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1 Medicine, Vanderbilt University, Nashville, Tennessee, United States
2 School of Medicine, Johns Hopkins University, Baltimore, Maryland, United States
* To whom correspondence should be addressed. E-mail: hchampi{at}jhmi.edu.
Pulmonary hypertension frequently complicates interstitial lung disease, where it is associated with a high mortality. Patients with this dual diagnosis often fare worse than those with PAH alone and respond poorly to standard PAH therapy, often dying of right ventricular (RV) failure. We hypothesize that nitric oxide synthase (NOS) uncoupling is important in the pathogenesis of interstitial lung disease-associated pulmonary hypertension and this process can be abrogated by PDE5 inhibition to improve pulmonary vascular remodeling and right ventricular function. Intratracheal bleomycin (4U/kg) or saline control was administered to C57/BL6 mice after anesthesia. After recovery, animals were fed a diet of sildenafil (100mg/kg/d) or vehicle for two weeks when they underwent hemodynamic measurements and tissues were harvested. Survival was reduced in animals treated with bleomycin compared with controls and was improved with sildenafil (100.0 vs. 73.7 vs. 84.2%, P<0.05). RV/LV+S ratio was higher in bleomycin alone mice with improvement in ratio when sildenafil was administered (33.00±0.01% vs. 20.98±0.01% P<0.05). Histology showed less pulmonary vascular and RV fibrosis in the group co-treated with sildenafil. Bleomycin was associated with a marked increase in superoxide generation by DHE histological staining and luminol activity in both heart and lung. Treatment with sildenafil resulted in a concomitant reduction in superoxide levels in both heart and lung. These data demonstrate that PDE5 inhibition ameliorates right ventricular hypertrophy and pulmonary fibrosis associated with intratracheal bleomycin in a manner that is associated with improved NOS coupling and a reduction in reactive oxygen species signaling.
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