Bench-to-bedside review: Angiopoietin signalling in critical illness – a future target?

Abstract

Multiple organ dysfunction syndrome (MODS) occurs in response to major insults such as sepsis, severe haemorrhage, trauma, major surgery and pancreatitis. The mortality rate is high despite intensive supportive care. The pathophysiological mechanism underlying MODS are not entirely clear, although several have been proposed. Overwhelming inflammation, immunoparesis, occult oxygen debt and other mechanisms have been investigated, and -despite many unanswered questions -therapies targeting these mechanisms have been developed. Unfortunately, only a few interventions, usually those targeting multiple mechanisms at the same time, have appeared to be beneficial. We clearly need to understand better the mechanisms that underlie MODS. The endothelium certainly plays an active role in MODS. It functions at the intersection of several systems, including inflammation, coagulation, haemodynamics, fluid and electrolyte balance, and cell migration. An important regulator of these systems is the angiopoietin/ Tie2 signalling system. In this review we describe this signalling system, giving special attention to what is known about it in critically ill patients and its potential as a target for therapy. IntroductionCritical illness is a life-threatening disease by definition. Patients treated for critical illness in the intensive care unit have underlying causes such as infection, trauma, major surgery, hemorrhagic shock, pancreatitis and other major insults. Despite maximal supportive care, severely ill patients treated in intensive care units are still likely to die, usually after an episode of increasing failure of multiple organs [1].The mechanisms that underlie multiple organ dysfunction syndrome (MODS) are not known [2], although several have been proposed, including overwhelming infection or immune response, immune paralysis, occult oxygen debt and mitochondrial dysfunction [3][4][5]. Although these potential mechanisms have features in common, it is not clear whether MODS is a final common pathway or when it is engaged. The innate and adaptive immune systems, coagulation, and hormonal and neuronal signalling are undoubtedly involved and are all connected. For example, the hypoxic response is linked to innate immunity and inflammation by the transcription factor nuclear factor-κB (NF-κB) [6]. It is no coincidence that the few interventions that appear to be of benefit, although this is still under debate, have pleiotropic mechanisms of action [7][8][9]. Thus, it seems reasonable to study the intersections between and within cellular and molecular systems to elucidate the interactions and to develop therapeutic options.One of the central cellular players in this system is the endothelial cell (EC). Once thought to serve as an inert vascular lining, ECs are highly heterogeneous and constitute an active disseminated organ throughout the circulatory system. ECs form the border between every organ and the bloodstream and thus with the rest of the body. The EC receives and gives signals, stores active substances of mul...

Lipopolysaccharide (LPS)-mediated Angiopoietin-2-dependent Autocrine Angiogenesis Is Regulated by NADPH Oxidase 2 (Nox2) in Human Pulmonary Microvascular Endothelial Cells

“…To the best of our knowledge, this is one of the initial reports to demonstrate regulation of Ang2 expression and proinflammatory angiogenesis by Nox-dependent signaling. Increased Ang2 expression in the systemic circulation or in the lung has been associated with mortality in humans with sepsis, severity of acute lung injury, and with development of BPD in premature infants (30,31,51). Although we showed that mouse lung endothelial cells express increased Ang2 and Tie2 after systemic LPS, the rest of our data were obtained in primary cells in vitro, and, therefore, verification of the results of this study in animal models expressing angiogenic factors in a tissue-restricted manner will enable us to better understand the significance of these findings.…”

“…Although we showed that mouse lung endothelial cells express increased Ang2 and Tie2 after systemic LPS, the rest of our data were obtained in primary cells in vitro, and, therefore, verification of the results of this study in animal models expressing angiogenic factors in a tissue-restricted manner will enable us to better understand the significance of these findings. This assumes translational significance because inhibiting Ang2 using antibodies or modulating Nox2 activity are emerging as promising strategies to decrease lung injury in bacterial sepsis (51,52).…”

Imbalance of Angiopoietin-1 and Angiopoetin-2 in Severe Dengue and Relationship with Thrombocytopenia, Endothelial Activation, and Vascular Stability

“…9 Angiopoietin-1-mediated Tie2 activation maintains the quiescent state of the endothelium by stabilizing endothelial cell-cell junctions and by countering the permeabilizing effects of VEGF. 10 Angiopoietin-2 antagonizes the effects of Ang-1; it destabilizes the endothelium by disrupting cell-cell adhesion and primes the endothelial cells to the effects of pro-inflammatory cytokines and VEGF.…”

Shedding of the endothelial receptor tyrosine kinase Tie2 correlates with leukemic blast burden and outcome after allogeneic hematopoietic stem cell transplantation for AML

“…As circulating or matrix-bound molecules, angiopoietin-1 (Ang-1) and its antagonist angiopoietin-2 (Ang-2) bind to the extracellular domain of the receptor tyrosine kinase Tie2, which is almost exclusively expressed on endothelial cells [15][16][17]. Produced by vascular smooth muscle cells (SMCs) and precursor pericytes, Ang-1-induced activation of the Tie2 receptor promotes quiescence and structural integrity of mature vessels, thus protecting the endothelium from activation by cytokines and growth factors [18][19][20][21][22][23]. In contrast, Ang-2 disrupts the constitutive Ang-1/Tie2 signaling by preventing Ang-1 from binding to the common receptor [15,[24][25][26].…”