Longitudinal transcriptomic analysis reveals persistent enrichment of iron homeostasis and erythrocyte function pathways in severe COVID-19 ARDS.

Introduction: The acute respiratory distress syndrome (ARDS) is a common complication of severe COVID-19 and contributes to patient morbidity and mortality. ARDS is a heterogeneous syndrome caused by various insults, and results in acute hypoxemic respiratory failure. Patients with ARDS from COVID-19 may represent a subgroup of ARDS patients with distinct molecular profiles that drive disease outcomes.

Targeted degradation of extracellular mitochondrial aspartyl-tRNA synthetase modulates immune responses.

The severity of bacterial pneumonia can be worsened by impaired innate immunity resulting in ineffective pathogen clearance. We describe a mitochondrial protein, aspartyl-tRNA synthetase (DARS2), which is released in circulation during bacterial pneumonia in humans and displays intrinsic innate immune properties and cellular repair properties. DARS2 interacts with a bacterial-induced ubiquitin E3 ligase subunit, FBXO24, which targets the synthetase for ubiquitylation and degradation, a process that is inhibited by DARS2 acetylation.

RAB7 deficiency impairs pulmonary artery endothelial function and promotes pulmonary hypertension.

Pulmonary arterial hypertension (PAH) is a devastating and progressive disease with limited treatment options. Endothelial dysfunction plays a central role in the development and progression of PAH, yet the underlying mechanisms are incompletely understood. The endosome-lysosome system is important to maintain cellular health, and the small GTPase RAB7 regulates many functions of this system.

Influenza virus reduces ubiquitin E3 ligase MARCH10 expression to decrease ciliary beat frequency.

Respiratory viruses, such as influenza, decrease airway cilia function and expression, which leads to reduced mucociliary clearance and inhibited overall immune defense. Ubiquitination is a posttranslational modification using E3 ligases, which plays a role in the assembly and disassembly of cilia. We examined the role of membrane-associated RING-CH (MARCH) family of E3 ligases during influenza infection and determined that MARCH10, specifically expressed in ciliated epithelial cells, is significantly decreased during influenza infection in mice, human lung epithelial cells, and human lung tissue.

RAB7 deficiency impairs pulmonary artery endothelial function and promotes pulmonary hypertension.

Pulmonary arterial hypertension (PAH) is a devastating and progressive disease with limited treatment options. Endothelial dysfunction plays a central role in development and progression of PAH, yet the underlying mechanisms are incompletely understood. The endosome-lysosome system is important to maintain cellular health and the small GTPase RAB7 regulates many functions of this system.

A role for Toll-like receptor 3 in lung vascular remodeling associated with SARS-CoV-2 infection.

Cardiovascular sequelae of severe acute respiratory syndrome (SARS) coronavirus-2 (CoV-2) disease 2019 (COVID-19) contribute to the complications of the disease. One potential complication is lung vascular remodeling, but the exact cause is still unknown. We hypothesized that endothelial TLR3 insufficiency contributes to lung vascular remodeling induced by SARS-CoV-2.

Inhibiting the Deubiquitinase UCHL1 Reduces SARS-CoV-2 Viral Uptake by ACE2.

Coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a significant public health burden with limited treatment options. Many β-coronaviruses, including SARS-CoV-2, gain entry to host cells through the interaction of SARS-CoV-2 spike protein with membrane-bound ACE2 (angiotensin-converting enzyme 2). Given its necessity for SARS-CoV-2 infection, ACE2 represents a potential therapeutic target in COVID-19.

Regulation of Mesenchymal Cell Fate by Transfer of Active Gasdermin-D via Monocyte-Derived Extracellular Vesicles.

Fibrosis is characterized by inappropriately persistent myofibroblast accumulation and excessive extracellular matrix deposition with the disruption of tissue architecture and organ dysfunction. Regulated death of reparative mesenchymal cells is critical for normal wound repair, but profibrotic signaling promotes myofibroblast resistance to apoptotic stimuli. A complex interplay between immune cells and structural cells underlies lung fibrogenesis.

