involved in metabolism and ferroptosis. We find increased ferritin light chain associated with severe COVID-19 lung pathology. Iron overload promotes ferroptosis in both primary cells and cancerous lung epithelial cells. In addition, ferroptosis markers strongly correlate with lung injury severity in a COVID-19 lung disease model using male Syrian hamsters. These results reveal a role for ferroptosis in COVID-19 pulmonary disease; pharmacological ferroptosis inhibition may serve as an adjuvant therapy to prevent lung damage during SARS-CoV-2 infection.
Asunto(s)
COVID-19 , Ferroptosis , Pulmón , Mesocricetus , SARS-CoV-2 , COVID-19/virología , COVID-19/metabolismo , COVID-19/patología , Animales , Humanos , Masculino , Pulmón/patología , Pulmón/virología , Pulmón/metabolismo , SARS-CoV-2/fisiología , Femenino , Hierro/metabolismo , Persona de Mediana Edad , Modelos Animales de Enfermedad , Anciano , Lesión Pulmonar/virología , Lesión Pulmonar/metabolismo , Lesión Pulmonar/patología , Sobrecarga de Hierro/metabolismo , Adulto , CricetinaeRESUMEN
Numerous cases of lung injury caused by viral infection were reported during the coronavirus disease-19 pandemic. While there have been significant efforts to develop drugs that block viral infection and spread, the development of drugs to reduce or reverse lung injury has been a lower priority. This study aimed to identify compounds from a library of compounds that prevent viral infection that could reduce and prevent lung epithelial cell damage. We investigated the cytotoxicity of the compounds, their activity in inhibiting viral spike protein binding to cells, and their activity in reducing IL-8 production in lung epithelial cells damaged by amodiaquine (AQ). We identified N-(4-(4-methoxyphenoxy)-3-methylphenyl)-N-methylacetamide (MPoMA) as a non-cytotoxic inhibitor against viral infection and AQ-induced cell damage. MPoMA inhibited the expression of IL-8, IL-6, IL-1ß, and fibronectin induced by AQ and protected against AQ-induced morphological changes. However, MPoMA did not affect basal IL-8 expression in lung epithelial cells in the absence of AQ. Further mechanistic analysis confirmed that MPoMA selectively promoted the proteasomal degradation of inflammatory mediator p65, thereby reducing intracellular p65 expression and p65-mediated inflammatory responses. MPoMA exerted potent anti-inflammatory and protective functions in epithelial cells against LPS-induced acute lung injury in vivo. These findings suggest that MPoMA may have beneficial effects in suppressing viral infection and preventing lung epithelial cell damage through the degradation of p65 and inhibition of the production of inflammatory cytokines.
Asunto(s)
Células Epiteliales , Animales , Humanos , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Células Epiteliales/patología , Ratones , Pulmón/patología , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Factor de Transcripción ReIA/metabolismo , Tratamiento Farmacológico de COVID-19 , Células A549 , SARS-CoV-2/efectos de los fármacos , COVID-19/prevención & control , Proteolisis/efectos de los fármacos , Lesión Pulmonar/prevención & control , Lesión Pulmonar/patología , Lesión Pulmonar/metabolismo , Lesión Pulmonar/virología , Masculino , Lesión Pulmonar Aguda/prevención & control , Lesión Pulmonar Aguda/patología , Lesión Pulmonar Aguda/metabolismo , Acetamidas/farmacologíaRESUMEN
Severe influenza A virus (IAV) infections can result in hyper-inflammation, lung injury and acute respiratory distress syndrome1-5 (ARDS), for which there are no effective pharmacological therapies. Necroptosis is an attractive entry point for therapeutic intervention in ARDS and related inflammatory conditions because it drives pathogenic lung inflammation and lethality during severe IAV infection6-8 and can potentially be targeted by receptor interacting protein kinase 3 (RIPK3) inhibitors. Here we show that a newly developed RIPK3 inhibitor, UH15-38, potently and selectively blocked IAV-triggered necroptosis in alveolar epithelial cells in vivo. UH15-38 ameliorated lung inflammation and prevented mortality following infection with laboratory-adapted and pandemic strains of IAV, without compromising antiviral adaptive immune responses or impeding viral clearance. UH15-38 displayed robust therapeutic efficacy even when administered late in the course of infection, suggesting that RIPK3 blockade may provide clinical benefit in patients with IAV-driven ARDS and other hyper-inflammatory pathologies.
