Modulation of soluble guanylate cyclase ameliorates pulmonary hypertension in a rat model of chronic thromboembolic pulmonary hypertension by stimulating angiogenesis.

Acute pulmonary embolism (PE) does not always resolve after treatment and can progress to chronic thromboembolic disease (CTED) or the more severe chronic thromboembolic pulmonary hypertension (CTEPH). The mechanisms surrounding the likelihood of PE resolution or progress to CTED/CTEPH remain largely unknown. We have developed a rat model of CTEPH that closely resembles the human disease in terms of hemodynamics and cardiac manifestations.

Inhaled nitric oxide to control platelet hyper-reactivity in patients with acute submassive pulmonary embolism.

Background: We test if inhaled nitric oxide (NO) attenuates platelet functional and metabolic hyper-reactivity in subjects with submassive pulmonary embolism (PE).

Methods: Participants with PE were randomized to either 50 ppm NO + O2 or O2 only for 24 h with blood sampling at enrollment and after treatment; results were compared with healthy controls. Platelet metabolic activity was assessed by oxygen consumption (basal and uncoupled) and reactivity was assessed with agonist-stimulated thromboelastography (TEG) and fluorometric measurement of agonist-stimulated cytosolic [Ca] without and with pharmacological soluble guanylate (sGC) modulation.

Differential effect of mild and severe pulmonary embolism on the rat lung transcriptome.

Background: Pulmonary thromboembolism (PTE) is a common diagnosis and a leading cause of cardiovascular morbidity and mortality. A growing literature has associated PE with systemic inflammation, and global hyper-coagulability, which contribute to lung remodeling and clot recurrence. The source and mechanism of inflammation remains unstudied.

A novel nontoxic inhibitor of the activation of NADPH oxidase reduces reactive oxygen species production in mouse lung.

1-Hexadecyl-3-trifluoroethylglycero-sn-2-phosphomethanol (MJ33) is a fluorinated phospholipid analog that inhibits the phospholipase A2 (PLA2) activity of peroxiredoxin 6 (Prdx6). Prdx6 PLA2 activity is required for activation of NADPH oxidase 2 and subsequent generation of reactive oxygen species (ROS). In vitro, MJ33 inhibited agonist-stimulated production of ROS by the isolated perfused mouse lung, lung microvascular endothelial cells, and polymorphonuclear leukocytes.

Transcriptional changes in right ventricular tissues are enriched in the outflow tract compared with the apex during chronic pulmonary embolism in rats.

Moderate to severe pulmonary embolism (PE) can cause pulmonary arterial hypertension and right ventricular (RV) heart damage. Previous studies from our laboratory indicate that the basal outflow tract of the RV is injured and has acute inflammation followed by tissue remodeling while the apex appears normal. The present studies examine transcription responses to chronic PE in RV apex and outflow tracts using DNA microarrays to identify transcription responses by region.

Role of inflammation in right ventricular damage and repair following experimental pulmonary embolism in rats.

Right ventricular (RV) dysfunction is associated with poor clinical outcome following pulmonary embolism (PE). Previous studies in our laboratory show that influx of neutrophils contributes to acute RV damage seen in an 18 h rat model of PE. The present study describes the further progression of inflammation over 6 weeks and compares the neutrophil and monocyte responses.

Transcriptional profile of right ventricular tissue during acute pulmonary embolism in rats.

Acute pulmonary embolism (PE) is the third leading cause of cardiovascular death in the United States. Moderate to severe PE can cause pulmonary arterial hypertension (PH) with resultant right ventricular (RV) heart damage. The mechanisms leading to RV failure after PE are not well defined, although it is becoming clear that PH-induced inflammatory responses are involved.

Inhibition of CINC-1 decreases right ventricular damage caused by experimental pulmonary embolism in rats.

Right ventricular (RV) dysfunction is a strong risk factor for poor clinical outcome following pulmonary embolism (PE), the third most prevalent cardiovascular disease. Previous studies in our laboratory demonstrated that RV failure during PE is mediated, in part, by neutrophil-dependant cardiac inflammation. In this study we use DNA microarray analysis of gene expression to demonstrate that PE results in increased expression of the CXC chemokines CINC-1 and CINC-2 between 6 and 18 h after the start of PE in a rat model of PE.

Cardiac inflammation contributes to right ventricular dysfunction following experimental pulmonary embolism in rats.

Acute right ventricular (RV) failure following pulmonary embolism (PE) is a strong predictor of poor clinical outcome. Present studies test for an association between RV failure from experimental PE, inflammation, and upregulated chemokine expression. Additional experiments test if neutrophil influx contributes to RV dysfunction.

Angiotensin II induces neutrophil accumulation in vivo through generation and release of CXC chemokines.

Background: Angiotensin II (Ang II) is implicated in the development of cardiac ischemic disorders in which prominent neutrophil accumulation occurs. Ang II can be generated intravascularly by the renin-angiotensin system or extravascularly by mast cell chymase. In this study, we characterized the ability of Ang II to induce neutrophil accumulation.

Contrasting roles for CXCR2 during experimental colitis.

Neutrophil recruitment into the colon is believed to play a crucial pathogenic role in the progression of clinical and experimental inflammatory bowel diseases (IBDs). The chemokine receptor CXCR2 is highly expressed on neutrophils, and promotes neutrophil recruitment in several inflammatory diseases. The present study determined the biological role of CXCR2 during trinitrobenzene sulfonic acid (TNBS)-induced colitis in the rat by assessing effects of CXCR2 antibody neutralization on neutrophil accumulation during the early (8 h) and late phase (day 7) of TNBS-induced colitis.

Chemokines accumulate in the lungs of rats with severe pulmonary embolism induced by polystyrene microspheres.

Pulmonary thromboembolism (PEm) is a serious and life threatening disease and the most common cause of acute pulmonary vascular occlusion. Even following successful treatment of PEm, many patients experience long-term disability due to diminished heart and lung function. Considerable damage to the lungs presumably occurs due to reperfusion injury following anti-occlusive treatments for PEm and the resulting chronic inflammatory state in the lung vasculature.