Bioinformatics insights into acute lung injury/acute respiratory distress syndrome.
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ABSTRACT:
SUBMITTER: Fang X
PROVIDER: S-EPMC3560991 | biostudies-literature | 2012 Jun
REPOSITORIES: biostudies-literature
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Project description:The acute respiratory distress syndrome (ARDS) is characterized by intense dysregulated inflammation leading to acute lung injury (ALI) and respiratory failure. There are no effective pharmacologic therapies for ARDS. Colchicine is a low-cost, widely available drug, effective in the treatment of inflammatory conditions. We studied the effects of colchicine pre-treatment on oleic acid-induced ARDS in rats. Rats were treated with colchicine (1 mg/kg) or placebo for three days prior to intravenous oleic acid-induced ALI (150 mg/kg). Four hours later they were studied and compared to a sham group. Colchicine reduced the area of histological lung injury by 61%, reduced lung edema, and markedly improved oxygenation by increasing PaO2/FiO2 from 66 ± 13 mmHg (mean ± SEM) to 246 ± 45 mmHg compared to 380 ± 18 mmHg in sham animals. Colchicine also reduced PaCO2 and respiratory acidosis. Lung neutrophil recruitment, assessed by myeloperoxidase immunostaining, was greatly increased after injury from 1.16 ± 0.19% to 8.86 ± 0.66% and significantly reduced by colchicine to 5.95 ± 1.13%. Increased lung NETosis was also reduced by therapy. Circulating leukocytosis after ALI was not reduced by colchicine therapy, but neutrophils reactivity and CD4 and CD8 cell surface expression on lymphocyte populations were restored. Colchicine reduces ALI and respiratory failure in experimental ARDS in relation with reduced lung neutrophil recruitment and reduced circulating leukocyte activation. This study supports the clinical development of colchicine for the prevention of ARDS in conditions causing ALI.
| S-EPMC7710059 | biostudies-literature
Project description:BackgroundSetting and strategies of mechanical ventilation with positive end-expiratory pressure (PEEP) in acute lung injury (ALI) remains controversial. This study compares the effects between lung-protective mechanical ventilation according to the Acute Respiratory Distress Syndrome Network recommendations (ARDSnet) and the open lung approach (OLA) on pulmonary function and inflammatory response.MethodsEighteen juvenile pigs were anaesthetized, mechanically ventilated, and instrumented. ALI was induced by surfactant washout. Animals were randomly assigned to mechanical ventilation according to the ARDSnet protocol or the OLA (n=9 per group). Gas exchange, haemodynamics, pulmonary blood flow (PBF) distribution, and respiratory mechanics were measured at intervals and the lungs were removed after 6 h of mechanical ventilation for further analysis.ResultsPEEP and mean airway pressure were higher in the OLA than in the ARDSnet group [15 cmH(2)O, range 14-18 cmH(2)O, compared with 12 cmH(2)O; 20.5 (sd 2.3) compared with 18 (1.4) cmH(2)O by the end of the experiment, respectively], and OLA was associated with improved oxygenation compared with the ARDSnet group after 6 h. OLA showed more alveolar overdistension, especially in gravitationally non-dependent regions, while the ARDSnet group was associated with more intra-alveolar haemorrhage. Inflammatory mediators and markers of lung parenchymal stress did not differ significantly between groups. The PBF shifted from ventral to dorsal during OLA compared with ARDSnet protocol [-0.02 (-0.09 to -0.01) compared with -0.08 (-0.12 to -0.06), dorsal-ventral gradients after 6 h, respectively].ConclusionsAccording to the OLA, mechanical ventilation improved oxygenation and redistributed pulmonary perfusion when compared with the ARDSnet protocol, without differences in lung inflammatory response.
| S-EPMC9174723 | biostudies-literature
Project description:Acute lung injury and acute respiratory distress syndrome (ALI/ARDS) are characterized by an inflammatory response, alveolar edema, and hypoxemia. ARDS occurs most often in the settings of pneumonia, sepsis, aspiration of gastric contents, or severe trauma. The prevalence of ARDS is approximately 10% in patients of intensive care. There is no effective remedy with mortality high at 30-40%. Most functional proteins are dynamic and stringently governed by ubiquitin proteasomal degradation. Protein ubiquitination is reversible, the covalently attached monoubiquitin or polyubiquitin moieties within the targeted protein can be removed by a group of enzymes called deubiquitinating enzymes (DUBs). Deubiquitination plays an important role in the pathobiology of ALI/ARDS as it regulates proteins critical in engagement of the alveolo-capillary barrier and in the inflammatory response. In this review, we provide an overview of how DUBs emerge in pathogen-induced pulmonary inflammation and related aspects in ALI/ARDS. Better understanding of deubiquitination-relatedsignaling may lead to novel therapeutic approaches by targeting specific elements of the deubiquitination pathways.