Asunto(s)
Lesión Pulmonar , Necroptosis , Infecciones por Orthomyxoviridae , Inhibidores de Proteínas Quinasas , Proteína Serina-Treonina Quinasas de Interacción con Receptores , Animales , Femenino , Humanos , Masculino , Ratones , Células Epiteliales Alveolares/patología , Células Epiteliales Alveolares/efectos de los fármacos , Células Epiteliales Alveolares/virología , Células Epiteliales Alveolares/metabolismo , Virus de la Influenza A/clasificación , Virus de la Influenza A/efectos de los fármacos , Virus de la Influenza A/inmunología , Virus de la Influenza A/patogenicidad , Lesión Pulmonar/complicaciones , Lesión Pulmonar/patología , Lesión Pulmonar/prevención & control , Lesión Pulmonar/virología , Ratones Endogámicos C57BL , Necroptosis/efectos de los fármacos , Infecciones por Orthomyxoviridae/complicaciones , Infecciones por Orthomyxoviridae/tratamiento farmacológico , Infecciones por Orthomyxoviridae/inmunología , Infecciones por Orthomyxoviridae/mortalidad , Infecciones por Orthomyxoviridae/virología , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Proteína Serina-Treonina Quinasas de Interacción con Receptores/antagonistas & inhibidores , Síndrome de Dificultad Respiratoria/complicaciones , Síndrome de Dificultad Respiratoria/patología , Síndrome de Dificultad Respiratoria/prevención & control , Síndrome de Dificultad Respiratoria/virologíaRESUMEN
The high risk of SARS-CoV-2 infection and reinfection and the occurrence of post-acute pulmonary sequelae have highlighted the importance of understanding the mechanism underlying lung repair after injury. To address this concern, comparative and systematic analyses of SARS-CoV-2 infection in COVID-19 patients and animals were conducted. In the lungs of nine patients who died of COVID-19 and one recovered from COVID-19 but died of unrelated disease in early 2020, damage-related transient progenitor (DATP) cells expressing CK8 marker proliferated significantly. These CK8+ DATP cells were derived from bronchial CK5+ basal cells. However, they showed different cell fate toward differentiation into type I alveolar cells in the deceased and convalescent patients, respectively. By using a self-limiting hamster infection model mimicking the dynamic process of lung injury remodeling in mild COVID-19 patients, the accumulation and regression of CK8+ cell marker were found to be closely associated with the disease course. Finally, we examined the autopsied lungs of two patients who died of infection by the recent Omicron variant and found that they only exhibited mild pathological injury with no CK8+ cell proliferation. These results indicate a clear pulmonary cell remodeling route and suggest that CK8+ DATP cells play a primary role in mediating alveolar remodeling, highlighting their potential applications as diagnostic markers and therapeutic targets.
