Acute respiratory distress syndrome induced by a swine 2009 H1N1 variant in mice

BACKGROUND: Acute respiratory distress syndrome (ARDS) induced by pandemic 2009 H1N1 influenza virus has been widely reported and was considered the main cause of death in critically ill patients with 2009 H1N1 infection. However, no animal model has been developed for ARDS caused by infection with 2009 H1N1 virus. Here, we present a mouse model of ARDS induced by 2009 H1N1 virus. METHODOLOGY PRINCIPAL FINDINGS: Mice were inoculated with A/swine/Shandong/731/2009 (SD/09), which was a 2009 H1N1 influenza variant with a G222D mutation in the hemagglutinin. Clinical symptoms were recorded every day. Lung injury was assessed by lung water content and histopathological observation. Arterial blood gas, leukocyte count in the bronchial alveolar lavage fluid and blood, virus titers, and cytokine levels in the lung were measured at various times post-inoculation. Mice infected with SD/09 virus showed typical ARDS symptoms characterized by 60% lethality on days 8-10 post-inoculation, highly edematous lungs, inflammatory cellular infiltration, alveolar and interstitial edema, lung hemorrhage, progressive and severe hypoxemia, and elevated levels of proinflammatory cytokines and chemokines. CONCLUSIONS/SIGNIFICANCE: These results suggested that we successfully established an ARDS mouse model induced by a virulent 2009 H1N1 variant without previous adaptation, which may be of benefit for evaluating the pathogenesis or therapy of human ARDS caused by 2009 H1N1 virus.     

乌司他丁对急性肺损伤/急性呼吸窘迫综合征的治疗研究

目的研究大剂量乌司他丁在急性肺损伤/急性呼吸窘迫综合征中的治疗效果。方法回顾性分析2006年1月至2010年1月广西医科大学第一附属医院ICU收治的154例ALI/ARDS患者的临床资料,根据治疗方案分为乌司他丁组(UTI组)(n=80),对照组(n=74)。记录两组患者开始治疗、治疗第3天、治疗第7天的生命体征、动脉血气分析、血生化检查结果;记录患者在ICU治疗的转归。应用SPSS 13.0软件对结果进行统计学分析。结果经治疗3天UTI组呼吸频率低于对照组;动脉血气分析提示两组患者PaO2、PaO2/Fi O2、SaO2均有上升,UTI组PaO2/Fi O2略低于对照组(P0.01),而两组患者PaO2、SaO2比较无统计学差异。UTI组与对照组的死亡率比较(UTI组52.5%,对照组52.7%,P=0.980)无统计学差异,机械通气时间UTI组低于对照组[UTI组(14.8±3.9)天,对照组(16.7±4.2)天,P=0.020]。根据ALI/ARDS发生的病因分为肺内源性及肺外源性进行亚组分析(A组:肺内源性ALI/ARDS,使用UTI治疗;B组:肺内源性ALI/ARDS,不使用UTI治疗;C组:肺外源性ALI/ARDS,使用UTI治疗;D组:肺外源性ALI/ARDS,不使用UTI治疗),发现乌司他丁对肺外源性ALI/ARDS患者(C组)的ICU时间、ICU内死亡率及机械通气时间均低于不使用UTI的患者(D组)。结论大剂量乌司他丁用于ALI/ARDS的临床治疗可有效改善患者氧合指数,减少机械通气时间,且高血糖的发生率低,尤其是乌司他丁治疗肺外源性ALI/ARDS患者的预后优于肺内源性的ALI/ARDS。     

肺水相关指数对重症烧伤并发急性呼吸窘迫综合征患者病情预后的评估价值

目的评价肺水相关指数对重症烧伤并发急性呼吸窘迫综合征(ARDS)患者严重程度、预后判断的价值。方法对31例重症烧伤并发ARDS患者,除记录一般临床资料及主要合并症外,均利用脉搏指示剂连续心输出量(PiCCO)监测仪监测,并记录置入PiCCO导管时的急性生理和慢性健康状况(APACHE)Ⅱ评分,置管后0、24、48、72h氧合指数,肺血管通透性指数(PVPI)和血管外肺水指数(EVLWI)值。根据28天预后分为存活组和死亡组,分析两组各指数之间的差异及其对预后的评估能力。结果纳入研究的31例患者中,28天内死亡21例(67.7%),吸入性损伤、脓毒血症是主要合并症及影响预后的主要因素。存活组患者置管后72h氧合指数高于死亡组,差异有统计学意义(P0.05);存活组患者置管后48、72hPVPI低于死亡组,差异有统计学意义(P0.05);存活组患者置管后24、48、72hEVLWI低于死亡组,差异有统计学意义(P0.05);且随着置管时间延长,氧合指数、PVPI、EVLWI均对预后评价准确性增加,置管后72h的氧合指数、PVPI、EVLWI值对预后的评价最佳,3个指数对预后评估价值差异无统计学意义(P0.05)。结论运用PiCCO监测仪对肺水相关指数连续监测对重症烧伤并发ARDS患者严重程度、预后评价具有重要临床意义。     

