Modeling lung endothelial dysfunction in sepsis-associated ARDS using a microphysiological system.

Endothelial dysfunction is a critical feature of acute respiratory distress syndrome (ARDS) associated with higher disease severity and worse outcomes. Preclinical in vivo models of sepsis and ARDS have failed to yield useful therapies in humans, perhaps due to interspecies differences in inflammatory responses and heterogeneity of human host responses. Use of microphysiological systems (MPS) to investigate lung endothelial function may shed light on underlying mechanisms and targeted treatments for ARDS.

Modeling Sepsis-Associated ARDS Using a Lung Endothelial Microphysiological System.

Acute respiratory distress syndrome due to non-pulmonary causes exhibits prominent endothelial activation which is challenging to assess in critically ill patients. Preclinical models of sepsis and ARDS have failed to yield useful therapies in humans, perhaps due to interspecies differences in inflammatory responses. Use of microphysiological systems (MPS) offer improved fidelity to human biological responses and better predict pharmacological responses than traditional culture.

Early Plasma Nuclear DNA, Mitochondrial DNA, and Nucleosome Concentrations Are Associated With Acute Kidney Injury in Critically Ill Trauma Patients.

Unlabelled: Circulating nucleic acids, alone and in complex with histones as nucleosomes, have been proposed to link systemic inflammation and coagulation after trauma to acute kidney injury (AKI). We sought to determine the association of circulating nucleic acids measured at multiple time points after trauma with AKI risk.

Design: We conducted a prospective cohort study of trauma patients, collecting plasma on presentation and at 6, 12, 24, and 48 hours, defining AKI over the first 6 days by Kidney Disease Improving Global Outcomes serum creatinine and dialysis criteria.

Regional citrate and systemic heparin are adequate to maintain filter half-life for COVID-19 patients on continuous renal replacement therapy.

Introduction: The aim of our study is to compare clotting of CRRT filters in patients with COVID-19-associated AKI versus septic shock-associated AKI.

Methods: Retrospective study of adult ICU patients with COVID-19 compared to those with septic shock admitted to a tertiary hospital April-October 2020. Independent t test and chi-square test used to determine statistical significance of CRRT filter clotting between the two groups.

Thromboelastography to Detect Hypercoagulability and Reduced Fibrinolysis in Coronavirus Disease 2019 Acute Respiratory Distress Syndrome Patients.

Objectives: Microvascular thrombosis contributes to acute respiratory distress syndrome pathophysiology and has been demonstrated in coronavirus disease 2019-associated acute respiratory distress syndrome. Clinical laboratory measurements of coagulation and disseminated intravascular coagulation, such as coagulation factor function, platelet count, and fibrinogen, may not fully reflect the extent of microvascular thrombosis present in these patients. We investigated thromboelastography in patients with coronavirus disease 2019-associated acute respiratory distress syndrome with the objective of characterizing suspected coagulopathy and impaired fibrinolysis.

RAGE interacts with the necroptotic protein RIPK3 and mediates transfusion-induced danger signal release.

RBC transfusion is associated with increased morbidity and mortality in critically ill patients. Endothelial cell necroptosis and subsequent damage-associated molecular pattern (DAMP) release has been identified as a mechanism of injury following RBC transfusion. Mounting evidence implicates the pro-inflammatory pattern recognition receptor, Receptor for Advanced Glycation End Products (RAGE), in initiating cell death programmes such as necroptosis.

Collateral damage: necroptosis in the development of lung injury.

Cell death is increasingly recognized as a driving factor in the development of acute lung injury. Necroptosis, an immunogenic regulated cell death program important in innate immunity, has been implicated in the development of lung injury in a diverse range of conditions. Characterized by lytic cell death and consequent extracellular release of endogenous inflammatory mediators, necroptosis can be both beneficial and deleterious to the host, depending on the context.

Plasma Mitochondrial DNA Levels Are Associated With ARDS in Trauma and Sepsis Patients.

Background: Critically ill patients who develop ARDS have substantial associated morbidity and mortality. Circulating mitochondrial DNA (mtDNA) released during critical illness causes endothelial dysfunction and lung injury in experimental models. This study hypothesized that elevated plasma mtDNA is associated with ARDS in critically ill patients with trauma and sepsis.

Plasma receptor interacting protein kinase-3 levels are associated with acute respiratory distress syndrome in sepsis and trauma: a cohort study.

Background: Necroptosis, a form of programmed cell death mediated by receptor interacting serine/threonine-protein kinase-3 (RIPK3), is implicated in murine models of acute respiratory distress syndrome (ARDS). We hypothesized that plasma RIPK3 concentrations in sepsis and trauma would be associated with ARDS development and that plasma RIPK3 would reflect changes in lung tissue RIPK3 in a murine model of systemic inflammation.

Methods: We utilized prospective cohort studies of critically ill sepsis (n = 120) and trauma (n = 180) patients and measured plasma RIPK3 at presentation and 48 h.

Genotypes associated with tacrolimus pharmacokinetics impact clinical outcomes in lung transplant recipients.

Most lung transplantation immunosuppression regimens include tacrolimus. Single nucleotide polymorphisms (SNPs) in genes important to tacrolimus bioavailability and clearance (ABCB1, CYP3A4, and CYP3A5) are associated with differences in tacrolimus pharmacokinetics. We hypothesized that polymorphisms in these genes would impact immunosuppression-related outcomes.

Red Blood Cells Homeostatically Bind Mitochondrial DNA through TLR9 to Maintain Quiescence and to Prevent Lung Injury.

Rationale: Potentially hazardous CpG-containing cell-free mitochondrial DNA (cf-mtDNA) is routinely released into the circulation and is associated with morbidity and mortality in critically ill patients. How the body avoids inappropriate innate immune activation by cf-mtDNA remains unknown. Because red blood cells (RBCs) modulate innate immune responses by scavenging chemokines, we hypothesized that RBCs may attenuate CpG-induced lung inflammation through direct scavenging of CpG-containing DNA.

Short lung transplant donor telomere length is associated with decreased CLAD-free survival.

Telomere length (TL) decreases with cellular ageing and biological stressors. As advanced donor and recipient ages are risk factors for chronic lung allograft dysfunction (CLAD), we hypothesised that decreased age-adjusted donor TL would predict earlier onset of CLAD. Shorter donor TL was associated with increased risk of CLAD or death (HR 1.

Clinician Perception of the Effectiveness of an Automated Early Warning and Response System for Sepsis in an Academic Medical Center.

Rationale: We implemented an electronic early warning and response system (EWRS) to improve detection of and response to severe sepsis. Sustainability of such a system requires stakeholder acceptance. We hypothesized that clinicians receiving such alerts perceive them to be useful and effective.