Autoimmune Encephalitis Induced by SARS-CoV-2 Infection Treated with Thymectomy.

Thymomas have been associated with the generation of paraneoplastic autoantibodies to neurogenic epitopes, collapsin-response-mediator protein-5 receptor (CRMP-5) and alpha-amino-3-hydroxyl-5methyl-4isoxazolepropionic acid receptor (AMPAR), in patients with acute viral infection. We report a patient with thymoma and myasthenia gravis, with SARS-CoV-2 infection, who became comatose secondary to autoimmune encephalitis. Plasmapheresis, high-dose steroids, pyridostigmine, eculizumab, and rituximab did not restore neurologic function.

Store-operated Ca entry is involved in endothelium-to-mesenchymal transition in lung vascular endothelial cells.

Unlabelled: Endothelial-to-mesenchymal transition (EndMT) is a biological process that converts endothelial cells to mesenchymal cells with increased proliferative and migrative abilities. EndMT has been implicated in the development of pulmonary vascular remodeling in pulmonary arterial hypertension (PAH), a fatal and progressive lung vascular disease. Transforming growth factor β (TGF-β ), an inflammatory cytokine, is known to induce EndMT in many types of endothelial cells including lung vascular endothelial cells (LVEC).

Delta-like ligand 4 inhibitor drug treatment induces pulmonary hypertension in cancer clinical trials.

Delta-like ligand 4 (DLL-4) inhibitor drugs are an emerging cancer treatment. In clinical trials for solid organ malignancies, intravenous administration of monoclonal antibodies that inhibit DLL-4 is associated with development of pulmonary hypertension, in the absence of left ventricular dysfunction. Analysis of 13 clinical trials showed that pulmonary hypertension is a complication of DLL-4 inhibition.

Apelin modulates inflammation and leukocyte recruitment in experimental autoimmune encephalomyelitis.

Demyelination due to autoreactive T cells and inflammation in the central nervous system are principal features of multiple sclerosis (MS), a chronic and highly disabling human disease affecting brain and spinal cord. Here, we show that treatment with apelin, a secreted peptide ligand for the G protein-coupled receptor APJ/Aplnr, is protective in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Apelin reduces immune cell entry into the brain, delays the onset and reduces the severity of EAE.

NOTCH3 and Pulmonary Arterial Hypertension.

NOTCH3 receptor signaling has been linked to the regulation of smooth muscle cell proliferation and the maintenance of smooth muscle cells in an undifferentiated state. Pulmonary arterial hypertension (World Health Organization Group 1 idiopathic disease: PAH) is a fatal disease characterized clinically by elevated pulmonary vascular resistance caused by extensive vascular smooth muscle cell proliferation, perivascular inflammation, and asymmetric neointimal hyperplasia in precapillary pulmonary arteries. In this review, a detailed overview of the specific role of NOTCH3 signaling in PAH, including its mechanisms of activation by a select ligand, downstream signaling effectors, and physiologic effects within the pulmonary vascular tree, is provided.

BRCC3 Regulation of ALK2 in Vascular Smooth Muscle Cells: Implication in Pulmonary Hypertension.

Background: An imbalance of antiproliferative BMP (bone morphogenetic protein) signaling and proliferative TGF-β (transforming growth factor-β) signaling is implicated in the development of pulmonary arterial hypertension (PAH). The posttranslational modification (eg, phosphorylation and ubiquitination) of TGF-β family receptors, including BMPR2 (bone morphogenetic protein type 2 receptor)/ALK2 (activin receptor-like kinase-2) and TGF-βR2/R1, and receptor-regulated Smads significantly affects their activity and thus regulates the target cell fate. BRCC3 modifies the activity and stability of its substrate proteins through K63-dependent deubiquitination.

MED1 Regulates BMP/TGF-β in Endothelium: Implication for Pulmonary Hypertension.

