{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T02:04:24Z","timestamp":1784772264318,"version":"3.55.0"},"reference-count":77,"publisher":"American Physiological Society","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Lung Cellular and Molecular Physiology"],"published-print":{"date-parts":[[2012,7,1]]},"abstract":"<jats:p> Bleomycin-induced lung injury is characterized in the neonatal rat by inflammation, arrested lung growth, and pulmonary hypertension (PHT), as observed in human infants with severe bronchopulmonary dysplasia. Inhalation of CO<jats:sub>2<\/jats:sub> (therapeutic hypercapnia) has been described to limit cytokine production and to have anti-inflammatory effects on the injured lung; we therefore hypothesized that therapeutic hypercapnia would prevent bleomycin-induced lung injury. Spontaneously breathing rat pups were treated with bleomycin (1 mg\/kg\/d ip) or saline vehicle from postnatal days 1\u201314 while being continuously exposed to 5% CO<jats:sub>2<\/jats:sub> (Pa<jats:sub>CO<jats:sub>2<\/jats:sub><\/jats:sub> elevated by 15\u201320 mmHg), 7% CO<jats:sub>2<\/jats:sub> (Pa<jats:sub>CO<jats:sub>2<\/jats:sub><\/jats:sub> elevated by 35 mmHg), or normocapnia. Bleomycin-treated animals exposed to 7%, but not 5%, CO<jats:sub>2<\/jats:sub>, had significantly attenuated lung tissue macrophage influx and PHT, as evidenced by normalized pulmonary vascular resistance and right ventricular systolic function, decreased right ventricular hypertrophy, and attenuated remodeling of pulmonary resistance arteries. The level of CO<jats:sub>2<\/jats:sub> neither prevented increased tissue neutrophil influx nor led to improvements in decreased lung weight, septal thinning, impaired alveolarization, or decreased numbers of peripheral arteries. Bleomycin led to increased expression and content of lung tumor necrosis factor (TNF)-\u03b1, which was found to colocalize with tissue macrophages and to be attenuated by exposure to 7% CO<jats:sub>2<\/jats:sub>. Inhibition of TNF-\u03b1 signaling with the soluble TNF-2 receptor etanercept (0.4 mg\/kg ip from days 1\u201314 on alternate days) prevented bleomycin-induced PHT without decreasing tissue macrophages and, similar to CO<jats:sub>2<\/jats:sub>, had no effect on arrested alveolar development. Our findings are consistent with a preventive effect of therapeutic hypercapnia with 7% CO<jats:sub>2<\/jats:sub> on bleomycin-induced PHT via attenuation of macrophage-derived TNF-\u03b1. Neither tissue macrophages nor TNF-\u03b1 appeared to contribute to arrested lung development induced by bleomycin. That 7% CO<jats:sub>2<\/jats:sub> normalized pulmonary vascular resistance and right ventricular function without improving inhibited airway and vascular development suggests that vascular hypoplasia does not contribute significantly to functional changes of PHT in this model. <\/jats:p>","DOI":"10.1152\/ajplung.00072.2012","type":"journal-article","created":{"date-parts":[[2012,5,12]],"date-time":"2012-05-12T01:00:18Z","timestamp":1336784418000},"page":"L75-L87","source":"Crossref","is-referenced-by-count":27,"title":["Therapeutic hypercapnia prevents bleomycin-induced pulmonary hypertension in neonatal rats by limiting macrophage-derived tumor necrosis factor-\u03b1"],"prefix":"10.1152","volume":"303","author":[{"given":"A. 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