Asunto(s)
COVID-19 , SARS-CoV-2 , COVID-19/inmunología , COVID-19/patología , COVID-19/virología , Humanos , Animales , Masculino , Persona de Mediana Edad , Femenino , Cricetinae , Pulmón/patología , Pulmón/virología , Pulmón/inmunología , Adulto , Alveolos Pulmonares/patología , Alveolos Pulmonares/virología , Alveolos Pulmonares/inmunología , Anciano , Modelos Animales de Enfermedad , Lesión Pulmonar/virología , Lesión Pulmonar/patología , Lesión Pulmonar/inmunología , Proliferación Celular , Diferenciación CelularRESUMEN
The pandemic of coronavirus disease 2019 (COVID-19) has been the foremost modern global public health challenge. The airway is the primary target in severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) infection, with substantial cell death and lung injury being signature hallmarks of exposure. The viral factors that contribute to cell death and lung injury remain incompletely understood. Thus, this study investigated the role of open reading frame 7b (Orf7b), an accessory protein of the virus, in causing lung injury. In screening viral proteins, we identified Orf7b as one of the major viral factors that mediates lung epithelial cell death. Overexpression of Orf7b leads to apoptosis and ferroptosis in lung epithelial cells, and inhibitors of apoptosis and ferroptosis ablate Orf7b-induced cell death. Orf7b upregulates the transcription regulator, c-Myc, which is integral in the activation of lung cell death pathways. Depletion of c-Myc alleviates both apoptotic and ferroptotic cell deaths and lung injury in mouse models. Our study suggests a major role of Orf7b in the cell death and lung injury attributable to COVID-19 exposure, supporting it as a potential therapeutic target.
Asunto(s)
COVID-19 , Ferroptosis , Lesión Pulmonar , Proteínas Virales , Animales , Ratones , Apoptosis , Lesión Pulmonar/virología , Sistemas de Lectura Abierta , SARS-CoV-2 , Proteínas Virales/genéticaRESUMEN
The new predominant circulating SARS-CoV-2 variant, Omicron, can robustly escape current vaccines and neutralizing antibodies. Although Omicron has been reported to have milder replication and disease manifestations than some earlier variants, its pathogenicity in different age groups has not been well elucidated. Here, we report that the SARS-CoV-2 Omicron BA.1 sublineage causes elevated infection and lung pathogenesis in juvenile and aged hamsters, with more body weight loss, respiratory tract viral burden, and lung injury in these hamsters than in adult hamsters. Juvenile hamsters show a reduced interferon response against Omicron BA.1 infection, whereas aged hamsters show excessive proinflammatory cytokine expression, delayed viral clearance, and aggravated lung injury. Early inhaled IFN-α2b treatment suppresses Omicron BA.1 infection and lung pathogenesis in juvenile and adult hamsters. Overall, the data suggest that the diverse patterns of the innate immune response affect the disease outcomes of Omicron BA.1 infection in different age groups.
Asunto(s)
Tratamiento Farmacológico de COVID-19 , COVID-19 , Interferón-alfa , Lesión Pulmonar , Animales , Cricetinae , Anticuerpos Neutralizantes/uso terapéutico , Anticuerpos Antivirales , Antivirales , COVID-19/patología , Interferón-alfa/uso terapéutico , Lesión Pulmonar/virología , Mesocricetus , SARS-CoV-2RESUMEN
BACKGROUND: COVID-19 global pandemic started in late 2019 with the first wave. In this cross-sectional and observational study, we evaluated the associations between the biomarkers, COVID-19 pneumonia severity and 1-year mortality. METHODS: A sample of 276 polymerase chain reaction (PCR)-positive patients for SARS-CoV-2 was included. Computerized tomography severity score (CT-SS) was used to assess the severity of COVID-19 pneumonia in 222 cases. Multivariate analyses were performed to find the predictors of CT-SS, severe CT-SS (≥20) and 1-year mortality. Biomarkers of ferritin, high-sensitive C-reactive protein (CRP), lactate dehydrogenase (LDH), cardiac troponin (cTn), neutrophil-to-lymphocyte ratio (NLR), uric acid (UA) and d-dimer were routinely measured. RESULTS: Severe CT-SS (>20) was observed in 86 (31.2%) cases. Mortality was observed in 75 (27.2%) patients at 1 year. LDH displayed the highest predictive accuracy for severe CT-SS (AUC 0.741, sensitivity = 81% and specificity = 68%, cut-off value: 360 mg/dl). Linear regression analysis displayed that LDH predicted CT-SS [B = 11 (95% CI for B = 5-17, p < .001)]. Age was the most significant parameter that was associated with severe CT-SS (OR 0.96, 95% CI 0.92-0.99, p = .015). d-dimer was the only biomarker that predicted with 1-year mortality (OR 1.62, 95% CI 1.08-2.42, p = .020). CONCLUSION: LDH is a sensitive and specific biomarker to determine patients with severe lung injury in COVID-19. d-dimer is the only biomarker that predicts 1-year mortality. Neither LDH nor CT-SS is associated with 1-year mortality.
