Background-The dual endothelin-receptor antagonist bosentan has been reported to improve pulmonary arterial hypertension, but the role of endothelins in the pathogenesis of the condition remains uncertain. We investigated the roles of endothelin-1 (ET-1), nitric oxide (NO), vascular endothelial growth factor (VEGF), and tenascin in overcirculation-induced pulmonary hypertension in piglets, as a model of early pulmonary arterial hypertension, with or without bosentan therapy. Methods and Results-Thirty 3-week-old piglets were randomized to placebo or to bosentan 15 mg/kg BID after the anastomosis of the left subclavian artery to the pulmonary arterial trunk or after a sham operation. Three months later, the animals underwent a hemodynamic evaluation followed by cardiac and pulmonary tissue sampling for morphometry, immunohistochemistry, and real-time quantitative PCR. Chronic systemic-to-pulmonary shunting increased circulating plasma ET-1, pulmonary mRNA for ET-1, ET B receptor, inducible NO synthase, VEGF, and pulmonary ET-1 and VEGF proteins. There were increases in myocardial mRNA for ET A receptor and VEGF and in myocardial VEGF protein. Pulmonary and myocardial tissue mRNA for tenascin did not change. Normalized-flow pulmonary artery pressure increased from 20 (2) to 33 (1) mm Hg [mean (SEM)], arteriolar medial thickness increased on average by 83%, and these changes were completely prevented by bosentan therapy. Right ventricular end-systolic elastance increased in proportion to pulmonary arterial elastance with or without bosentan. Conclusions-Experimental overcirculation-induced pulmonary arterial hypertension appears to be causally related to an activation of the pulmonary ET-1 system and as such is completely prevented by the dual endothelin receptor antagonist bosentan. (Circulation. 2003;107:1329-1335.)

Eosinophilic bronchopneumopathy was diagnosed in 23 young dogs. Clinical signs included cough, gagging, and retching in all dogs, dyspnea in 21 dogs (91%), and nasal discharge in 12 dogs (52%). The most common radiographic findings were a moderate to severe bronchointerstitial pattern (68%, 13 of 19 dogs). Bronchoscopic findings included the presence of abundant yellow-green mucus or mucopurulent material (70%, 16 of 23 dogs) and severe mucosal thickening with an irregular or polypoid appearance (52%, 12 of 23 dogs), with partial airway closure during expiration in 3 dogs (13%). Peripheral blood eosinophilia was noted in 14 of 23 dogs (61%). Inflammatory cells in brush or bronchoalveolar lavage fluid cytologic preparations comprised more than 50% eosinophils in 14 of 23 dogs (61%), and 20-50% eosinophils in 6 dogs (26%). Eosinophilic infiltration of the bronchial mucosa was observed in biopsies from 19 dogs and was graded as mild (37%, 7 dogs), moderate (32%, 6 dogs), or severe (32%, 6 dogs). The mean serum immunoglobulin A concentration was almost double that of a population of 20 healthy dogs of various breeds. Oral glucocorticoids were administered on alternate days with progressive tapering of the dose; the dosage at maintenance varied between 0.1 and 1.0 mg/kg every other day. No relationship was found between the duration of clinical signs and the maintenance dosage or the cytologic and histopathologic grades.

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IW, Heyndrickx GR. Pretreatment of adult bone marrow mesenchymal stem cells with cardiomyogenic growth factors and repair of the chronically infarcted myocardium.

Eosinophilic bronchopneumopathy was diagnosed in 23 young dogs. Clinical signs included cough, gagging, and retching in all dogs, dyspnea in 21 dogs (91%), and nasal discharge in 12 dogs (52%). The most common radiographic findings were a moderate to severe bronchointerstitial pattern (68%, 13 of 19 dogs). Bronchoscopic findings included the presence of abundant yellow‐green mucus or mucopurulent material (70%, 16 of 23 dogs) and severe mucosal thickening with an irregular or polypoid appearance (52%, 12 of 23 dogs), with partial airway closure during expiration in 3 dogs (13%). Peripheral blood eosinophilia was noted in 14 of 23 dogs (61%). Inflammatory cells in brush or bronchoalveolar lavage fluid cytologic preparations comprised more than 50% eosinophils in 14 of 23 dogs (61%), and 20–50% eosinophils in 6 dogs (26%). Eosinophilic infiltration of the bronchial mucosa was observed in biopsies from 19 dogs and was graded as mild (37%, 7 dogs), moderate (32%, 6 dogs), or severe (32%, 6 dogs). The mean serum immunoglobulin A concentration was almost double that of a population of 20 healthy dogs of various breeds. Oral glucocorticoids were administered on alternate days with progressive tapering of the dose; the dosage at maintenance varied between 0.1 and 1.0 mg/kg every other day. No relationship was found between the duration of clinical signs and the maintenance dosage or the cytologic and histopathologic grades.