A p53-TLR3 axis ameliorates pulmonary hypertension by inducing BMPR2 via IRF3.

Pulmonary arterial hypertension (PAH) features pathogenic and abnormal endothelial cells (ECs), and one potential origin is clonal selection. We studied the role of p53 and toll-like receptor 3 (TLR3) in clonal expansion and pulmonary hypertension (PH) via regulation of bone morphogenetic protein (BMPR2) signaling. ECs of PAH patients had reduced p53 expression.

Dichotomous role of integrin-β5 in lung endothelial cells.

Pulmonary arterial hypertension (PAH) is a progressive, devastating disease, and its main histological manifestation is an occlusive pulmonary arteriopathy. One important functional component of PAH is aberrant endothelial cell (EC) function including apoptosis-resistance, unchecked proliferation, and impaired migration. The mechanisms leading to and maintaining physiologic and aberrant EC function are not fully understood.

The E3 ligase subunit FBXO45 binds the interferon-λ receptor and promotes its degradation during influenza virus infection.

Influenza remains a major public health challenge, as the viral infection activates multiple biological networks linked to altered host innate immunity. Following infection, IFN-λ, a ligand crucial for the resolution of viral infections, is known to bind to its cognate receptor, IFNLR1, in lung epithelia. However, little is known regarding the molecular expression and regulation of IFNLR1.

MicroID2: A Novel Biotin Ligase Enables Rapid Proximity-Dependent Proteomics.

Identifying protein-protein and other proximal interactions is central to dissecting signaling and regulatory processes in cells. BioID is a proximity-dependent biotinylation method that uses an "abortive" biotin ligase to detect proximal interactions in cells in a highly reproducible manner. Recent advancements in proximity-dependent biotinylation tools have improved efficiency and timing of labeling, allowing for measurement of interactions on a cellular timescale.

Mice infected with Mycobacterium tuberculosis are resistant to acute disease caused by secondary infection with SARS-CoV-2.

Mycobacterium tuberculosis (Mtb) and SARS-CoV-2 (CoV2) are the leading causes of death due to infectious disease. Although Mtb and CoV2 both cause serious and sometimes fatal respiratory infections, the effect of Mtb infection and its associated immune response on secondary infection with CoV2 is unknown. To address this question we applied two mouse models of COVID19, using mice which were chronically infected with Mtb.

Interferon Lambda Signaling in Macrophages Is Necessary for the Antiviral Response to Influenza.

Interferon lambda (IFNλ) signaling is a promising therapeutic target against viral infection in murine models, yet little is known about its molecular regulation and its cognate receptor, interferon lambda receptor 1 (IFNLR1) in human lung. We hypothesized that the IFNλ signaling axis was active in human lung macrophages. In human alveolar macrophages (HAMs), we observed increased IFNLR1 expression and robust increase in interferon-stimulated gene (ISG) expression in response to IFNλ ligand.

Mice infected with are resistant to secondary infection with SARS-CoV-2.

Unlabelled: (Mtb) and SARS-CoV-2 (CoV2) are the leading causes of death due to infectious disease. Although Mtb and CoV2 both cause serious and sometimes fatal respiratory infections, the effect of Mtb infection and its associated immune response on secondary infection with CoV2 is unknown. To address this question we applied two mouse models of COVID19, using mice which were chronically infected with Mtb.

Clonally selected primitive endothelial cells promote occlusive pulmonary arteriopathy and severe pulmonary hypertension in rats exposed to chronic hypoxia.

One current concept suggests that unchecked proliferation of clonally selected precursors of endothelial cells (ECs) contribute to severe pulmonary arterial hypertension (PAH). We hypothesized that clonally selected ECs expressing the progenitor marker CD117 promote severe occlusive pulmonary hypertension (PH). The remodelled pulmonary arteries of PAH patients harboured CD117 ECs.

Endothelial cells are a source of Nestin expression in Pulmonary Arterial Hypertension.