Background: Dysregulated BMP (bone morphogenetic protein) or TGF-β (transforming growth factor beta) signaling pathways are imperative in idiopathic and familial pulmonary arterial hypertension (PAH) as well as experimental pulmonary hypertension (PH) in rodent models. MED1 (mediator complex subunit 1) is a key transcriptional co-activator and KLF4 (Krüppel-like factor 4) is a master transcription factor in endothelium. However, MED1 and KLF4 epigenetic and transcriptional regulations of the BMP/TGF-β axes in pulmonary endothelium and their dysregulations leading to PAH remain elusive.

Mechanosensitive cation currents through TRPC6 and Piezo1 channels in human pulmonary arterial endothelial cells.

Mechanosensitive cation channels and Ca influx through these channels play an important role in the regulation of endothelial cell functions. Transient receptor potential canonical channel 6 (TRPC6) is a diacylglycerol-sensitive nonselective cation channel that forms receptor-operated Ca channels in a variety of cell types. Piezo1 is a mechanosensitive cation channel activated by membrane stretch and shear stress in lung endothelial cells.

Racial and ethnic variation in referral times for thoracic oncologic surgery in a major metropolitan area.

Objective: The study objective was to understand the impact of race/ethnicity on access to thoracic surgical care for patients undergoing lung resection for cancer.

Methods: We performed a retrospective analysis on 206 consecutive patients who underwent lung resection for cancer (120 female, 86 male; median age 66 years), with respect to how race and ethnicity impact time to referral for thoracic surgery to a major healthcare center. Time between initial radiographic appearance of a lung nodule/mass 1 cm or greater to surgical referral and time from surgical referral to operation were evaluated for 121 White, 30 Asian, 26 Hispanic, 12 African American, and 17 mixed or other race patients.

In Vivo and Ex Vivo Experimental Approach for Studying Functional Role of Notch in Pulmonary Vascular Disease.

Pulmonary arterial hypertension (PAH) is a severe disease characterized by sustained vasoconstriction, concentric wall thickening and vascular remodeling leading to increased pulmonary vascular resistance, causing right heart failure and death. Acute alveolar hypoxia causes pulmonary vasoconstriction, while sustained hypoxia causes pulmonary hypertension (PH). Activation of Notch signaling is implicated in the development of PAH and chronic hypoxia induced PH via partially its enhancing effect on Ca signaling in pulmonary arterial smooth muscle cells (PASMCs).

JAGGED-NOTCH3 signaling in vascular remodeling in pulmonary arterial hypertension.

Within the pulmonary arterial tree, the NOTCH3 pathway is crucial in controlling vascular smooth muscle cell proliferation and maintaining smooth muscle cells in an undifferentiated state. Pulmonary arterial hypertension (PAH) is a fatal disease without cure, characterized by elevated pulmonary vascular resistance due to vascular smooth muscle cell proliferation in precapillary arteries, perivascular inflammation, and asymmetric neointimal hyperplasia. Here, we show that human PAH is characterized by overexpression of the NOTCH ligand JAGGED-1 (JAG-1) in small pulmonary artery smooth muscle cells and that JAG-1 selectively controls NOTCH3 signaling and cellular proliferation in an autocrine fashion.

Mechanosensitive channel Piezo1 is required for pulmonary artery smooth muscle cell proliferation.

Concentric pulmonary vascular wall thickening due partially to increased pulmonary artery (PA) smooth muscle cell (PASMC) proliferation contributes to elevating pulmonary vascular resistance (PVR) in patients with pulmonary hypertension (PH). Although pulmonary vasoconstriction may be an early contributor to increasing PVR, the transition of contractile PASMCs to proliferative PASMCs may play an important role in the development and progression of pulmonary vascular remodeling in PH. A rise in cytosolic Ca concentration ([Ca]) is a trigger for PASMC contraction and proliferation.

Excess neuropeptides in lung signal through endothelial cells to impair gas exchange.

Although increased neuropeptides are often detected in lungs that exhibit respiratory distress, whether they contribute to the condition is unknown. Here, we show in a mouse model of neuroendocrine cell hyperplasia of infancy, a pediatric disease with increased pulmonary neuroendocrine cells (PNECs), excess PNEC-derived neuropeptides are responsible for pulmonary manifestations including hypoxemia. In mouse postnatal lung, prolonged signaling from elevated neuropeptides such as calcitonin gene-related peptide (CGRP) activate receptors enriched on endothelial cells, leading to reduced cellular junction gene expression, increased endothelium permeability, excess lung fluid, and hypoxemia.