Asunto(s)
COVID-19 , Lesión Pulmonar , Biomarcadores/sangre , COVID-19/diagnóstico , COVID-19/mortalidad , Estudios Transversales , Productos de Degradación de Fibrina-Fibrinógeno/análisis , Humanos , L-Lactato Deshidrogenasa/sangre , Lesión Pulmonar/virología , Estudios Retrospectivos , SARS-CoV-2 , Índice de Severidad de la EnfermedadRESUMEN
Importance: SARS-CoV-2 viral entry may disrupt angiotensin II (AII) homeostasis, contributing to COVID-19 induced lung injury. AII type 1 receptor blockade mitigates lung injury in preclinical models, although data in humans with COVID-19 remain mixed. Objective: To test the efficacy of losartan to reduce lung injury in hospitalized patients with COVID-19. Design, Setting, and Participants: This blinded, placebo-controlled randomized clinical trial was conducted in 13 hospitals in the United States from April 2020 to February 2021. Hospitalized patients with COVID-19 and a respiratory sequential organ failure assessment score of at least 1 and not already using a renin-angiotensin-aldosterone system (RAAS) inhibitor were eligible for participation. Data were analyzed from April 19 to August 24, 2021. Interventions: Losartan 50 mg orally twice daily vs equivalent placebo for 10 days or until hospital discharge. Main Outcomes and Measures: The primary outcome was the imputed arterial partial pressure of oxygen to fraction of inspired oxygen (Pao2:Fio2) ratio at 7 days. Secondary outcomes included ordinal COVID-19 severity; days without supplemental o2, ventilation, or vasopressors; and mortality. Losartan pharmacokinetics and RAAS components (AII, angiotensin-[1-7] and angiotensin-converting enzymes 1 and 2)] were measured in a subgroup of participants. Results: A total of 205 participants (mean [SD] age, 55.2 [15.7] years; 123 [60.0%] men) were randomized, with 101 participants assigned to losartan and 104 participants assigned to placebo. Compared with placebo, losartan did not significantly affect Pao2:Fio2 ratio at 7 days (difference, -24.8 [95%, -55.6 to 6.1]; P = .12). Compared with placebo, losartan did not improve any secondary clinical outcomes and led to fewer vasopressor-free days than placebo (median [IQR], 9.4 [9.1-9.8] vasopressor-free days vs 8.7 [8.2-9.3] vasopressor-free days). Conclusions and Relevance: This randomized clinical trial found that initiation of orally administered losartan to hospitalized patients with COVID-19 and acute lung injury did not improve Pao2:Fio2 ratio at 7 days. These data may have implications for ongoing clinical trials. Trial Registration: ClinicalTrials.gov Identifier: NCT04312009.
Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Tratamiento Farmacológico de COVID-19 , COVID-19/complicaciones , Losartán/uso terapéutico , Lesión Pulmonar/prevención & control , Lesión Pulmonar/virología , Adulto , Anciano , COVID-19/diagnóstico , Método Doble Ciego , Femenino , Hospitalización , Humanos , Lesión Pulmonar/diagnóstico , Masculino , Persona de Mediana Edad , Puntuaciones en la Disfunción de Órganos , Pruebas de Función Respiratoria , Estados UnidosRESUMEN
NEW FINDINGS: What is the topic of this review? This review presents the fundamental concepts of respiratory physiology and pathophysiology, with particular reference to lung mechanics and the pulmonary phenotype associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and subsequent coronavirus disease 2019 (COVID-19) pneumonia. What advances does it highlight? The review provides a critical summary of the main physiological aspects to be considered for safe and effective mechanical ventilation in patients with severe COVID-19 in the intensive care unit. ABSTRACT: Severe respiratory failure from coronavirus disease 2019 (COVID-19) pneumonia not responding to non-invasive respiratory support requires mechanical ventilation. Although ventilation can be a life-saving therapy, it can cause further lung injury if airway pressure and flow and their timing are not tailored to the respiratory system mechanics of the individual patient. The pathophysiology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to a pattern of lung injury in patients with severe COVID-19 pneumonia typically associated with two distinct phenotypes, along a temporal and pathophysiological continuum, characterized by different levels of elastance, ventilation-to-perfusion ratio, right-to-left shunt, lung weight and recruitability. Understanding the underlying pathophysiology, duration of symptoms, radiological characteristics and lung mechanics at the individual patient level is crucial for the appropriate choice of mechanical ventilation settings to optimize gas exchange and prevent further lung injury. By critical analysis of the literature, we propose fundamental physiological and mechanical criteria for the selection of ventilation settings for COVID-19 patients in intensive care units. In particular, the choice of tidal volume should be based on obtaining a driving pressure < 14 cmH2 O, ensuring the avoidance of hypoventilation in patients with preserved compliance and of excessive strain in patients with smaller lung volumes and lower lung compliance. The level of positive end-expiratory pressure (PEEP) should be informed by the measurement of the potential for lung recruitability, where patients with greater recruitability potential may benefit from higher PEEP levels. Prone positioning is often beneficial and should be considered early. The rationale for the proposed mechanical ventilation settings criteria is presented and discussed.
Asunto(s)
COVID-19/terapia , Lesión Pulmonar/virología , Respiración Artificial , Síndrome de Dificultad Respiratoria/virología , SARS-CoV-2 , COVID-19/fisiopatología , Humanos , Unidades de Cuidados Intensivos/normas , Lesión Pulmonar/terapia , Respiración Artificial/efectos adversos , Respiración Artificial/normas , Síndrome de Dificultad Respiratoria/terapia , Mecánica Respiratoria/fisiología , Volumen de Ventilación Pulmonar/fisiologíaRESUMEN
The lung is the major target organ of SARS-CoV-2 infection, which causes COVID-19. Here, we outline the multistep mechanisms of lung epithelial and endothelial injury induced by SARS-CoV-2: direct viral infection, chemokine/cytokine-mediated damage, and immune cell-mediated lung injury. Finally, we discuss the recent progress in terms of antiviral therapeutics as well as the development of anti-inflammatory or immunomodulatory therapeutic approaches. This review also provides a systematic overview of the models for studying SARS-CoV-2 infection and discusses how an understanding of mechanisms of lung injury will help identify potential targets for future drug development to mitigate lung injury.
Asunto(s)
COVID-19 , Lesión Pulmonar , Antivirales/uso terapéutico , COVID-19/complicaciones , Humanos , Pulmón , Lesión Pulmonar/tratamiento farmacológico , Lesión Pulmonar/virología , SARS-CoV-2RESUMEN
SARS-CoV-2 infection-induced hyper-inflammation links to the acute lung injury and COVID-19 severity. Identifying the primary mediators that initiate the uncontrolled hypercytokinemia is essential for treatments. Mast cells (MCs) are strategically located at the mucosa and beneficially or detrimentally regulate immune inflammations. In this study, we showed that SARS-CoV-2-triggered MC degranulation initiated alveolar epithelial inflammation and lung injury. SARS-CoV-2 challenge induced MC degranulation in ACE-2 humanized mice and rhesus macaques, and a rapid MC degranulation could be recapitulated with Spike-RBD binding to ACE2 in cells; MC degranulation altered various signaling pathways in alveolar epithelial cells, particularly, the induction of pro-inflammatory factors and consequential disruption of tight junctions. Importantly, the administration of clinical MC stabilizers for blocking degranulation dampened SARS-CoV-2-induced production of pro-inflammatory factors and prevented lung injury. These findings uncover a novel mechanism for SARS-CoV-2 initiating lung inflammation, and suggest an off-label use of MC stabilizer as immunomodulators for COVID-19 treatments.