| S-EPMC7402294 | biostudies-literature
Project description:Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a devastating respiratory disorder with high rates of mortality and morbidity, but the detailed underlying mechanisms of ALI/ARDS remain largely unknown. Mechanosensitive ion channels (MSCs), including epithelial sodium channel (ENaC), Piezo channels, transient receptor potential channels (TRPs), and two-pore domain potassium ion (K2P) channels, are highly expressed in lung tissues, and the activity of these MSCs can be modulated by mechanical forces (e.g., mechanical ventilation) and other stimuli (e.g., LPS, hyperoxia). Dysfunction of MSCs has been found in various types of ALI/ARDS, and MSCs play a key role in regulating alveolar fluid clearance, alveolar epithelial/endothelial barrier function, the inflammatory response and surfactant secretion in ALI/ARDS lungs. Targeting MSCs exerts therapeutic effects in the treatment of ALI/ARDS. In this review, we summarize the structure and functions of several well-recognized MSCs, the role of MSCs in the pathogenesis of ALI/ARDS and recent advances in the pharmacological and molecular modulation of MSCs in the treatment of ALI/ARDS. According to the current literature, targeting MSCs might be a very promising therapeutic approach against ALI/ARDS.
| S-EPMC9764320 | biostudies-literature
Project description:Monitoring of lung function is essential to assess changes in the lung condition, and to correct and improve ventilator and adjuvant therapies in acute respiratory distress syndrome (ARDS). In this review we discuss the use of monitoring of gas exchange, lung mechanics and shortly on lung imaging in this condition.
| S-EPMC5537117 | biostudies-other
Project description:RationalePoint-of-care ultrasound (POCUS) is used to evaluate pulmonary edema in adults with acute respiratory distress syndrome (ARDS). Its use has not been validated in neonatal models.ObjectivesWe compared an in vivo lung ultrasound score against clinical and histological markers of acute lung injury, in a neonatal animal model, hypothesizing that POCUS would sensitively diagnose early acute lung injury in neonates and discern its severity.MethodsFifteen anesthetized, ventilated 3-day-old neonatal piglets were divided into controls, moderate lung injury, or severe lung injury by graded treatment with oleic acid. Degree of lung injury was quantified at baseline, immediately after oleic acid administration, and 1 hour after the evolution of acute lung injury, by blood gases, ventilation parameters and calculated oxygenation deficit; hemodynamic indices by echocardiography, and lung ultrasound obtained in an 8-region grid of anterior and posterior zones, semi-quantitatively analyzed by a blinded observer. Lungs were inflation-fixed postmortem at last mean airway pressure, for histological assessment.ResultsAcute lung injury manifested in oleic acid-treated groups as dose-dependent capillary leak causing intravascular depletion and cardiac failure, hypoxemia with increasing intrapulmonary shunt fraction, decreased lung compliance, and resistance. Ultrasound scores of anterior regions distinguished moderate from severe injury; scores in posterior regions reached maximum values immediately after lung injury. POCUS score correlated with calculated intrapulmonary shunt fraction (R2 = .65) and with histological injury score (R2 = .61), P < .01.ConclusionWe conclude that POCUS may be valuable in neonates for early quantification of acute lung injury or ARDS; and that nondependent ultrasound regions clearly distinguish severity of pulmonary edema.
| S-EPMC7436735 | biostudies-literature
Project description:Malaria remains one of the greatest burdens to global health, causing nearly 500,000 deaths in 2014. When manifesting in the lungs, severe malaria causes acute lung injury/acute respiratory distress syndrome (ALI/ARDS). We have previously shown that a proportion of DBA/2 mice infected with Plasmodium berghei ANKA (PbA) develop ALI/ARDS and that these mice recapitulate various aspects of the human syndrome, such as pulmonary edema, hemorrhaging, pleural effusion and hypoxemia. Herein, we investigated the role of neutrophils in the pathogenesis of malaria-associated ALI/ARDS. Mice developing ALI/ARDS showed greater neutrophil accumulation in the lungs compared with mice that did not develop pulmonary complications. In addition, mice with ALI/ARDS produced more neutrophil-attracting chemokines, myeloperoxidase and reactive oxygen species. We also observed that the parasites Plasmodium falciparum and PbA induced the formation of neutrophil extracellular traps (NETs) ex vivo, which were associated with inflammation and tissue injury. The depletion of neutrophils, treatment with AMD3100 (a CXCR4 antagonist), Pulmozyme (human recombinant DNase) or Sivelestat (inhibitor of neutrophil elastase) decreased the development of malaria-associated ALI/ARDS and significantly increased mouse survival. This study implicates neutrophils and NETs in the genesis of experimentally induced malaria-associated ALI/ARDS and proposes a new therapeutic approach to improve the prognosis of severe malaria.
