Plasma angiopoietin-2 outperforms other markers of endothelial injury in prognosticating pediatric ARDS mortality

Zinter, Matt S.; Spicer, Aaron C.; Orwoll, Benjamin; Alkhouli, Mustafa F.; Dvorak, Christopher C.; Calfee, Carolyn S.; Matthay, Michael A.; Sapru, Anil

doi:10.1152/ajplung.00336.2015

Cited by 76 publications

(64 citation statements)

References 54 publications

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“…Prolonged elevations in Angpt2 levels in patients are associated with a higher rate of MOF and poor prognosis (4). Recent studies have identified Angpt2 as a potential mediator of MOF in sepsis and ARDS (4,19,33,41). However, the role of Angpt2 in remote organ injury due to VILI has not been previously described.…”

Section: Discussionmentioning

confidence: 99%

Ventilator-induced lung injury increases expression of endothelial inflammatory mediators in the kidney

Hepokoski

Englert

Baron

et al. 2017

American Journal of Physiology-Renal Physiology

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In critical illness, such as sepsis or the acute respiratory distress syndrome, acute kidney injury (AKI) is common and associated with increased morbidity and mortality. Mechanical ventilation in critical illnesses is also a risk factor for AKI, but it is potentially modifiable. Injurious ventilation strategies may lead to the systemic release of inflammatory mediators from the lung due to ventilator induced lung injury (VILI). The systemic consequences of VILI are difficult to differentiate clinically from other systemic inflammatory syndromes, such as sepsis. The purpose of this study was to identify unique changes in the expression of inflammatory mediators in kidney tissue in response to VILI compared with systemic sepsis to gain insight into direct effects of VILI on the kidney. Four groups of mice were compared—mice with sepsis from cecal ligation and puncture (CLP), mice subjected to injurious mechanical ventilation with high tidal volumes (VILI), mice exposed to CLP followed by VILI (CLP+VILI), and sham controls. Protein expression of common inflammatory mediators in kidneys was analyzed using a proteome array and confirmed by Western blot analysis or ELISA. VEGF and VCAM-1 were found to be significantly elevated in kidneys from VILI mice compared with sham and CLP. Angiopoietin-2 was significantly increased in CLP+VILI compared with CLP alone and was also correlated with higher levels of AKI biomarker, neutrophil gelatinase-associated lipocalin. These results suggest that VILI alters the renal expression of VEGF, VCAM-1, and angiopoietin-2, and these proteins warrant further investigation as potential biomarkers and therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

Ventilator-induced lung injury increases expression of endothelial inflammatory mediators in the kidney

Hepokoski

Englert

Baron

et al. 2017

American Journal of Physiology-Renal Physiology

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“…This interpretation is supported by the fact that VCV, but not VV, increased the expression of amphiregulin, a marker of pulmonary stretch [34]; IL-6 and CINC-1, which are inflammatory mediators of VILI [35]; and Ang-2, a marker of endothelial integrity [36]. …”

Section: Discussionmentioning

confidence: 99%

Variable ventilation improves pulmonary function and reduces lung damage without increasing bacterial translocation in a rat model of experimental pneumonia

et al. 2016

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BackgroundVariable ventilation has been shown to improve pulmonary function and reduce lung damage in different models of acute respiratory distress syndrome. Nevertheless, variable ventilation has not been tested during pneumonia. Theoretically, periodic increases in tidal volume (VT) and airway pressures might worsen the impairment of alveolar barrier function usually seen in pneumonia and could increase bacterial translocation into the bloodstream. We investigated the impact of variable ventilation on lung function and histologic damage, as well as markers of lung inflammation, epithelial and endothelial cell damage, and alveolar stress, and bacterial translocation in experimental pneumonia.MethodsThirty-two Wistar rats were randomly assigned to receive intratracheal of Pseudomonas aeruginosa (PA) or saline (SAL) (n = 16/group). After 24-h, animals were anesthetized and ventilated for 2 h with either conventional volume-controlled (VCV) or variable volume-controlled ventilation (VV), with mean VT = 6 mL/kg, PEEP = 5cmH2O, and FiO2 = 0.4. During VV, tidal volume varied randomly with a coefficient of variation of 30% and a Gaussian distribution. Additional animals assigned to receive either PA or SAL (n = 8/group) were not ventilated (NV) to serve as controls.ResultsIn both SAL and PA, VV improved oxygenation and lung elastance compared to VCV. In SAL, VV decreased interleukin (IL)-6 expression compared to VCV (median [interquartile range]: 1.3 [0.3–2.3] vs. 5.3 [3.6–7.0]; p = 0.02) and increased surfactant protein-D expression compared to NV (2.5 [1.9–3.5] vs. 1.2 [0.8–1.2]; p = 0.0005). In PA, compared to VCV, VV reduced perivascular edema (2.5 [2.0–3.75] vs. 6.0 [4.5–6.0]; p < 0.0001), septum neutrophils (2.0 [1.0–4.0] vs. 5.0 [3.3–6.0]; p = 0.0008), necrotizing vasculitis (3.0 [2.0–5.5] vs. 6.0 [6.0–6.0]; p = 0.0003), and ultrastructural lung damage scores (16 [14–17] vs. 24 [14–27], p < 0.0001). Blood colony-forming-unit (CFU) counts were comparable (7 [0–28] vs. 6 [0–26], p = 0.77). Compared to NV, VCV, but not VV, increased expression amphiregulin, IL-6, and cytokine-induced neutrophil chemoattractant (CINC)-1 (2.1 [1.6–2.5] vs. 0.9 [0.7–1.2], p = 0.025; 12.3 [7.9–22.0] vs. 0.8 [0.6–1.9], p = 0.006; and 4.4 [2.9–5.6] vs. 0.9 [0.8–1.4], p = 0.003, respectively). Angiopoietin-2 expression was lower in VV compared to NV animals (0.5 [0.3–0.8] vs. 1.3 [1.0–1.5], p = 0.01).ConclusionIn this rat model of pneumonia, VV improved pulmonary function and reduced lung damage as compared to VCV, without increasing bacterial translocation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-016-0476-7) contains supplementary material, which is available to authorized users.