TRPC6, a therapeutic target for pulmonary hypertension.

Idiopathic pulmonary arterial hypertension (PAH) is a fatal and progressive disease. Sustained vasoconstriction due to pulmonary arterial smooth muscle cell (PASMC) contraction and concentric arterial remodeling due partially to PASMC proliferation are the major causes for increased pulmonary vascular resistance and increased pulmonary arterial pressure in patients with precapillary pulmonary hypertension (PH) including PAH and PH due to respiratory diseases or hypoxemia. We and others observed upregulation of TRPC6 channels in PASMCs from patients with PAH.

Endothelial upregulation of mechanosensitive channel Piezo1 in pulmonary hypertension.

Piezo is a mechanosensitive cation channel responsible for stretch-mediated Ca and Na influx in multiple types of cells. Little is known about the functional role of Piezo1 in the lung vasculature and its potential pathogenic role in pulmonary arterial hypertension (PAH). Pulmonary arterial endothelial cells (PAECs) are constantly under mechanic stretch and shear stress that are sufficient to activate Piezo channels.

Mouse model of experimental pulmonary hypertension: Lung angiogram and right heart catheterization.

Pulmonary arterial hypertension is a progressive and fatal disease and rodents with experimental pulmonary hypertension (PH) are often used to study pathogenic mechanisms, identify therapeutic targets, and develop novel drugs for treatment. Here we describe a hands-on set of experimental approaches including ex vivo lung angiography and histology and in vivo right heart catheterization (RHC) to phenotypically characterize pulmonary hemodynamics and lung vascular structure in normal mice and mice with experimental PH. We utilized Microfil polymer as contrast in our ex vivo lung angiogram to quantitatively examine pulmonary vascular remodeling in mice with experimental PH, and lung histology to estimate pulmonary artery wall thickness.

Iatrogenic intrathoracic encapsulated siliconoma from a ruptured breast implant.

Our patient was a 57-year-old woman with a history of bilateral retropectoral silicone breast augmentation and axillary hyperhidrosis who underwent a bilateral thoracic sympathectomy via video-assisted thoracoscopic surgery by a surgeon at an outside hospital approximately 20 years ago. The left side required an open thoracotomy. Shortly after the surgery, she developed a left-sided Baker 4 capsular contracture and the left implant was noted to be ruptured.

Upregulation of Calcium Homeostasis Modulators in Contractile-To-Proliferative Phenotypical Transition of Pulmonary Arterial Smooth Muscle Cells.

Excessive pulmonary artery (PA) smooth muscle cell (PASMC) proliferation and migration are implicated in the development of pathogenic pulmonary vascular remodeling characterized by concentric arterial wall thickening and arteriole muscularization in patients with pulmonary arterial hypertension (PAH). Pulmonary artery smooth muscle cell contractile-to-proliferative phenotypical transition is a process that promotes pulmonary vascular remodeling. A rise in cytosolic Ca concentration [(Ca) ] in PASMCs is a trigger for pulmonary vasoconstriction and a stimulus for pulmonary vascular remodeling.

Endothelial platelet-derived growth factor-mediated activation of smooth muscle platelet-derived growth factor receptors in pulmonary arterial hypertension.

Platelet-derived growth factor is one of the major growth factors found in human and mammalian serum and tissues. Abnormal activation of platelet-derived growth factor signaling pathway through platelet-derived growth factor receptors may contribute to the development and progression of pulmonary vascular remodeling and obliterative vascular lesions in patients with pulmonary arterial hypertension. In this study, we examined the expression of platelet-derived growth factor receptor isoforms in pulmonary arterial smooth muscle and pulmonary arterial endothelial cells and investigated whether platelet-derived growth factor secreted from pulmonary arterial smooth muscle cell or pulmonary arterial endothelial cell promotes pulmonary arterial smooth muscle cell proliferation.