The hepcidin-ferroportin axis influences mitochondrial function, proliferation, and migration in pulmonary artery endothelial and smooth muscle cells.

Elevated circulating hepcidin levels have been reported in patients with pulmonary artery hypertension (PAH). Hepcidin has been shown to promote proliferation of human pulmonary artery smooth muscle cells (PASMCs) in vitro, suggesting a potential role in PAH pathogenesis. However, the role of human pulmonary artery endothelial cells (PAECs) as either a source of hepcidin, or the effect of hepcidin on PAEC function is not as well described.

Human pulmonary artery endothelial cells upregulate ACE2 expression in response to iron-regulatory elements: Potential implications for SARS-CoV-2 infection.

Vascular endothelial cell dysfunction is reported in severe coronavirus disease 2019 disease, however, controversy exists regarding levels of angiotensin-converting enzyme 2 (ACE2) expression, a coreceptor for severe acute respiratory syndrome coronavirus 2, in these cells. We report ACE2 expression and positive regulation by both interleuki-6, hepcidin, and ferroportin knock-down in pulmonary artery endothelial cells with potential implications for viral infection.

Clotting Dysfunction in Sepsis: A Role for ROS and Potential for Therapeutic Intervention.

Sepsis is regarded as one of the main causes of death among the critically ill. Pathogen infection results in a host-mediated pro-inflammatory response to fight infection; as part of this response, significant endogenous reactive oxygen (ROS) and nitrogen species (RNS) production occurs, instigated by a variety of sources, including activated inflammatory cells, such as neutrophils, platelets, and cells from the vascular endothelium. Inflammation can become an inappropriate self-sustaining and expansive process, resulting in sepsis.

Phagomimetic action of antibiotics: Revisited. How do antibiotics know where to go?

Phagocytic cells know exactly where an infection is by following chemotactic signals. The phagocytosis of bacteria results in a 'respiratory burst' in which superoxide radicals are released. We have previously compared the release of reactive oxygen species (ROS) by antibiotics, during electron transfer reactions, to this event.

Plasma S100A8/A9 heterodimer is an early prognostic marker of acute kidney injury associated with cardiac surgery.

Aim: We investigated whether plasma levels of the inflammation marker S100A8/A9, could predict acute kidney injury (AKI) onset in patients undergoing cardiac surgery necessitating cardiopulmonary bypass (CPB).

Patients & Methods: Plasma levels of S100A8/A9 and other neutrophil cytosolic proteins were measured in 39 patients pre- and immediately post-CPB.

Results: All markers increased significantly post-CPB with S100A8/A9, S100A12 and myeloperoxidase levels significantly higher in patients who developed AKI within 7 days.

Development of a novel UHPLC-MS/MS-based platform to quantify amines, amino acids and methylarginines for applications in human disease phenotyping.

Amine quantification is an important strategy in patient stratification and personalised medicine. This is because amines, including amino acids and methylarginines impact on many homeostatic processes. One important pathway regulated by amine levels is nitric oxide synthase (NOS).

The Hepcidin/Ferroportin axis modulates proliferation of pulmonary artery smooth muscle cells.

Studies were undertaken to examine any role for the hepcidin/ferroportin axis in proliferative responses of human pulmonary artery smooth muscle cells (hPASMCs). Entirely novel findings have demonstrated the presence of ferroportin in hPASMCs. Hepcidin treatment caused increased proliferation of these cells most likely by binding ferroportin resulting in internalisation and cellular iron retention.

Pulmonary Arterial Hypertension: Iron Matters.

The interplay between iron and oxygen is longstanding and central to all aerobic life. Tight regulation of these interactions including homeostatic regulation of iron utilization ensures safe usage of this limited resource. However, when control is lost adverse events can ensue, which are known to contribute to an array of disease processes.

Metabolomic profiling of amines in sepsis predicts changes in NOS canonical pathways.

Rationale: Nitric oxide synthase (NOS) is a biomarker/target in sepsis. NOS activity is driven by amino acids, which cycle to regulate the substrate L-arginine in parallel with cycles which regulate the endogenous inhibitors ADMA and L-NMMA. The relationship between amines and the consequence of plasma changes on iNOS activity in early sepsis is not known.

Modified criteria for the systemic inflammatory response syndrome improves their utility following cardiac surgery.

Background: Debate remains regarding whether the systemic inflammatory response syndrome (SIRS) identifies patients with clinically important inflammation. Defining criteria may be disproportionately sensitive and lack specificity. We investigated the incidence and evolution of SIRS in a homogenous population (following cardiac surgery) over 7 days to establish the relationship between SIRS and outcome, modeling alternative permutations of the criteria to increase their discriminatory power for mortality, length of stay, and organ dysfunction.