X-ray diagnosis of acute respiratory distress syndrome in acute hematogenous osteomyelitis in children

OBJECTIVE: to analyze the x-ray signs of acute respiratory distress syndrome (ARDS) in children with the septicopyemic form of acute hematogenous osteomyelitis (AHO) for the first time, by using the authors' material. METHODS: X-ray study of respiratory organs was conducted in 221 children with AHO. SUBJECTS AND BASIC RESULTS: ARDS had a rather characteristic x-ray pattern that permitted a differential diagnosis of this condition and another abnormality, that with septic pneumonia in particular.     

急性呼吸窘迫综合征中miRNAs的生物标记作用与调控机制

MiRNAs作为非编码单链RNA分子,具有时空特异性和较高的保守性。近年来,许多实验数据证明,miRNA对细胞基因表达、细胞分化和组织发育等过程有着重要的调控作用,特别是在一些疾病的发生与发展中,miRNAs会异常表达且通过某些机制促进或抑制疾病的恶化。急性呼吸窘迫综合征(acute respiratory distress syndrome, ARDS)的发生由多种因素造成,主要临床表现为肺泡-毛细血管损伤。在ARDS发病过程中,一些miRNAs表达异常,且通过调控mRNA转录和表达,参与整个发病过程。在ARDS发病过程中明显上调或下调且具有特异性的miRNA分子可能为ARDS的预前及预后提供新的标志物,同时研究其调控机制也为诊疗提供新靶点。     

Phenotypic characterization of alveolar monocyte recruitment in acute respiratory distress syndrome

In 49 acute respiratory distress syndrome (ARDS) patients, the phenotype of alveolar macrophages (AMs) was analyzed by flow cytometry. Bronchoalveolar lavage (BAL) was performed within 24 h after intubation and on days 3-5, 9-12, and 18-21 of mechanical ventilation. The 27E10(high)/CD11b(high)/CD71(low)/ 25F9(low)/HLA DR(low)/RM3/1(low) AM population in the first BAL indicated extensive monocyte influx into the alveolar compartment. There was no evidence of increased local AM proliferation as assessed by nuclear Ki67 staining. Sequential BAL revealed two distinct patient groups. In one, a decrease in 27E10 and CD11b and an increase in CD71, 25F9, HLA DR, and RM3/1 suggested a reduction in monocyte influx and maturation of recruited cells into AMs, whereas the second group displayed sustained monocyte recruitment. In the first BAL from all patients, monocyte chemoattractant protein (MCP)-1 was increased, and AMs displayed elevated MCP-1 gene expression. In sequential BALs, a decrease in MCP-1 coincided with the disappearance of monocyte-like AMs, whereas persistent upregulation of MCP-1 paralleled ongoing monocyte influx. A highly significant correlation between BAL fluid MCP-1 concentration, the predominance of monocyte-like AMs, and the severity of respiratory failure was noted.     

Multiple potential targets of opioids in the treatment of acute respiratory distress syndrome from COVID-19

COVID-19 can present with a variety of clinical features, ranging from asymptomatic or mild respiratory symptoms to fulminant acute respiratory distress syndrome (ARDS) depending on the host's immune responses and the extent of the associated pathologies. This implies that several measures need to be taken to limit severely impairing symptoms caused by viral-induced pathology in vital organs. Opioids are most exploited for their analgesic effects but their usage in the palliation of dyspnoea, immunomodulation and lysosomotropism may represent potential usages of opioids in COVID-19. Here, we describe the mechanisms involved in each of these potential usages, highlighting the benefits of using opioids in the treatment of ARDS from SARS-CoV-2 infection.     

Skeleton binding protein-1-mediated parasite sequestration inhibits spontaneous resolution of malaria-associated acute respiratory distress syndrome

Malaria is a hazardous disease caused by Plasmodium parasites and often results in lethal complications, including malaria-associated acute respiratory distress syndrome (MA-ARDS). Parasite sequestration in the microvasculature is often observed, but its role in malaria pathogenesis and complications is still incompletely understood. We used skeleton binding protein-1 (SBP-1) KO parasites to study the role of sequestration in experimental MA-ARDS. The sequestration-deficiency of these SBP-1 KO parasites was confirmed with bioluminescence imaging and by measuring parasite accumulation in the lungs with RT-qPCR. The SBP-1 KO parasites induced similar lung pathology in the early stage of experimental MA-ARDS compared to wildtype (WT) parasites. Strikingly, the lung pathology resolved subsequently in more than 60% of the SBP-1 KO infected mice, resulting in prolonged survival despite the continuous presence of the parasite. This spontaneous disease resolution was associated with decreased inflammatory cytokine expression measured by RT-qPCR and lower expression of cytotoxic markers in pathogenic CD8⁺ T cells in the lungs of SBP-1 KO infected mice. These data suggest that SBP-1-mediated parasite sequestration and subsequent high parasite load are not essential for the development of experimental MA-ARDS but inhibit the resolution of the disease.     

