Plasma angiopoietin-2 in clinical acute lung injury: Prognostic and pathogenetic significance

Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of California San Francisco, San Francisco, CA, USA.
Critical care medicine (Impact Factor: 6.31). 06/2012; 40(6):1731-7. DOI: 10.1097/CCM.0b013e3182451c87
Source: PubMed


Angiopoietin-2 is a proinflammatory mediator of endothelial injury in animal models, and increased plasma angiopoietin-2 levels are associated with poor outcomes in patients with sepsis-associated acute lung injury. Whether angiopoietin-2 levels are modified by treatment strategies in patients with acute lung injury is unknown.
To determine whether plasma angiopoietin-2 levels are associated with clinical outcomes and affected by fluid management strategy in a broad cohort of patients with acute lung injury.
Plasma levels of angiopoietin-2 and von Willebrand factor (a traditional marker of endothelial injury) were measured in 931 subjects with acute lung injury enrolled in a randomized trial of fluid liberal vs. fluid conservative management.
The presence of infection (sepsis or pneumonia) as the primary acute lung injury risk factor significantly modified the relationship between baseline angiopoietin-2 levels and mortality (p = .01 for interaction). In noninfection-related acute lung injury, higher baseline angiopoietin-2 levels were strongly associated with increased mortality (odds ratio, 2.43 per 1-log increase in angiopoietin-2; 95% confidence interval, 1.57-3.75; p < .001). In infection-related acute lung injury, baseline angiopoietin-2 levels were similarly elevated in survivors and nonsurvivors; however, patients whose plasma angiopoietin-2 levels increased from day 0 to day 3 had more than double the odds of death compared with patients whose angiopoietin-2 levels declined over the same period of time (odds ratio, 2.29; 95% confidence interval, 1.54-3.43; p < .001). Fluid-conservative therapy led to a 15% greater decline in angiopoietin-2 levels from day 0 to day 3 (95% confidence interval, 4.6-24.8%; p = .006) compared with fluid-liberal therapy in patients with infection-related acute lung injury. In contrast, plasma levels of von Willebrand factor were significantly associated with mortality in both infection-related and noninfection-related acute lung injury and were not affected by fluid therapy.
Unlike von Willebrand factor, plasma angiopoietin-2 has differential prognostic value for mortality depending on the presence or absence of infection as an acute lung injury risk factor. Fluid conservative therapy preferentially lowers plasma angiopoietin-2 levels over time and thus may be beneficial in part by decreasing endothelial inflammation.

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    • "In critically-ill patients, the release of Ang- 2 directly reflects vascular barrier breakdown [14] [15] and has been proposed to be a potentially strong biomarker in sepsis [9]. Ang-2 levels are higher in patients with severe sepsis compared to patients with or without SIRS or sepsis [16] [17] [18] [19] and increased Ang-2 plasma levels have been associated with worst clinical outcome in patients with major trauma and severe sepsis or shock [20] [21] [22] [23], and in non-survivors compared to survivors [24] [25]. Fewer studies have focused on Ang-1, showing either decreased levels in critically-ill septic or non-septic patients compared to healthy controls, or associating decreased levels at ICU admission with higher mortality [20] [26]. "
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    ABSTRACT: Widespread endothelial activation and dysfunction often precede clinical sepsis. Several endothelium-related molecules have been investigated as potential biomarkers for early diagnosis and/or prognosis of sepsis, providing different results depending on study designs. Such factors include endothelial adhesion molecules like E- and P-selectin, and the intercellular adhesion molecule-1, vascular endothelial cadherin, growth factors such as Angiopoietin-1 and -2 and vascular endothelial growth factor, as well as von Willebrand factor antigen. We sought to investigate whether circulating biomarkers of endothelial activation/dysfunction measured at ICU admission are associated with subsequent sepsis development.
    Full-text · Article · Jul 2014 · Cytokine
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    • "After the initial demonstration that the mechanisms that regulate endothelial barrier formation in the embryo are also involved in the pathological disruption of the endothelial barrier in adults during sepsis [7], several studies explored the role of these proteins as biomarkers of septic shock development. Encouraging results were reported by several groups, and Ang-1 and Ang-2 emerged among the most promising endothelial-associated sepsis biomarkers [8-19]. "
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    ABSTRACT: Endothelial barrier breakdown is a hallmark of septic shock, and proteins that physiologically regulate endothelial barrier integrity are emerging as promising biomarkers of septic shock development. Patients with cancer and febrile neutropenia (FN) present a higher risk of sepsis complications such as septic shock. Nonetheless, these patients are normally excluded or under-represented in sepsis biomarker studies. The aim of our study was to validate the measurement of a panel of microvascular permeability modulators as biomarkers of septic shock development in cancer patients with chemotherapy-associated FN. This was a prospective study of diagnostic accuracy, performed in two distinct in-patient units of a University Hospital. Levels of vascular endothelial growth factor A (VEGF-A), soluble fms-like tyrosine kinase-1 (sFlt-1) and angiopoietin (Ang) 1 and 2 were measured after the onset of neutropenic fever, in conditions designed to mimic the real-world use of a sepsis biomarker, based on our local practice. Patients were categorized based on the development of septic shock by 28 days as an outcome. 99 consecutive patients were evaluated in the study, of which 20 developed septic shock and 79 were classified as non-complicated FN. VEGF-A and sFlt-1 levels were similar between both outcome groups. In contrast, Ang-2 concentrations were increased in patients with septic shock, whereas an inverse finding was observed for Ang-1, resulting in a higher Ang-2/Ang-1 ratio in patients with septic shock (5.29, range 0.58-57.14) compared to non-complicated FN (1.99, range 0.06-64.62; P = 0.01). After multivariate analysis, the Ang-2/Ang-1 ratio remained an independent factor for shock septic development and 28-day mortality. A high Ang-2/Ang-1 ratio can predict the development of septic shock in cancer patients with febrile neutropenia.
    Full-text · Article · Aug 2013 · Critical care (London, England)
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    • ". Calfee and colleagues included an impressive 931 patients with ALI of infectious and noninfectious origin in their study [52]. In non-infection-related ALI, higher baseline Angpt- 2 levels were strongly associated with increased mortality. "
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    ABSTRACT: Critical illness is a descriptive, broad term for a serious clinical condition that can result from enormously heterogeneous etiologies. A common end feature these patients regularly suffer from is the so-called multiple organ dysfunction syndrome (MODS), often a consequence of organ hypoperfusion and ischemia, coagulopathies, overwhelming inflammatory responses, immune paralysis and mitochondrial dysfunction. Mechanistically, endothelial injury and particularly microvascular leakage is a major step in the pathophysiology of MODS and contributes to its mortality. The angiopoietin (Angpt)/Tie2 system consists of the endothelial tyrosine kinase Tie2 and its 4 circulating ligands (Angpt1-4). The balance between the agonistic ligand “Angpt-1" and the antagonistic one “Angpt-2" regulates baseline endothelial barrier function and its response to injury and is therefore considered a gatekeeper of endothelial activation. This paper provides a systematic overview of the Angpt/Tie2 system with respect to (1) its role as a global biomarker of endothelial activation in critical ill patients, (2) its contribution to MODS pathophysiology as a disease mediator, and last but not least (3) putative therapeutic applications to modify the activation state of Tie2 in mice and men.
    Full-text · Article · Aug 2012
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