Methemoglobin-induced signaling and chemokine responses in human alveolar epithelial cells.

Diffuse alveolar hemorrhage is characterized by the presence of red blood cells and free hemoglobin in the alveoli and complicates a number of serious medical and surgical lung conditions including the pulmonary vasculitides and acute respiratory distress syndrome. In this study we investigated the hypothesis that exposure of human alveolar epithelial cells to hemoglobin and its breakdown products regulates chemokine release via iron- and oxidant-mediated activation of the transcription factor NF-κB. Methemoglobin alone stimulated the release of IL-8 and MCP-1 from A549 cells via activation of the NF-κB pathway; additionally, IL-8 required ERK activation and MCP-1 required JNK activation.

Association between preoperative plasma sRAGE levels and recovery from cardiac surgery.

Background: The receptor for advanced glycation end products (RAGE) is an inflammation-perpetuating receptor, and soluble RAGE (sRAGE) is a marker of cellular RAGE expression. This study investigated whether raised plasma levels prior to surgery of sRAGE or S100A8/A9 (a RAGE ligand) were associated with longer duration of hospital care in patients undergoing cardiac surgery necessitating cardiopulmonary bypass.

Methods: Patients (n = 130) undergoing elective cardiac surgery were enrolled prospectively.

Biomarkers of lung injury after one-lung ventilation for lung resection.

Background And Objective: Acute lung injury contributes to the mortality of patients after lung resection and one-lung ventilation (OLV). The objective of this study was to characterise the effect of lung resection and OLV on proposed biomarkers of lung injury in exhaled breath condensate (EBC) and plasma.

Methods: In adults undergoing lung resection, EBC was collected before and at 30-min intervals during OLV.

The RAGE axis in systemic inflammation, acute lung injury and myocardial dysfunction: an important therapeutic target?

Background: The sepsis syndromes, frequently complicated by pulmonary and cardiac dysfunction, remain a major cause of death amongst the critically ill. Targeted therapies aimed at ameliorating the systemic inflammation that characterises the sepsis syndromes have largely yielded disappointing results in clinical trials. Whilst there are many potential reasons for lack of success of clinical trials, one possibility is that the pathways targeted, to date, are only modifiable very early in the course of the illness.

Increased plasma thioredoxin levels in patients with sepsis: positive association with macrophage migration inhibitory factor.

Purpose: To establish the relationship between plasma levels of thioredoxin (Trx) and macrophage migration inhibitory factor (MIF) in systemic inflammatory stress syndrome (SIRS)/sepsis.

Methods: Enzyme-linked immunosorbent assay measurements of Trx, MIF, IL-6, -8, and -10 and enzyme-linked fluorescent assay determination of procalcitonin (PCT) in plasma from patients with SIRS/sepsis, neutropenic sepsis, healthy volunteers and pre-oesophagectomy patients.

Results: Thioredoxin was significantly higher in SIRS/sepsis patients [101.

Pathogenesis of the systemic inflammatory syndrome and acute lung injury: role of iron mobilization and decompartmentalization.

Changes in iron homeostatic responses routinely accompany infectious or proinflammatory insults. The systemic inflammatory response syndrome (SIRS) and the development of acute lung injury (ALI) feature pronounced systemic and lung-specific alterations in iron/heme mobilization and decompartmentalization; such responses may be of pathological significance for both the onset and progression of acute inflammation. The potential for excessive iron-catalyzed oxidative stress, altered proinflammatory redox signaling, and provision of iron as a microbial growth factor represent obvious adverse aspects of altered in vivo iron handling.

Variation in iron homeostasis genes between patients with ARDS and healthy control subjects.

Background: Abnormal plasma and lung iron mobilization is associated with the onset and progression of ARDS and is detectable in specific at-risk populations. Patients with ARDS also have pronounced oxidative and nitrosative stress that can be catalyzed and thereby aggravated by the bioavailability of redox active iron. ARDS of pulmonary and extrapulmonary origin may differ pathophysiologically and require different ventilatory strategies.

Arterial carboxyhemoglobin level and outcome in critically ill patients.

Objective: Arterial carboxyhemoglobin is elevated in patients with critical illness. It is an indicator of the endogenous production of carbon monoxide by the enzyme heme oxygenase, which modulates the response to oxidant stress. The objective was to explore the hypothesis that arterial carboxyhemoglobin level is associated with inflammation and survival in patients requiring cardiothoracic intensive care.