Blockade of caspase cascade overcomes malaria-associated acute respiratory distress syndrome in mice

Malaria is an enormous burden on global health that caused 409,000 deaths in 2019. Severe malaria can manifest in the lungs, an illness known as acute respiratory distress syndrome (ARDS). Not much is known about the development of malaria-associated ARDS (MA-ARDS), especially regarding cell death in the lungs. We had previously established a murine model that mimics various human ARDS aspects, such as pulmonary edema, hemorrhages, pleural effusion, and hypoxemia, using DBA/2 mice infected with Plasmodium berghei ANKA. Here, we explored the mechanisms and the involvement of apoptosis in this syndrome. We found that apoptosis contributes to the pathogenesis of MA-ARDS, primarily as facilitators of the alveolar-capillary barrier breakdown. The protection of pulmonary endothelium by inhibiting caspase activation could be a promising therapeutic strategy to prevent the pathogenicity of MA-ARDS. Therefore, intervention in the programmed death cell mechanism could help patients not to develop severe malaria.Subject terms: Immunology, Infection     

Mesenchymal stromal cell therapy for acute respiratory distress syndrome due to coronavirus disease 2019

Background aimsThe acute respiratory distress syndrome (ARDS) resulting from coronavirus disease 2019 (COVID-19) is associated with a massive release of inflammatory cytokines and high mortality. Mesenchymal stromal cells (MSCs) have anti-inflammatory properties and have shown activity in treating acute lung injury. Here the authors report a case series of 11 patients with COVID-19-associated ARDS (CARDS) requiring mechanical ventilation who were treated with remestemcel-L, an allogeneic MSC product, under individual patient emergency investigational new drug applications.MethodsPatients were eligible if they were mechanically ventilated for less than 72 h prior to the first infusion. Patients with pre-existing lung disease requiring supplemental oxygen or severe liver or kidney injury were excluded. Each patient received two infusions of remestemcel-L at a dose of 2 million cells/kg per infusion given 48–120 h apart.ResultsRemestemcel-L infusions were well tolerated in all 11 patients. At the end of the 28-day follow-up period, 10 (91%, 95% confidence interval [CI], 59–100%) patients were extubated, nine (82%, 95% CI, 48–97%) patients remained liberated from mechanical ventilation and were discharged from the intensive care unit and two (18%, 95 CI%, 2–52%) patients died. The median time to extubation was 10 days. Eight (73%, 95% CI, 34–100%) patients were discharged from the hospital. C-reactive protein levels significantly declined within 5 days of MSC infusion.ConclusionsThe authors demonstrate in this case series that remestemcel-L infusions to treat moderate to severe CARDS were safe and well tolerated and resulted in improved clinical outcomes.     

The protective effects of C16 peptide and angiopoietin-1 compound in lipopolysaccharide-induced acute respiratory distress syndrome

C16 peptide and angiopoietin-1 (Ang-1) have been found to have anti-inflammatory activity in various inflammation-related diseases. However, their combined role in acute respiratory distress syndrome (ARDS) has not been investigated yet. The objective of this study was to investigate the effects of C16 peptide and Ang-1 in combination with lipopolysaccharide (LPS)-induced inflammatory insult in vitro and in vivo. Human pulmonary microvascular endothelial cells and human pulmonary alveolar epithelial cells were used as cell culture systems, and an ARDS rodent model was used for in vivo studies. Our results demonstrated that C16 and Ang-1 in combination significantly suppressed inflammatory cell transmigration by 33% in comparison with the vehicle alone, and decreased the lung tissue wet-to-dry lung weight ratio to a maximum of 1.53, compared to 3.55 in the vehicle group in ARDS rats. Moreover, C  +  A treatment reduced the histology injury score to 60% of the vehicle control, enhanced arterial oxygen saturation (SO₂), decreased arterial carbon dioxide partial pressure (PCO₂), and increased oxygen partial pressure (PO₂) in ARDS rats, while also improving the survival rate from 47% (7/15) to 80% (12/15) and diminishing fibrosis, necrosis, and apoptosis in lung tissue. Furthermore, when C  +  A therapy was administered 4 h following LPS injection, the treatment showed significant alleviating effects on pulmonary inflammatory cell infiltration 24 h postinsult. In conclusion, our in vitro and in vivo studies show that C16 and Ang-1 exert protective effects against LPS-induced inflammatory insult. C16 and Ang-1 hold promise as a novel agent against LPS-induced ARDS. Further studies are needed to determine the potential for C16 and Ang-1 in combination in treating inflammatory lung diseases.     