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“…When an arterial line was not present, PaO2 was imputed from SpO2 ≤97% according to a log-linear equation (22). Finally, we measured associations between day 1 cytokines and three biomarkers of endothelial injury (Ang-2, vWF, and sTM) (13, 14). …”

Section: Methodsmentioning

confidence: 99%

“…In concert, these mechanisms lead to an increase in lung endothelial permeability and ongoing immune activation, which can further propagate the cycle of cell damage (11, 12). We have previously identified evidence of this cell damage in pediatric ARDS patients by correlating mortality with circulating markers of endothelial cell injury, including angiopoietin-2, von Willebrand Factor, and soluble thrombomodulin (13, 14). To date, however, little direct evidence exists linking systemic immune activation with pediatric ARDS outcomes or markers of endothelial damage.…”

Section: Introductionmentioning

confidence: 99%

Incorporating Inflammation into Mortality Risk in Pediatric Acute Respiratory Distress Syndrome

Zinter

Orwoll

Spicer

et al. 2017

Critical Care Medicine

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Objective In pediatric ARDS, lung injury is mediated by immune activation and severe inflammation. Therefore, we hypothesized that patients with elevated pro- and anti-inflammatory cytokines would have higher mortality rates and that these biomarkers could improve risk-stratification of poor outcomes. Design Multicenter prospective observational study. Setting We enrolled patients from 5 academic PICUs between 2008–2015. Patients Patients were 1 month to 18 years old, used noninvasive or invasive ventilation, and met the American European Consensus Conference definition of ARDS. Interventions None. Methods Eight pro-inflammatory and anti-inflammatory cytokines were measured on ARDS day 1 and correlated with mortality, ICU morbidity as measured by survivor PELOD score, and biomarkers of endothelial injury, including angiopoietin-2, von Willebrand Factor, and soluble thrombomodulin. Measurements & Main Results We measured biomarker levels in 194 patients, including 38 ARDS nonsurvivors. IL-6, IL-8, IL-10, IL-18, and TNF-R2 were each strongly associated with all-cause mortality, multiple markers of ICU morbidity, and endothelial injury. A multiple logistic regression model incorporating OI, IL-8, and TNF-R2 was superior to a model of OI alone in predicting the composite outcome of mortality or severe morbidity (AUROC 0.77 [0.70–0.83] vs. 0.70 [0.62–0.77], p=0.042). Conclusions In pediatric ARDS, pro- and anti-inflammatory cytokines are strongly associated with mortality, ICU morbidity, and biochemical evidence of endothelial injury. These cytokines significantly improve the ability of the OI to discriminate risk of mortality or severe morbidity and may allow for identification and enrollment of high-risk subgroups for future studies.

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Plasma angiopoietin-2 outperforms other markers of endothelial injury in prognosticating pediatric ARDS mortality

Cited by 76 publications

References 54 publications

Ventilator-induced lung injury increases expression of endothelial inflammatory mediators in the kidney

Ventilator-induced lung injury increases expression of endothelial inflammatory mediators in the kidney

Variable ventilation improves pulmonary function and reduces lung damage without increasing bacterial translocation in a rat model of experimental pneumonia

Incorporating Inflammation into Mortality Risk in Pediatric Acute Respiratory Distress Syndrome

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