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Release of endothelial activation markers in lungs of patients with malaria-associated acute respiratory distress syndrome.

ABSTRACT: BACKGROUND:Malaria-associated acute respiratory distress syndrome (MA-ARDS) is an understudied complication of malaria and is characterized by pulmonary inflammation and disruption of the alveolar-capillary membrane. Its pathogenesis remains poorly understood. Since endothelial activation plays an important role in other malarial complications, the expression of two endothelial activation markers, von Willebrand factor (VWF) and angiopoietin-2 (ANG-2), was investigated in the lungs of patients with MA-ARDS. METHODS:Post-mortem lung sections of Plasmodium falciparum-infected patients without alveolar oedema (NA), P. falciparum-infected patients with alveolar oedema (MA-ARDS), and uninfected people who died accidentally with no pathological changes to the lungs (CON) were immunohistochemically stained for VWF and ANG-2, and were evaluated with semi-quantitative analysis. RESULTS:Alveolar oedematous VWF and ANG-2 and intravascular VWF staining were significantly increased in patients with MA-ARDS versus infected and uninfected control groups. The levels of VWF in the alveolar septa and endothelial lining of large blood vessels of patients with MA-ARDS was significantly decreased compared to controls. ANG-2 expression was increased in the alveolar septa of malaria patients without alveolar oedema versus control patients, while ANG-2+ leukocytes were increased in the alveoli in both infected patient groups. CONCLUSIONS:This study documents a high level of VWF and ANG-2, two endothelial activation markers in the oedematous alveoli of post-mortem lung sections of Thai patients with MA-ARDS. Decreased detection of VWF in the endothelial lining of blood vessels, in parallel with an increased presence of intravascular VWF staining suggests marked endothelial activation and Weibel-Palade body release in the lungs of patients with MA-ARDS.

SUBMITTER: Pham TT

PROVIDER: S-EPMC6891978 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Release of endothelial activation markers in lungs of patients with malaria-associated acute respiratory distress syndrome.

Pham Thao-Thy TT Punsawad Chuchard C Glaharn Supattra S De Meyer Simon F SF Viriyavejakul Parnpen P Van den Steen Philippe E PE

Malaria journal 20191203 1

<h4>Background</h4>Malaria-associated acute respiratory distress syndrome (MA-ARDS) is an understudied complication of malaria and is characterized by pulmonary inflammation and disruption of the alveolar-capillary membrane. Its pathogenesis remains poorly understood. Since endothelial activation plays an important role in other malarial complications, the expression of two endothelial activation markers, von Willebrand factor (VWF) and angiopoietin-2 (ANG-2), was investigated in the lungs of pa ...[more]

PMID: 31796023

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Project description:Acute respiratory distress syndrome (ARDS) is triggered by a variety of insults, including bacterial and viral infections, and this leads to high mortality. While the role of the aryl hydrocarbon receptor (AhR) in mucosal immunity is being increasingly recognized, its function during ARDS is unclear. In the current study, we investigated the role of AhR in LPS-induced ARDS. AhR ligand, indole-3-carbinol (I3C), attenuated ARDS which was associated with a decrease in CD4+ RORγt +IL-17a+IL-22+ pathogenic Th17 cells, but not CD4+RORγt +IL-17a+IL-22- homeostatic Th 17 cells, in the lungs. AhR activation also led to a significant increase in CD4+IL-17a-IL-22+ Th22 cells. I3C-mediated Th22 cell expansion was dependent on the AhR expression on RORγt+ cells. AhR activation downregulated miR-29b-2-5p in immune cells from the lungs, which in turn downregulated RORc expression and upregulated IL-22. Collectively, the current study suggests that AhR activation can attenuate ARDS and may serve as a therapeutic modality by which to treat this complex disorder. IMPORTANCE Acute respiratory distress syndrome (ARDS) is a type of respiratory failure that is triggered by a variety of bacterial and viral infections, including the coronavirus SARS-CoV2. ARDS is associated with a hyperimmune response in the lungs that which is challenging to treat. Because of this difficulty, approximately 40% of patients with ARDS die. Thus, it is critical to understand the nature of the immune response that is functional in the lungs during ARDS as well as approaches by which to attenuate it. AhR is a transcription factor that is activated by a variety of endogenous and exogenous environmental chemicals as well as bacterial metabolites. While AhR has been shown to regulate inflammation, its role in ARDS is unclear. In the current study, we provide evidence that AhR activation can attenuate LPS-mediated ARDS through the activation of Th22 cells in the lungs, which are regulated through miR-29b-2-5p. Thus, AhR can be targeted to attenuate ARDS.