Proteomic study of acute respiratory distress syndrome: current knowledge and implications for drug development

The acute respiratory distress syndrome (ARDS) is a common cause of acute respiratory failure, and is associated with substantial mortality and morbidity. Dozens of clinical trials targeting ARDS have failed, with no drug specifically targeting lung injury in widespread clinical use. Thus, the need for drug development in ARDS is great. Targeted proteomic studies in ARDS have identified many key pathways in the disease, including inflammation, epithelial injury, endothelial injury or activation, and disordered coagulation and repair. Recent studies reveal the potential for proteomic changes to identify novel subphenotypes of ARDS patients who may be most likely to respond to therapy and could thus be targeted for enrollment in clinical trials. Nontargeted studies of proteomics in ARDS are just beginning and have the potential to identify novel drug targets and key pathways in the disease. Proteomics will play an important role in phenotyping of patients and developing novel therapies for ARDS in the future.     

Corticosteroids in the prevention and treatment of acute respiratory distress syndrome (ARDS) in adults: meta-analysis

Objective To systematically review the efficacy of steroids in the prevention of acute respiratory distress syndrome (ARDS) in critically ill adults, and treatment for established ARDS.Data sources Search of randomised controlled trials (1966-April 2007) of PubMed, Cochrane central register of controlled trials, Cochrane database of systematic reviews, American College of Physicians Journal Club, health technology assessment database, and database of abstracts of reviews of effects.Data extraction Two investigators independently assessed trials for inclusion and extracted data into standardised forms; differences were resolved by consensus.Data synthesis Steroid efficacy was assessed through a Bayesian hierarchical model for comparing the odds of developing ARDS and mortality (both expressed as odds ratio with 95% credible interval) and duration of ventilator free days, assessed as mean difference. Bayesian outcome probabilities were calculated as the probability that the odds ratio would be ≥1 or the probability that the mean difference would be ≥0. Nine randomised trials using variable dose and duration of steroids were identified. Preventive steroids (four studies) were associated with a trend to increase both the odds of patients developing ARDS (odds ratio 1.55, 95% credible interval 0.58 to 4.05; P(odds ratio ≥1)=86.6%), and the risk of mortality in those who subsequently developed ARDS (three studies, odds ratio 1.52, 95% credible interval 0.30 to 5.94; P(odds ratio ≥1)=72.8%). Steroid administration after onset of ARDS (five studies) was associated with a trend towards reduction in mortality (odds ratio 0.62, 95% credible interval 0.23 to 1.26; P(odds ratio ≥1)=6.8%). Steroid therapy increased the number of ventilator free days compared with controls (three studies, mean difference 4.05 days, 95% credible interval 0.22 to 8.71; P(mean difference ≥0)=97.9%). Steroids were not associated with increase in risk of infection.Conclusions A definitive role of corticosteroids in the treatment of ARDS in adults is not established. A possibility of reduced mortality and increased ventilator free days with steroids started after the onset of ARDS was suggested. Preventive steroids possibly increase the incidence of ARDS in critically ill adults.     

Mesenchymal stem cells as living anti-inflammatory therapy for COVID-19 related acute respiratory distress syndrome

Coronavirus disease 2019(COVID-19), a pandemic disease caused by the severe acute respiratory syndrome coronavirus 2(SARS-Co V2), is growing at an exponential rate worldwide. Manifestations of this disease are heterogeneous; however, advanced cases often exhibit various acute respiratory distress syndrome-like symptoms, systemic inflammatory reactions, coagulopathy, and organ involvements. A common theme in advanced COVID-19 is unrestrained immune activation, classically referred to as a cytokine storm, as well as deficiencies in immune regulatory mechanisms such as T regulatory cells. While mesenchymal stem cells(MSCs) themselves are objects of cytokine regulation, they can secrete cytokines to modulate immune cells by inducing antiinflammatory regulatory Treg cells, macrophages and neutrophils; and by reducing the activation of T and B cells, dendritic and nature killer cells. Consequently, they have therapeutic potential for treating severe cases of COVID-19. Here we discuss the unique ability of MSCs, to act as a living antiinflammatory, which can rebalance the cytokine/immune responses to restore equilibrium. We also discuss current MSC trials and present different concepts for optimization of MSC therapy in patients with COVID-19 acute respiratory distress syndrome.