Asunto(s)
COVID-19/metabolismo , Degranulación de la Célula , Lesión Pulmonar/metabolismo , Mastocitos/metabolismo , Alveolos Pulmonares/metabolismo , SARS-CoV-2/metabolismo , Enzima Convertidora de Angiotensina 2/genética , Enzima Convertidora de Angiotensina 2/metabolismo , Animales , COVID-19/genética , Línea Celular Tumoral , Femenino , Humanos , Lesión Pulmonar/genética , Lesión Pulmonar/virología , Macaca mulatta , Masculino , Ratones Endogámicos BALB C , Ratones Transgénicos , Alveolos Pulmonares/virología , SARS-CoV-2/genética , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/metabolismoRESUMEN
Background: Corona Virus Disease 2019 (COVID-19) is an acute respiratory infectious disease caused by severe respiratory syndrome coronavirus 2 (SARS-CoV-2). The primary pathogenesis is over-activation of the immune system. SARS-CoV-2 continues to mutate and spread rapidly and no effective treatment options are yet available. Mesenchymal stem cells (MSCs) are known to induce anti-inflammatory macrophages, regulatory T cells and dendritic cells. There are a rapidly increasing number of clinical investigations of cell-based therapy approaches for COVID-19. Objective: To summarize the pathogenic mechanism of SARS-CoV-2, and systematically formulated the immunomodulation of COVID-19 by MSCs and their exosomes, as well as research progress. Method: Searching PubMed, clinicaltrials.gov and Chictr.cn for eligible studies to be published or registered by May 2021. Main keywords and search strategies were as follows: ((Mesenchymal stem cells) OR (MSCs)) AND (COVID-19). Results: MSCs regulate the immune system to prevent cytokine release syndrome (CRS) and to promote endogenous repair by releasing various paracrine factors and exosomes. Conclusions: MSC therapy is thus a promising candidate for COVID-19.
Asunto(s)
COVID-19/terapia , Exosomas/trasplante , Inmunomodulación/inmunología , Lesión Pulmonar/terapia , Trasplante de Células Madre Mesenquimatosas/métodos , Células Madre Mesenquimatosas/metabolismo , COVID-19/epidemiología , COVID-19/virología , Ensayos Clínicos como Asunto , Exosomas/inmunología , Exosomas/metabolismo , Humanos , Lesión Pulmonar/fisiopatología , Lesión Pulmonar/virología , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/inmunología , Evaluación de Resultado en la Atención de Salud/métodos , Evaluación de Resultado en la Atención de Salud/estadística & datos numéricos , Pandemias , Regeneración/inmunología , Regeneración/fisiología , SARS-CoV-2/inmunología , SARS-CoV-2/fisiologíaRESUMEN
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a major public health issue. COVID-19 is considered an airway/multi-systemic disease, and demise has been associated with an uncontrolled immune response and a cytokine storm in response to the virus. However, the lung pathology, immune response, and tissue damage associated with COVID-19 demise are poorly described and understood due to safety concerns. Using post-mortem lung tissues from uninfected and COVID-19 deadly cases as well as an unbiased combined analysis of histology, multi-viral and host markers staining, correlative microscopy, confocal, and image analysis, we identified three distinct phenotypes of COVID-19-induced lung damage. First, a COVID-19-induced hemorrhage characterized by minimal immune infiltration and large thrombus; Second, a COVID-19-induced immune infiltration with excessive immune cell infiltration but no hemorrhagic events. The third phenotype correspond to the combination of the two previous ones. We observed the loss of alveolar wall integrity, detachment of lung tissue pieces, fibroblast proliferation, and extensive fibrosis in all three phenotypes. Although lung tissues studied were from lethal COVID-19, a strong immune response was observed in all cases analyzed with significant B cell and poor T cell infiltrations, suggesting an exhausted or compromised immune cellular response in these patients. Overall, our data show that SARS-CoV-2-induced lung damage is highly heterogeneous. These individual differences need to be considered to understand the acute and long-term COVID-19 consequences.