Uncontrolled proliferation of endothelial cells is essential to the pathogenesis of pulmonary arterial hypertension (PAH). Both proliferation and cytoskeleton reorganization are associated with upregulation of the intermediate filament protein Nestin. Recently, accumulation of Nestin-expressing cells was found in pulmonary vascular lesions of PAH patients.

Toll-like Receptor 3 Is a Therapeutic Target for Pulmonary Hypertension.

Rationale: Pulmonary arterial hypertension (PAH) is characterized by vascular cell proliferation and endothelial cell apoptosis. TLR3 (Toll-like receptor 3) is a receptor for double-stranded RNA and has been recently implicated in vascular protection.

Objectives: To study the expression and role of TLR3 in PAH and to determine whether a TLR3 agonist reduces pulmonary hypertension in preclinical models.

Vascular endothelial growth factor receptor 3 signaling contributes to angioobliterative pulmonary hypertension.

The mechanisms involved in the development of severe angioobliterative pulmonary arterial hypertension (PAH) are multicellular and complex. Many of the features of human severe PAH, including angioobliteration, lung perivascular inflammation, and right heart failure, are reproduced in the Sugen 5416/chronic hypoxia (SuHx) rat model. Here we address, at first glance, the confusing and paradoxical aspect of the model, namely, that treatment of rats with the antiangiogenic vascular endothelial growth factor (VEGF) receptor 1 and 2 kinase inhibitor, Sugen 5416, when combined with chronic hypoxia, causes angioproliferative pulmonary vascular disease.

Histone deacetylase inhibition with trichostatin A does not reverse severe angioproliferative pulmonary hypertension in rats (2013 Grover Conference series).

Pulmonary arterial hypertension (PAH) is a rapidly progressive and devastating disease characterized by remodeling of lung vessels, increased pulmonary vascular resistance, and eventually right ventricular hypertrophy and failure. Because histone deacetylase (HDAC) inhibitors are agents hampering tumor growth and cardiac hypertrophy, they have been attributed a therapeutic potential for patients with PAH. Outcomes of studies evaluating the use of HDAC inhibitors in models of PAH and right ventricular pressure overload have been equivocal, however.

Nuclear factor κB inhibition reduces lung vascular lumen obliteration in severe pulmonary hypertension in rats.

NF-κB and IL-6, a NF-κB downstream mediator, play a central role in the inflammatory response of tissues. We aimed to determine the role of the classical NF-κB pathway in severe pulmonary arterial hypertension (PAH) induced by SU5416 and chronic hypoxia (SuHx) in rats. Tissue samples from patients with idiopathic PAH (iPAH) and control subjects were investigated.

CXCR4 inhibition ameliorates severe obliterative pulmonary hypertension and accumulation of C-kit⁺ cells in rats.

Successful curative treatment of severe pulmonary arterial hypertension with luminal obliteration will require a thorough understanding of the mechanism underlying the development and progression of pulmonary vascular lesions. But the cells that obliterate the pulmonary arterial lumen in severe pulmonary arterial hypertension are incompletely characterized. The goal of our study was to evaluate whether inhibition of CXC chemokine receptor 4 will prevent the accumulation of c-kit⁺ cells and severe pulmonary arterial hypertension.

Vitamin C: a novel regulator of neutrophil extracellular trap formation.

Introduction: Neutrophil extracellular trap (NET) formation was recently identified as a novel mechanism to kill pathogens. However, excessive NET formation in sepsis can injure host tissues. We have recently shown that parenteral vitamin C (VitC) is protective in sepsis.

Attenuation of sepsis-induced organ injury in mice by vitamin C.

Background: Multiple organ dysfunction syndrome (MODS) is the principal cause of death in patients with sepsis. Recent work supports the notion that parenteral vitamin C (VitC) is protective in sepsis through pleiotropic mechanisms. Whether suboptimal levels of circulating VitC increase susceptibility to sepsis-induced MODS is unknown.