Unlocking the Untapped Potential of Endothelial Kinase and Phosphatase Involvement in Sepsis for Drug Treatment Design

Sepsis is a devastating clinical condition that can lead to multiple organ failure and death. Despite advancements in our understanding of molecular mechanisms underlying sepsis and sepsis-associated multiple organ failure, no effective therapeutic treatment to directly counteract it has yet been established. The endothelium is considered to play an important role in sepsis. This review highlights a number of signal transduction pathways involved in endothelial inflammatory activation and dysregulated endothelial barrier function in response to sepsis conditions. Within these pathways – NF-κB, Rac1/RhoA GTPases, AP-1, APC/S1P, Angpt/Tie2, and VEGF/VEGFR2 – we focus on the role of kinases and phosphatases as potential druggable targets for therapeutic intervention. Animal studies and clinical trials that have been conducted for this purpose are discussed, highlighting reasons why they might not have resulted in the expected outcomes, and which lessons can be learned from this. Lastly, opportunities and challenges that sepsis and sepsis-associated multiple organ failure research are currently facing are presented, including recommendations on improved experimental design to increase the translational power of preclinical research to the clinic

Does low angiopoietin-1 predict adverse outcome in sepsis?

Endothelial injury has emerged as a crucial early event in the pathogenesis of microcirculatory dysfunction, capillary leakage and multiorgan dysfunction syndrome. The endothelial-specific angiopoietin (Ang)/Tie2 ligand-receptor system has been identified recently as a nonredundant regulator of endothelial responsiveness. Ang-1 is a Tie2 agonist and promotes endothelial stabilization and quiescence, whereas Ang-2 is a Tie2 antagonist and promotes endothelial activation, destabilization, and inflammation. While the mediator function of both Ang-1 and Ang-2 has been well established in preclinical research, only Ang-2 has been identified as a clinically useful biomarker in the critical care arena. In the previous issue of Critical Care, Mankhambo and colleagues report on angiogenic factors in Malawian children with severe bacterial infection. Among those children, diminished levels of the vessel-protective factor Ang-1 remained a significant predictor of outcome after multivariate adjustment. Whether low Ang-1 represents an important risk factor of adverse outcome in critically ill adults remains to be seen

Intra-abdominal hypertension and abdominal compartment syndrome in critically ill patients:A narrative review of past, present, and future steps

BACKGROUND AND OBJECTIVE: Intra-abdominal hypertension is frequently present in critically ill patients and is an independent predictor for mortality. In this narrative review, we aim to provide a comprehensive overview of current insights into intra-abdominal pressure monitoring, intra-abdominal hypertension, and abdominal compartment syndrome. The focus of this review is on the pathophysiology, risk factors and outcome of intra-abdominal hypertension and abdominal compartment syndrome, and on therapeutic strategies, such as non-operative management, surgical decompression, and management of the open abdomen. Finally, future steps are discussed, including propositions of what a future guideline should focus on. CONCLUSIONS: Pathological intra-abdominal pressure is a continuum ranging from mild intra-abdominal pressure elevation without clinically significant adverse effects to substantial increase in intra-abdominal pressure with serious consequences to all organ systems. Intra-abdominal pressure monitoring should be performed in all patients at risk of intra-abdominal hypertension. Although continuous intra-abdominal pressure monitoring is feasible, this is currently not standard practice. There are a number of effective non-operative medical interventions that may be performed early in the patient's course to reduce intra-abdominal pressure and decrease the need for surgical decompression. Abdominal decompression can be life-saving when abdominal compartment syndrome is refractory to non-operative treatment and should be performed expeditiously. The objectives of open abdomen management are to prevent fistula and to achieve delayed fascial closure at the earliest possible time. There is still a lot to learn and change. The 2013 World Society of Abdominal Compartment Syndrome guidelines should be updated and multicentre studies should evaluate the effect of intra-abdominal hypertension treatment on patient outcome

Identification of LPS-Activated Endothelial Subpopulations With Distinct Inflammatory Phenotypes and Regulatory Signaling Mechanisms

Sepsis is a life-threatening condition caused by a dysregulated host response to infection. Endothelial cells (EC) are actively involved in sepsis-associated (micro)vascular disturbances and subsequent organ dysfunction. Lipopolysaccharide (LPS), a Gram-negative bacterial product, can activate EC leading to the expression of pro-inflammatory molecules. This process is molecularly regulated by specific receptors and distinct, yet poorly understood intracellular signaling pathways. LPS-induced expression of endothelial adhesion molecules E-selectin and VCAM-1 in mice was previously shown to be organ- and microvascular-specific. Here we report that also within renal microvascular beds the endothelium expresses different extents of E-selectin and VCAM-1. This heterogeneity was recapitulated in vitro in LPS-activated human umbilical vein EC (HUVEC). Within 2 h after LPS exposure, four distinct HUVEC subpopulations were visible by flow cytometric analysis detecting E-selectin and VCAM-1 protein. These encompassed E-selectin−/VCAM-1− (–/–), E-selectin+/VCAM-1− (E-sel+), E-selectin+/VCAM-1+ (+/+), and E-selectin−/VCAM-1+ (VCAM-1+) subpopulations. The formation of subpopulations was a common response of endothelial cells to LPS challenge. Using fluorescence-activated cell sorting (FACS) we demonstrated that the +/+ subpopulation also expressed the highest levels of inflammatory cytokines and chemokines. The differences in responsiveness of EC subpopulations could not be explained by differential expression of LPS receptors TLR4 and RIG-I. Functional studies, however, demonstrated that the formation of the E-sel+ subpopulation was mainly TLR4-mediated, while the formation of the +/+ subpopulation was mediated by both TLR4 and RIG-I. Pharmacological blockade of NF-κB and p38 MAPK furthermore revealed a prominent role of their signaling cascades in E-sel+ and +/+ subpopulation formation. In contrast, the VCAM-1+ subpopulation was not controlled by any of these signaling pathways. Noteworthy is the existence of a “quiescent” subpopulation that was devoid of the two adhesion molecules and did not express cytokines or chemokines despite LPS exposure. Summarizing, our findings suggest that LPS activates different signaling mechanisms in EC that drive heterogeneous expression of EC inflammatory molecules. Further characterization of the signaling pathways involved will enhance our understanding of endothelial heterogeneous responses to sepsis related stimuli and enable the future design of effective therapeutic strategies to interfere in these processes to counteract sepsis-associated organ dysfunction