Host lung microbiota promotes malaria-associated acute respiratory distress syndrome.
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ABSTRACT:
SUBMITTER: Mukherjee D
PROVIDER: S-EPMC9243033 | biostudies-literature |
REPOSITORIES: biostudies-literature
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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:Malaria-associated acute respiratory distress syndrome (ARDS) is an inflammatory disease causing alveolar-pulmonary barrier lesion and increased vascular permeability characterized by severe hypoxemia. Computed tomography (CT), among other imaging techniques, allows the morphological and quantitative identification of lung lesions during ARDS. This study aims to identify the onset of malaria-associated ARDS development in an experimental model by imaging diagnosis. Our results demonstrated that ARDS-developing mice presented decreased gaseous exchange and pulmonary insufficiency, as shown by the SPECT/CT technique. The pulmonary aeration disturbance in ARDS-developing mice on the 5th day post infection was characterized by aerated tissues decrease and nonaerated tissue accumulation, demonstrating increased vascular permeability and pleural effusion. The SPECT/CT technique allowed the early diagnosis in the experimental model, as well as the identification of the pulmonary aeration. Notwithstanding, despite the fact that this study contributes to better understand lung lesions during malaria-associated ARDS, further imaging studies are needed.
| S-EPMC7259762 | biostudies-literature
Project description:Malaria-associated acute lung injury (MA-ALI) and its more severe form malaria-associated acute respiratory distress syndrome (MA-ARDS) are common, often fatal complications of severe malaria infections. However, little is known about their pathogenesis. In this study, biochemical alterations of the lipid composition of the lungs were investigated as possible contributing factors to the severity of murine MA-ALI/ARDS. C57BL/6J mice were infected with Plasmodium berghei NK65 to induce lethal MA-ARDS, or with Plasmodium chabaudi AS, a parasite strain that does not induce lung pathology. The lipid profile of the lung tissue from mice infected with Plasmodium berghei NK65 developing MA-ALI/ARDS, but not that from mice without lung pathology or controls, was characterized by high levels of phospholipids -mainly phosphatidylcholine- and esterified cholesterol. The high levels of polyunsaturated fatty acids and the linoleic/oleic fatty acid ratio of the latter reflect the fatty acid composition of plasma cholesterol esters. In spite of the increased total polyunsaturated fatty acid pool, which augments the relative oxidability of the lung membranes, and the presence of hemozoin, a known pro-oxidant, no excess oxidative stress was detected in the lungs of Plasmodium berghei NK65 infected mice. The bronchoalveolar lavage (BAL) fluid of Plasmodium berghei NK65 infected mice was characterized by high levels of plasma proteins. The phospholipid profile of BAL large and small aggregate fractions was also different from uninfected controls, with a significant increase in the amounts of sphingomyelin and lysophosphatidylcholine and the decrease in phosphatidylglycerol. Both the increase of proteins and lysophosphatidylcholine are known to decrease the intrinsic surface activity of surfactant. Together, these data indicate that an altered lipid composition of lung tissue and BAL fluid, partially ascribed to oedema and lipoprotein infiltration, is a characteristic feature of murine MA-ALI/ARDS and possibly contribute to lung dysfunction.
