Anatomy 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 …

The Paradox Of Pulmonary Vascular Resistance: Restoration Of Pulmonary Capillary Recruitment As A Sine Qua Non For True Therapeutic Success In Pulmonary Arterial Hypertension, David Langleben, Stylianos E. Orfanos, Benjamin D. Fox, Nathan Messas, Michele Giovinazzo, John D. Catravas

Bioelectrics Publications

Exercise-induced increases in pulmonary blood flow normally increase pulmonary arterial pressure only minimally, largely due to a reserve of pulmonary capillaries that are available for recruitment to carry the flow. In pulmonary arterial hypertension, due to precapillary arteriolar obstruction, such recruitment is greatly reduced. In exercising pulmonary arterial hypertension patients, pulmonary arterial pressure remains high and may even increase further. Current pulmonary arterial hypertension therapies, acting principally as vasodilators, decrease calculated pulmonary vascular resistance by increasing pulmonary blood flow but have a minimal effect in lowering pulmonary arterial pressure and do not restore significant capillary recruitment. Novel pulmonary arterial hypertension …

The Heat Shock Protein 90 Inhibitor, At13387, Protects The Alveolo-Capillary Barrier And Prevents Hci-Induced Chronic Lung Injury And Pulmonary Fibrosis, Ruben M.L. Colunga Biancatelli, Pavel Solopov, Christiana Dimitropoulou, Betsy Gregory, Tierney Day, John D. Catravas

Bioelectrics Publications

Hydrochloric acid (HCl) exposure causes asthma-like conditions, reactive airways dysfunction syndrome, and pulmonary fibrosis. Heat Shock Protein 90 (HSP90) is a molecular chaperone that regulates multiple cellular processes. HSP90 inhibitors are undergoing clinical trials for cancer and are also being studied in various pre-clinical settings for their anti-inflammatory and anti-fibrotic effects. Here we investigated the ability of the heat shock protein 90 (HSP90) inhibitor AT13387 to prevent chronic lung injury induced by exposure to HCl in vivo and its protective role in the endothelial barrier in vitro. We instilled C57Bl/6J mice with 0.1N HCl (2 µL/g body weight, intratracheally) and …

Activation Of Cannabinoid-2 Receptor Protects Against Pseudomonas Aeruginosa Induced Acute Lung Injury And Inflammation, Nagaraja Nagre, Gregory Nicholson, Xiaofei Cong, Janette Lockett, Andrew C. Pearson, Vincent Chan, Woong-Ki Kim, K. Yaragudri Vinod, John D. Catravas

Bioelectrics Publications

Background

Bacterial pneumonia is a major risk factor for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Pseudomonas aeruginosa (PA), an opportunistic pathogen with an increasing resistance acquired against multiple drugs, is one of the main causative agents of ALI and ARDS in diverse clinical settings. Given the anti-inflammatory role of the cannabinoid-2 receptor (CB2R), the effect of CB2R activation in the regulation of PA-induced ALI and inflammation was tested in a mouse model as an alternative to conventional antibiotic therapy.

Methods

In order to activate CB2R, a selective synthetic agonist, JWH133, was administered intraperitoneally (i.p.) to C57BL/6J …

Observations Of Delayed Changes In Respiratory Function Among Allergy Clinic Patients Exposed To Wildfire Smoke, James Blando, Michael Allen, Hadiza Galadima, Timothy Tolson, Muge Akpinar-Elci, Mariana Szklo-Coxe

Community & Environmental Health Faculty Publications

Wildfires have increased in frequency and magnitude and pose a significant public health challenge. The principal objective of this study was to assess the impact of wildfire smoke on respiratory peak flow performance of patients exposed to two different wildfire events. This longitudinal study utilized an observational approach and a cohort study design with a patient-level clinical dataset from a local outpatient allergy clinic (n = 842). Meteorological data from a local weather station served as a proxy for smoke exposure because air quality measurements were not available. This study found that there were decreases in respiratory peak flow among …

The Hsp90 Inhibitor, Auy-922, Protects And Repairs Human Lung Microvascular Endothelial Cells From Hydrochloric Acid-Induced Endothelial Barrier Dysfunction, Ruben M.L. Colunga Biancatelli, Pavel Solopov, Betsy Gregory, John D. Catravas

Bioelectrics Publications

Exposure to hydrochloric acid (HCl) leads acutely to asthma-like symptoms, acute respiratory distress syndrome (ARDS), including compromised alveolo-capillary barrier, and respiratory failure. To better understand the direct effects of HCl on pulmonary endothelial function, we studied the characteristics of HCl-induced endothelial barrier dysfunction in primary cultures of human lung microvascular endothelial cells (HLMVEC), defined the involved molecular pathways, and tested the potentially beneficial effects of Heat Shock Protein 90 (HSP90) inhibitors. HCl impaired barrier function in a time- and concentration-dependent manner and was associated with activation of Protein Kinase B (AKT), Ras homolog family member A (RhoA) and myosin light …

Age-Dependent Chronic Lung Injury And Pulmonary Fibrosis Following Single Exposure To Hydrochloric Acid, Ruben M.L. Colunga Biancatelli, Pavel Solopov, Christiana Dimitropoulou, John D. Catravas

Bioelectrics Publications

Exposure to hydrochloric acid (HCl) represents a threat to public health. Children may inhale higher doses and develop greater injury because of their smaller airways and faster respiratory rate. We have developed a mouse model of pediatric exposure to HCl by intratracheally instilling p24 mice (mice 24 days old; 8–10 g) with 2 µL/g 0.1 N HCl, and compared the profile of lung injury to that in HCl-instilled adults (10 weeks old; 25–30 g) and their age-matched saline controls. After 30 days, alveolar inflammation was observed with increased proteinosis and mononuclear cells in the bronchoalveolar lavage fluid (BALF) in both …