fumarates and Hypertension--Pulmonary

Topics: Adult; Angiography; Arteries; Biopsy; Cardiac Catheterization; Electrocardiography; Female; Fumarates; Humans; Hypertension, Pulmonary; Lung; Male; Medical History Taking; Middle Aged; Sex Factors

Chronic obstructive pulmonary disease (COPD) is a health problem that results in death, commonly due to the development of pulmonary hypertension (PH). Here, by utilizing a mouse model of intratracheal elastase-induced emphysema that presents three different phases of COPD, we sought to observe whether budesonide/glycopyrronium/formoterol fumarate (BGF) triple therapy could prevent COPD-PH in addition to ameliorating COPD progression.. We utilized intratracheal elastase-induced emphysema mouse model and performed experiments in three phases illustrating COPD progression: inflammatory (1 day post-elastase), emphysema (3 weeks post-elastase) and PH (4 weeks post-elastase), while treatments of BGF and controls (vehicle, one-drug, and two-drug combinations) were started in prior to elastase instillation (inflammatory phase), at day 7 (emphysema), or at day 14 (PH phase). Phenotype analyses were performed in each phase. In vitro, A549 cells or isolated mouse lung endothelial cells (MLEC) were treated with TNFα with/without BGF treatment to analyze NFκB signaling and cytokine expression changes.. We observed significant reductions in the proinflammatory phenotype observed in the lungs and bronchoalveolar lavage fluid (BALF) 1 day after elastase administration in mice treated with BGF compared with that in mice administered elastase alone (BALF neutrophil percentage, p = 0.0011 for PBS/Vehicle vs. PBS/Elastase, p = 0.0161 for PBS/Elastase vs. BGF). In contrast, only BGF treatment significantly ameliorated the elastase-induced emphysematous lung structure and desaturation after three weeks of elastase instillation (mean linear intercept, p = 0.0156 for PBS/Vehicle vs. PBS/Elastase, p = 0.0274 for PBS/Elastase vs. BGF). Furthermore, BGF treatment prevented COPD-PH development, as shown by improvements in the hemodynamic and histological phenotypes four weeks after elastase treatment (right ventricular systolic pressure, p = 0.0062 for PBS/Vehicle vs. PBS/Elastase, p = 0.027 for PBS/Elastase vs. BGF). Molecularly, BGF acts by inhibiting NFκB-p65 phosphorylation and subsequently decreasing the mRNA expression of proinflammatory cytokines in both alveolar epithelial and pulmonary endothelial cells.. Our results collectively showed that BGF treatment could prevent PH in addition to ameliorating COPD progression via the inhibition of inflammatory NFκB signaling.

Topics: Animals; Bronchodilator Agents; Budesonide; Budesonide, Formoterol Fumarate Drug Combination; Emphysema; Endothelial Cells; Formoterol Fumarate; Fumarates; Glycopyrrolate; Hypertension, Pulmonary; Mice; NF-kappa B; Pancreatic Elastase; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema

Topics: Administration, Oral; Amines; Animals; Appetite Depressants; Body Weight; Dietary Fats; Female; Fumarates; Heart; Hypertension, Pulmonary; Organ Size; Oxazoles; Pulmonary Circulation; Rats

Topics: Adult; Age Factors; Amines; Appetite Depressants; Epidemiologic Methods; Female; Fumarates; Germany, West; Humans; Hypertension, Pulmonary; Male; Middle Aged; Oxazoles; Sex Factors; Time Factors

Topics: Amines; Appetite Depressants; Blood Gas Analysis; Cardiac Catheterization; Electrocardiography; Female; Fumarates; Germany, West; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Oxazoles; Phenmetrazine; Prognosis; Radionuclide Imaging

Topics: Adult; Amines; Appetite Depressants; Female; Fumarates; Humans; Hypertension, Pulmonary; Middle Aged; Oxazoles; Time Factors

Topics: Adult; Amines; Appetite Depressants; Blood Pressure Determination; Female; Follow-Up Studies; Fumarates; Humans; Hypertension, Pulmonary; Male; Middle Aged; Oxazoles; Pulmonary Artery

Topics: Adult; Appetite Depressants; Ergoloid Mesylates; Fumarates; Humans; Hypertension, Pulmonary; Male; Oxazoles; Prednisone; Pulmonary Heart Disease; Radiography; Tricuspid Valve Insufficiency

Topics: Appetite Depressants; Fumarates; Humans; Hypertension, Pulmonary; Oxazoles

Topics: Appetite Depressants; Female; Fumarates; Humans; Hypertension, Pulmonary; Male; Oxazoles; Switzerland

Topics: Adult; Appetite Depressants; Electrocardiography; Female; Fumarates; Humans; Hypertension, Pulmonary; Male; Middle Aged; Oxazoles; Pulmonary Artery

Topics: Adolescent; Adult; Appetite Depressants; Cardiac Catheterization; Electrocardiography; Female; Fumarates; Humans; Hypertension, Pulmonary; Male; Middle Aged; Oxazoles

Topics: Adult; Appetite Depressants; Cardiac Output; Female; Fumarates; Humans; Hypertension, Pulmonary; Hypoxia; Male; Middle Aged; Oxazoles; Oxygen; Respiration

Topics: Animals; Appetite Depressants; Fumarates; Humans; Hyperplasia; Hypertension, Pulmonary; Hypertrophy; Oxazoles; Pulmonary Artery; Rats

Topics: Appetite Depressants; Dilatation; Fumarates; Humans; Hyperplasia; Hypertension, Pulmonary; Hypertrophy; Necrosis; Oxazoles; Pulmonary Artery

Topics: Adult; Appetite Depressants; Cardiac Catheterization; Cardiomyopathies; Electrocardiography; Female; Fumarates; Heart Failure; Humans; Hypertension, Pulmonary; Pulmonary Artery

Topics: Adult; Age Factors; Appetite Depressants; Cardiac Catheterization; Electrocardiography; Female; Fumarates; Humans; Hypertension, Pulmonary; Radiography, Thoracic; Radionuclide Imaging; Time Factors

Topics: Adult; Appetite Depressants; Cardiac Catheterization; Diagnosis, Differential; Electrocardiography; Female; Fumarates; Humans; Hypertension, Pulmonary; Male; Methods; Middle Aged; Obesity; Phonocardiography; Pulmonary Heart Disease; Radiography