| S-EPMC4666673 | 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:The association between severe malaria and Plasmodium vivax species is contentious. On the Thai-Myanmar border, all pregnant women are followed systematically with active weekly malaria screening. Over a 27-year period of providing antenatal care, 48,983 have been prospectively followed until pregnancy outcome (miscarriage or delivery) and 4,298 women have had P. vivax detected at least once. Reported here is the first known P. vivax-associated death amongst these women. The initial patient presentation was of uncomplicated P. vivax (0.5% parasitaemia) in a term, multigravida woman who responded rapidly to oral artesunate and mefloquine treatment, clearing her blood stage parasites within 48 hours. The patient appeared well, was ambulatory and due to be discharged but became unwell with acute respiratory distress syndrome (ARDS) requiring ventilation three days (67 hours) into treatment. Despite induction and delivery of a stillborn foetus, ventilatory requirements increased and the patient died on day 7. The patient had a low body mass index. Sensitive detection with nested PCR confirmed only the presence of P. vivax species and concomitant infections such as tuberculosis and human immunodeficiency virus (HIV) were also ruled out. The contemporaneous treatment of acute uncomplicated P. vivax and the onset of ARDS on day 3 in this patient implies a possible but unconfirmed association with death in this patient. Assuming this death was caused by P. vivax, the risk of ARDS-related maternal mortality in this setting did not differ significantly between Plasmodium falciparum and P. vivax (0.24 per 1,000 (1/4,158) versus 0.23 per 1,000 (1/4,298), contrary to the increased risk of maternal mortality from P. falciparum compared to P. vivax, 2.89 per 1,000 (12/4,158) versus 0.23 per 1,000 (1/4,298), P?=?0.003.
| S-EPMC4046059 | biostudies-literature
Project description: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.
| S-EPMC6913256 | biostudies-literature
Project description:Bioinformatics is the application of omics science, information technology, mathematics and statistics in the field of biomarker detection. Clinical bioinformatics can be applied for identification and validation of new biomarkers to improve current methods of monitoring disease activity and identify new therapeutic targets. Acute lung injurt (ALI)/Acute respiratory distress syndrome (ARDS) affects a large number of patients with a poor prognosis. The present review mainly focused on the progress in understanding disease heterogeneity through the use of evolving biological, genomic, and genetic approaches and the role of clinical bioinformatics in the pathogenesis and treatment of ALI/ARDS. The remarkable advances in clinical bioinformatics can be a new way for understanding disease pathogenesis, diagnosis and treatment.
| S-EPMC3560991 | biostudies-literature
Project description:BackgroundIn the acute respiratory distress syndrome (ARDS), inflammation in the lungs and other organs can cause life-threatening organ failure. Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins) can modulate inflammatory responses. Previous observational studies suggested that statins improved clinical outcomes in patients with sepsis. We hypothesized that rosuvastatin therapy would improve clinical outcomes in critically ill patients with sepsis-associated ARDS.MethodsWe conducted a multicenter trial in which patients with sepsis-associated ARDS were randomly assigned to receive either enteral rosuvastatin or placebo in a double-blind manner. The primary outcome was mortality before hospital discharge home or until study day 60 if the patient was still in a health care facility. Secondary outcomes included the number of ventilator-free days (days that patients were alive and breathing spontaneously) to day 28 and organ-failure-free days to day 14.ResultsThe study was stopped because of futility after 745 of an estimated 1000 patients had been enrolled. There was no significant difference between study groups in 60-day in-hospital mortality (28.5% with rosuvastatin and 24.9% with placebo, P=0.21) or in mean (±SD) ventilator-free days (15.1±10.8 with rosuvastatin and 15.1±11.0 with placebo, P=0.96). The groups were well matched with respect to demographic and key physiological variables. Rosuvastatin therapy, as compared with placebo, was associated with fewer days free of renal failure to day 14 (10.1±5.3 vs. 11.0±4.7, P=0.01) and fewer days free of hepatic failure to day 14 (10.8±5.0 vs. 11.8±4.3, P=0.003). Rosuvastatin was not associated with an increased incidence of serum creatine kinase levels that were more than 10 times the upper limit of the normal range.ConclusionsRosuvastatin therapy did not improve clinical outcomes in patients with sepsis-associated ARDS and may have contributed to hepatic and renal organ dysfunction. (Funded by the National Heart, Lung, and Blood Institute and the Investigator-Sponsored Study Program of AstraZeneca; ClinicalTrials.gov number, NCT00979121.).