Asunto(s)
COVID-19/mortalidad , COVID-19/patología , Lesión Pulmonar/patología , Alveolos Pulmonares/patología , Fibrosis Pulmonar/patología , Anciano , Anciano de 80 o más Años , Autopsia , Linfocitos T CD8-positivos/inmunología , Síndrome de Liberación de Citoquinas/mortalidad , Síndrome de Liberación de Citoquinas/patología , Células Epiteliales/patología , Femenino , Hemorragia/patología , Humanos , Inflamación/patología , Pulmón/patología , Lesión Pulmonar/virología , Linfopenia/patología , Activación de Macrófagos/inmunología , Macrófagos/inmunología , Masculino , Persona de Mediana Edad , Miocitos del Músculo Liso/patología , Neutrófilos/inmunología , SARS-CoV-2 , Trombosis/patologíaRESUMEN
Background: Lung injury is common in coronavirus disease 2019 (COVID-19) patients. The severity of lung injury appears to be reflected in serum Krebs von den Lungen-6 (KL-6), a glycoprotein expressed on type II alveolar epithelium. This study aims to assess the role of serum KL-6 in reflecting the severity of lung injury in COVID-19 patients. Methods: A systematic search was conducted in Scopus, PubMed, Wiley Online Library, and ProQuest. Articles were screened based on several eligibility criteria and assessed for study quality using Newcastle-Ottawa Scale. Results: This systematic review included four studies involving a total of 151 adult COVID-19 patients. Pooled analysis revealed that serum KL-6 was significantly higher in severe patients (SMD = 1.16; 95% CI = 0.691.63) with moderately high pooled sensitivity (79%; 95% CI = 6191%) and specificity (86%; 95% CI = 7295%). Conclusion: High serum KL-6 may depict more severe lung injury in COVID-19 patients with moderately high sensitivity and specificity.
Asunto(s)
COVID-19/complicaciones , Lesión Pulmonar/diagnóstico , Lesión Pulmonar/virología , Mucina-1/sangre , Índice de Severidad de la Enfermedad , Biomarcadores/sangre , COVID-19/sangre , COVID-19/diagnóstico , Humanos , Lesión Pulmonar/sangre , Sensibilidad y EspecificidadRESUMEN
Influenza A virus (H1N1), a swine-origin influenza A virus, causes seasonal epidemics that result in severe illnesses and deaths. Leonurine has been reported to function as an anti-inflammatory agent with protective effects on nervous, urinary and cardiovascular systems. However, the therapeutic effects of leonurine on the pneumonia caused by H1N1 infection remain unclear. Hematoxylin and eosin staining was performed to evaluate the lung injuries of mice infected by H1N1. The amount of immune cells was analyzed by flow cytometry. Enzyme-linked immunosorbent assay was used to evaluate the alteration of multiple cytokines in lung tissues. Real-time quantitative polymerase chain reaction assay was performed to investigate the ribonucleic acid (RNA) levels of certain genes. The protein levels in toll-like receptor 4/nuclear factor kappa-light-chain-enhancer of activated B cells (TLR4/NF-κB) signaling were estimated by western blot assay. Leonurine treatment significantly inhibited the mortality caused by H1N1 infection. Leonurine treatment (60 mg/kg) alleviated the lung injuries caused by virus infection. The inflammatory cell accumulation and cytokine expression were inhibited by the leonurine administration. Leonurine inhibited the mRNA expression of pro-inflammatory cytokines in the lung homogenates at day 5 postinfection. Leonurine regulated the TLR4/NF-κB signaling in the lung homogenates of H1N1-infected mice at day 5 postinfection. Leonurine protects against H1N1 infection-induced pneumonia in mice.