| S-EPMC5142790 | biostudies-literature
Project description:ObjectiveThe Lung Injury Prediction Score identifies patients at risk for acute respiratory distress syndrome in the emergency department, but it has not been validated in non-emergency department hospitalized patients. We aimed to evaluate whether Lung Injury Prediction Score identifies non-emergency department hospitalized patients at risk of developing acute respiratory distress syndrome at the time of critical care contact.DesignRetrospective study.SettingFive academic medical centers.PatientsNine hundred consecutive patients (≥ 18 yr old) with at least one acute respiratory distress syndrome risk factor at the time of critical care contact.InterventionsNone.Measurements and main resultsLung Injury Prediction Score was calculated using the worst values within the 12 hours before initial critical care contact. Patients with acute respiratory distress syndrome at the time of initial contact were excluded. Acute respiratory distress syndrome developed in 124 patients (13.7%) a median of 2 days (interquartile range, 2-3) after critical care contact. Hospital mortality was 22% and was significantly higher in acute respiratory distress syndrome than non-acute respiratory distress syndrome patients (48% vs 18%; p < 0.001). Increasing Lung Injury Prediction Score was significantly associated with development of acute respiratory distress syndrome (odds ratio, 1.31; 95% CI, 1.21-1.42) and the composite outcome of acute respiratory distress syndrome or death (odds ratio, 1.26; 95% CI, 1.18-1.34). A Lung Injury Prediction Score greater than or equal to 4 was associated with the development of acute respiratory distress syndrome (odds ratio, 4.17; 95% CI, 2.26-7.72), composite outcome of acute respiratory distress syndrome or death (odds ratio, 2.43; 95% CI, 1.68-3.49), and acute respiratory distress syndrome after accounting for the competing risk of death (hazard ratio, 3.71; 95% CI, 2.05-6.72). For acute respiratory distress syndrome development, the Lung Injury Prediction Score has an area under the receiver operating characteristic curve of 0.70 and a Lung Injury Prediction Score greater than or equal to 4 has 90% sensitivity (misses only 10% of acute respiratory distress syndrome cases), 31% specificity, 17% positive predictive value, and 95% negative predictive value.ConclusionsIn a cohort of non-emergency department hospitalized patients, the Lung Injury Prediction Score and Lung Injury Prediction Score greater than or equal to 4 can identify patients at increased risk of acute respiratory distress syndrome and/or death at the time of critical care contact but it does not perform as well as in the original emergency department cohort.
| S-EPMC5431079 | biostudies-literature
Project description:The generation of reactive oxygen species (ROS) plays an important role for the maintenance of cellular processes and functions in the body. However, the excessive generation of oxygen radicals under pathological conditions such as acute lung injury (ALI) and its most severe form acute respiratory distress syndrome (ARDS) leads to increased endothelial permeability. Within this hallmark of ALI and ARDS, vascular microvessels lose their junctional integrity and show increased myosin contractions that promote the migration of polymorphonuclear leukocytes (PMNs) and the transition of solutes and fluids in the alveolar lumen. These processes all have a redox component, and this chapter focuses on the role played by ROS during the development of ALI/ARDS. We discuss the origins of ROS within the cell, cellular defense mechanisms against oxidative damage, the role of ROS in the development of endothelial permeability, and potential therapies targeted at oxidative stress.
| S-EPMC7120947 | biostudies-literature
Project description:A growing understanding of the complexity of the pathophysiology of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), coupled with advances in stem cell biology, has led to a renewed interest in the therapeutic potential of stem cells for this devastating disease. Mesenchymal stem cells appear closest to clinical translation, given the evidence that they may favourably modulate the immune response to reduce lung injury, while maintaining host immune-competence and also facilitating lung regeneration and repair. The demonstration that human mesenchymal stem cells exert benefit in the endotoxin-injured human lung is particularly persuasive. Endothelial progenitor cells also demonstrate promise in reducing endothelial damage, which is a key pathophysiological feature of ALI. Embryonic and induced pluripotent stem cells are at an earlier stage in the translational process, but offer the hope of directly replacing injured lung tissue. The lung itself also contains endogenous stem cells, which may ultimately offer the greatest hope for lung diseases, given their physiologic role in replacing and regenerating native lung tissues. However, significant deficits remain in our knowledge regarding the mechanisms of action of stem cells, their efficacy in relevant pre-clinical models, and their safety, particularly in critically ill patients. These gaps need to be addressed before the enormous therapeutic potential of stem cells for ALI/ARDS can be realised.
| S-EPMC3681334 | biostudies-literature