| S-EPMC4241052 | biostudies-literature
Project description:RationaleThe aim of this study was to analyze the metabolomics of lung with different host inflammation of acute respiratory distress syndrome (ARDS) for the identification of biomarkers for predicting severity under different inflammatory conditions.MethodsCecal ligation and puncture (CLP) and lipopolysaccharide (LPS)-intratracheal injection induced acute lung injury (ALI) were used. A mouse model was used to explore lung metabolomic biomarkers in ALI/ARDS. The splenectomy model was used as an auxiliary method to distinguish between hyper- and hypo-inflammatory subtypes. Plasma, lung tissue and bronchoalveolar lavage fluid (BALF) samples were collected from mice after CLP/LPS. The severity of lung injury was evaluated. Expression of tumor necrosis factor-α (TNF-α) in mice serum and lung was tested by enzyme-linked immunosorbent assay (ELISA) and polymer chain reaction (PCR). Polymorphonuclear cells in BALF were counted. The lung metabolites were detected by gas chromatography/mass spectrometry (GC/MS), and the metabolic pathways predicted using the KEGG database.ResultsThe LPS/CLP-Splen group had more severe lung injury than the corresponding ALI group; that in the CLP-Splen group was more serious than in the LPS-Splen group. TNF-α expression was significantly elevated in the serum and lung tissue after LPS or CLP, and higher in the LPS/CLP-Splen group than in the corresponding ALI group. The level of TNF-α in the CLP-Splen group was elevated significantly over that in the LPS-Splen group. Both these groups also showed significant neutrophil exudation within the lungs. During differential inflammation, more differential metabolites were detected in the lungs of the CLP group ALI mice than in the LPS group. A total of 41 compounds were detected in the lungs of the CLP and CLP-Splen groups. Contrastingly, eight compounds were detected in the lungs of the LPS and LPS-Splen groups. The LPS-Splen and CLP-Splen groups had significant neutrophil exudation in the lung. Random forest analysis of lung-targeted metabolomics data indicated 4-hydroxyphenylacetic acid, 1-aminocyclopentanecarboxylic acid (ACPC), cis-aconitic acid, and hydroxybenzoic acid as strong predictors of the hyper-inflammatory subgroup in the CLP group. Furthermore, with splenectomy, 13 differential metabolic pathways between the CLP and LPS groups were revealed.ConclusionsHyper-inflammatory subgroups of ARDS have a greater inflammatory response and a more active lung metabolism. Combined with the host inflammation background, biomarkers from metabolomics could help evaluate the response severity of ARDS.
| S-EPMC7646044 | biostudies-literature
Project description:Plasmodium parasites cause malaria, a global health disease that is responsible for more than 200 million clinical cases and 600 000 deaths each year. Most deaths are caused by various complications, including malaria-associated acute respiratory distress syndrome (MA-ARDS). Despite the very rapid and efficient killing of parasites with antimalarial drugs, 15% of patients with complicated malaria succumb. This stresses the importance of investigating resolution mechanisms that are involved in the recovery from these complications once the parasite is killed. To study the resolution of MA-ARDS, P. berghei NK65-infected C57BL/6 mice were treated with antimalarial drugs after onset of symptoms, resulting in 80% survival. Micro-Computed Tomography revealed an altered morphology of the lungs upon infection, with an increase in total and non-aerated lung volume due to edema. Whole body plethysmography confirmed a drastically altered lung ventilation, which was restored during resolution. Single-cell RNA sequencing indicated an increased inflammatory state in the lungs upon infection, which was accompanied by a drastic decrease in endothelial cells, consistent with CD8+ T cell mediated killing. During resolution, anti-inflammatory pathways were upregulated and proliferation of endothelial cells was observed. MultiNicheNet interactome analysis provided a wealth of possible pathways that could be involved in the disease resolution, which might be interesting to functionally validate. In conclusion, promotion of pro-resolving pathways that limit inflammation and promotion of endothelial cell proliferation may be an interesting approach for the design of adjunctive treatments to promote resolution after Plasmodium parasite killing by antimalarial drugs.
2024-01-03 | GSE244528 | GEO