Respiratory System Commons^™

Hsp90 Inhibitors Modulate Sars-Cov-2 Spike Protein Subunit 1-Induced Human Pulmonary Microvascular Endothelial Activation And Barrier Dysfunction, Ruben Manuel Luciano Colunga Biancatelli, Pavel Solopov, Betsy W. Gregory, Yara Khodour, John D. Catravas

Bioelectrics Publications

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused more than 5 million deaths worldwide. Multiple reports indicate that the endothelium is involved during SARS-Cov-2-related disease (COVID-19). Indeed, COVID-19 patients display increased thrombophilia with arterial and venous embolism and lung microcapillary thrombotic disease as major determinants of deaths. The pathophysiology of endothelial dysfunction in COVID-19 is not completely understood. We have investigated the role of subunit 1 of the SARS-CoV-2 spike protein (S1SP) in eliciting endothelial barrier dysfunction, characterized dose and time relationships, and tested the hypothesis that heat shock protein 90 (HSP90) inhibitors would prevent and repair such injury. S1SP …

Efficacy Of Pulmonary Ultrasound Compared To N-Terminal Prohormone Brain Natriuretic Peptide As A Diagnostic Tool For Congestive Heart Failure In Patients Presenting With Acute Dyspnea In The Emergency Setting, Leah Krohn, Michael Burns

Physician Assistant Capstones, 2020-current

Objective: To determine the efficacy of using pulmonary ultrasound as a diagnostic tool in acute dyspnea of undetermined cause compared to the use of serum N-Terminal prohormone Brain Natriuretic Peptide (NT-proBNP) in the diagnosis of heart failure.

Design: Systematic literature review

Methods: Searches were conducted in PubMed and Scopus using the terms pulmonary ultrasound and congestive heart failure and studies within the last 10 years. Studies that used pulmonary ultrasound compared to BNP as a marker for the diagnosis of heart failure were included.

Results: All three studies found that the use of pulmonary ultrasound was a more specific …

Hypersensitivity Of Vagal Pulmonary Afferents Induced By Tumor Necrosis Factor Alpha In Mice, Ruei-Lung Lin, Qihai Gu, Lu-Yuan Lee

Physiology Faculty Publications

Tumor necrosis factor alpha (TNFα), a pro-inflammatory cytokine, plays a significant role in the pathogenesis of allergic asthma. Inhalation of TNFα also induces airway hyperresponsiveness in healthy human subjects, and the underlying mechanism is not fully understood. A recent study reported that TNFα caused airway inflammation and a sustained elevation of pulmonary chemoreflex responses in mice, suggesting a possible involvement of heightened sensitivity of vagal pulmonary C-fibers. To investigate this possibility, the present study aimed to investigate the effect of a pretreatment with TNFα on the sensitivity of vagal pulmonary afferents in anesthetized mice. After TNFα (10 μg/ml, 0.03 ml) …

Hsp90 Inhibition Suppresses Nf-Κb Transcriptional Activation Via Sirt-2 In Human Lung Microvascular Endothelial Cells, Gagan S. Thangjam, Charalampos Birmpas, Nektarios Barabutis, Betsy W. Gregory, Mary Ann Clemens, Joseph R. Newton, David Fulton, John D. Catravas

Bioelectrics Publications

The ability of anti-heat shock protein 90 (Hsp90) drugs to attenuate NF-κB-mediated transcription is the major basis for their anti-inflammatory properties. While the molecular mechanisms underlying this effect are not clear, they appear to be distinct in human endothelial cells. We now show for the first time that type 2 sirtuin (Sirt-2) histone deacetylase binds human NF-κB target gene promoter and prevents the recruitment of NF-κB proteins and subsequent assembly of RNA polymerase II complex in human lung microvascular endothelial cells. Hsp90 inhibitors stabilize the Sirt-2/promoter interaction and impose a “transcriptional block,” which is reversed by either inhibition or downregulation …

Histone Deacetylase Inhibitors Prevent Pulmonary Endothelial Hyperpermeability And Acute Lung Injury By Regulating Heat Shock Protein 90 Function, Atul D. Joshi, Nektarios Barabutis, Charalampos Birmpas, Christiana Dimitropoulou, Gagan Thangjam, Mary Cherian-Shaw, John Dennison, John D. Catravas

Bioelectrics Publications

Transendothelial hyperpermeability caused by numerous agonists is dependent on heat shock protein 90 (Hsp90) and leads to endothelial barrier dysfunction (EBD). Inhibition of Hsp90 protects and restores transendothelial permeability. Hyperacetylation of Hsp90, as by inhibitors of histone deacetylase (HDAC), suppresses its chaperone function and mimics the effects of Hsp90 inhibitors. In this study we assessed the role of HDAC in mediating lipopolysaccharide (LPS)-induced transendothelial hyperpermeability and acute lung injury (ALI). We demonstrate that HDAC inhibition protects against LPS-mediated EBD. Inhibition of multiple HDAC by the general inhibitors panobinostat or trichostatin provided protection against LPS-induced transendothelial hyperpermeability, acetylated and suppressed Hsp90 …