A Potential Role for Exosomal Translationally Controlled Tumor Protein Export in Vascular Remodeling in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is characterized by increased proliferation and resistance to apoptosis of pulmonary vascular cells. Increased expression of translationally controlled tumor protein (TCTP), a prosurvival and antiapoptotic mediator, has recently been demonstrated in patients with heritable PAH; however, its role in the pathobiology of PAH remains unclear. Silencing of TCTP in blood outgrowth endothelial cells (BOECs) isolated from control subjects led to significant changes in morphology, cytoskeletal organization, increased apoptosis, and decreased directionality during migration.

TNFα drives pulmonary arterial hypertension by suppressing the BMP type-II receptor and altering NOTCH signalling.

Heterozygous germ-line mutations in the bone morphogenetic protein type-II receptor (BMPR-II) gene underlie heritable pulmonary arterial hypertension (HPAH). Although inflammation promotes PAH, the mechanisms by which inflammation and BMPR-II dysfunction conspire to cause disease remain unknown. Here we identify that tumour necrosis factor-α (TNFα) selectively reduces BMPR-II transcription and mediates post-translational BMPR-II cleavage via the sheddases, ADAM10 and ADAM17 in pulmonary artery smooth muscle cells (PASMCs).

Assessing the efficacy of oral immunotherapy for the desensitisation of peanut allergy in children (STOP II): a phase 2 randomised controlled trial.

Background: Small studies suggest peanut oral immunotherapy (OIT) might be effective in the treatment of peanut allergy. We aimed to establish the efficacy of OIT for the desensitisation of children with allergy to peanuts.

Methods: We did a randomised controlled crossover trial to compare the efficacy of active OIT (using characterised peanut flour; protein doses of 2-800 mg/day) with control (peanut avoidance, the present standard of care) at the NIHR/Wellcome Trust Cambridge Clinical Research Facility (Cambridge, UK).

BMP type II receptor deficiency confers resistance to growth inhibition by TGF-β in pulmonary artery smooth muscle cells: role of proinflammatory cytokines.

Mutations in the bone morphogenetic protein (BMP) type II receptor (BMPR-II) underlie most cases of heritable pulmonary arterial hypertension (HPAH) and a significant proportion of sporadic cases. Pulmonary artery smooth muscle cells (PASMCs) from patients with pulmonary arterial hypertension (PAH) not only exhibit attenuated growth suppression by BMPs, but an abnormal mitogenic response to transforming growth factor (TGF)-β1. We sought to define the mechanism underlying this loss of the antiproliferative effects of TGF-β1 in BMPR-II-deficient PASMCs.

Eotaxin-1/CC chemokine ligand 11: a novel eosinophil survival factor secreted by human pulmonary artery endothelial cells.

Airway eosinophilia plays a major role in the pathogenesis of asthma with the inhibition of apoptosis by GM-CSF and IL-5 proposed as a mechanism underlying prolonged eosinophil survival. In vivo and ex vivo studies have indicated the capacity of interventions that drive human eosinophil apoptosis to promote the resolution of inflammation. Far less is known about the impact of transendothelial migration on eosinophil survival, in particular, the capacity of endothelial cell-derived factors to contribute toward the apoptosis-resistant phenotype characteristic of airway-resident eosinophils.

Aminopeptidase N (CD13) regulates tumor necrosis factor-alpha-induced apoptosis in human neutrophils.

Neutrophil apoptosis plays a central role in the resolution of granulocytic inflammation. We have shown previously that tumor necrosis factor-alpha (TNFalpha) enhances the rate of neutrophil apoptosis at early time points via a mechanism involving both TNF receptor (TNFR) I and TNFRII. Here we reveal a marked but consistent variation in the magnitude of the pro-apoptotic effect of TNFalpha in neutrophils isolated from healthy donors, and we show that inhibition of cell surface aminopeptidase N (APN) using actinonin, bestatin, or inhibitory peptides significantly enhanced the efficacy of TNFalpha-induced killing.

z-VAD-fmk augmentation of TNF alpha-stimulated neutrophil apoptosis is compound specific and does not involve the generation of reactive oxygen species.

In most cell types constitutive and ligand-induced apoptosis is a caspase-dependent process. In neutrophils, however, the broad-spectrum caspase inhibitor z-VAD-fmk enhances tumor necrosis factor-alpha (TNF alpha)-induced cell death, and this has been interpreted as evidence for caspase-dependent and -independent cell death pathways. Our aim was to determine the specificity of the effect of z-VAD-fmk in neutrophils and define the potential mechanism of action.

The survival effect of TNF-alpha in human neutrophils is mediated via NF-kappa B-dependent IL-8 release.

The capacity of cytokines to modulate neutrophil apoptosis is thought to be a major factor influencing the resolution of granulocytic inflammation. We have previously shown that the late survival effect of TNF-alpha in human neutrophils involves activation of both NF-kappa B and phosphoinositide 3-kinase (PI3-kinase) pathways. In this study, we address how these pathways integrate to prevent cell death.

Involvement of a ferroprotein sensor in hypoxia-mediated inhibition of neutrophil apoptosis.

Neutrophil apoptosis represents a major mechanism involved in the resolution of acute inflammation. In contrast to the effect of hypoxia observed in many other cell types, oxygen deprivation, as we have shown, causes a profound but reversible delay in the rate of constitutive apoptosis in human neutrophils when aged in vitro. This effect was mimicked by exposing cells to 2 structurally unrelated iron-chelating agents, desferrioxamine (DFO) and hydroxypyridines (CP-94), and it appeared specific for hypoxia in that no modulation of apoptosis was observed with mitochondrial electron transport inhibitors, glucose deprivation, or heat shock.