Asunto(s)
Citocinas/metabolismo , Ácido Gálico/análogos & derivados , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , FN-kappa B/metabolismo , Infecciones por Orthomyxoviridae/virología , Neumonía/virología , Receptor Toll-Like 4/metabolismo , Animales , Antiinflamatorios/farmacología , Modelos Animales de Enfermedad , Ácido Gálico/farmacología , Regulación de la Expresión Génica , Humanos , Gripe Humana/virología , Lesión Pulmonar/virología , Ratones , Ratones Endogámicos BALB C , Transducción de Señal , Organismos Libres de Patógenos Específicos , PorcinosRESUMEN
Despite the worldwide effect of the coronavirus disease 2019 (COVID-19) pandemic, the underlying mechanisms of fatal viral pneumonia remain elusive. Here, we show that critical COVID-19 is associated with enhanced eosinophil-mediated inflammation when compared to non-critical cases. In addition, we confirm increased T helper (Th)2-biased adaptive immune responses, accompanying overt complement activation, in the critical group. Moreover, enhanced antibody responses and complement activation are associated with disease pathogenesis as evidenced by formation of immune complexes and membrane attack complexes in airways and vasculature of lung biopsies from six fatal cases, as well as by enhanced hallmark gene set signatures of Fcγ receptor (FcγR) signaling and complement activation in myeloid cells of respiratory specimens from critical COVID-19 patients. These results suggest that SARS-CoV-2 infection may drive specific innate immune responses, including eosinophil-mediated inflammation, and subsequent pulmonary pathogenesis via enhanced Th2-biased immune responses, which might be crucial drivers of critical disease in COVID-19 patients.
Asunto(s)
Anticuerpos Antivirales/inmunología , COVID-19/inmunología , Proteínas del Sistema Complemento/inmunología , Eosinófilos/inmunología , Inflamación/inmunología , Neumonía Viral/inmunología , SARS-CoV-2/inmunología , Inmunidad Adaptativa , Adulto , Anciano , Anciano de 80 o más Años , Complejo Antígeno-Anticuerpo/metabolismo , COVID-19/metabolismo , COVID-19/virología , Activación de Complemento , Complejo de Ataque a Membrana del Sistema Complemento/metabolismo , Eosinófilos/virología , Femenino , Humanos , Inflamación/metabolismo , Inflamación/virología , Lesión Pulmonar/inmunología , Lesión Pulmonar/patología , Lesión Pulmonar/virología , Masculino , Persona de Mediana Edad , Neumonía Viral/metabolismo , Receptores de IgG/inmunología , Receptores de IgG/metabolismo , Índice de Severidad de la Enfermedad , Transducción de Señal , Células Th2/inmunología , Carga Viral , Adulto JovenRESUMEN
The coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has placed a global public burden on health authorities. Although the virological characteristics and pathogenesis of COVID-19 has been largely clarified, there is currently no specific therapeutic measure. In severe cases, acute SARS-CoV-2 infection leads to immune disorders and damage to both the adaptive and innate immune responses. Having roles in immune regulation and regeneration, mesenchymal stem cells (MSCs) serving as a therapeutic option may regulate the over-activated inflammatory response and promote recovery of lung damage. Since the outbreak of the COVID-19 pandemic, a series of MSC-therapy clinical trials has been conducted. The findings indicate that MSC treatment not only significantly reduces lung damage, but also improves patient recovery with safety and good immune tolerance. Herein, we summarize the recent progress in MSC therapy for COVID-19 and highlight the challenges in the field.