Project description:ObjectivesSystemic endothelial activation may contribute to sepsis-associated organ injury, including acute respiratory distress syndrome. We hypothesized that children with extrapulmonary sepsis with versus without acute respiratory distress syndrome would have plasma biomarkers indicative of increased endothelial activation and that persistent biomarker changes would be associated with poor outcome.DesignObservational cohort.SettingAcademic PICU.PatientsPatients less than 18 years old with sepsis from extrapulmonary infection with (n = 46) or without (n = 54) acute respiratory distress syndrome and noninfected controls (n = 19).InterventionsNone.Measurements and main resultsEndothelial (angiopoietin-1, angiopoietin-2, tyrosine kinase with immunoglobulin-like loop epidermal growth factor homology domain 2, vascular endothelial growth factor, soluble fms-like tyrosine kinase, von Willebrand factor, E-selectin, intercellular adhesion molecule, vascular cell adhesion molecule, thrombomodulin) and inflammatory biomarkers (C-reactive protein, interleukin-6, and interleukin-8) were measured from peripheral plasma collected within 3 days (time 1) of sepsis recognition and at 3-6 days (time 2) and 7-14 days (time 3). Time 1 biomarkers and longitudinal measurements were compared for sepsis patients with versus without acute respiratory distress syndrome and in relation to complicated course, defined as greater than or equal to two organ dysfunctions at day 7 or death by day 28. Angiopoietin-2, angiopoietin-2/angiopoietin-1 ratio, tyrosine kinase with immunoglobulin-like loop epidermal growth factor homology domain 2, vascular endothelial growth factor, von Willebrand factor, E-selectin, intercellular adhesion molecule, vascular cell adhesion molecule, thrombomodulin, endocan, C-reactive protein, interleukin-6, and interleukin-8 were different between sepsis and noninfected control patients at time 1. Among patients with sepsis, those with acute respiratory distress syndrome had higher angiopoietin-2/angiopoietin-1 ratio, vascular endothelial growth factor, vascular cell adhesion molecule, thrombomodulin, endocan, interleukin-6, and interleukin-8 than those without acute respiratory distress syndrome (all p < 0.003). Angiopoietin-2 and angiopoietin-2/angiopoietin-1 ratio remained higher in sepsis with versus without acute respiratory distress syndrome after multivariable analyses. Time 1 measures of angiopoietin-2, angiopoietin-2/-1 ratio, von Willebrand factor, and endocan were indicative of complicated course in all sepsis patients (all area under the receiver operating curve ≥ 0.80). In sepsis without acute respiratory distress syndrome, soluble fms-like tyrosine kinase decreased more quickly and von Willebrand factor and thrombomodulin decreased more slowly in those with complicated course.ConclusionsChildren with extrapulmonary sepsis with acute respiratory distress syndrome had plasma biomarkers indicative of greater systemic endothelial activation than those without acute respiratory distress syndrome. Several endothelial biomarkers measured near sepsis recognition were associated with complicated course, whereas longitudinal biomarker changes yielded prognostic information only in those without sepsis-associated acute respiratory distress syndrome.

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Release of endothelial activation markers in lungs of patients with malaria-associated acute respiratory distress syndrome.

Publications

Release of endothelial activation markers in lungs of patients with malaria-associated acute respiratory distress syndrome.

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