PDE5A inhibition attenuates bleomycin-induced pulmonary fibrosis and pulmonary hypertension through inhibition of ROS generation and RhoA/Rho kinase activation.
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 pulmonary arterial hypertension (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 phosphodiesterase type 5 (PDE5) inhibition to improve pulmonary vascular remodeling and right ventricular function. Intratracheal bleomycin (4 U/kg) or saline control was administered to C57/BL6 mice after anesthesia. After recovery, animals were fed a diet of sildenafil (100 mg.kg(-1).day(-1)) or vehicle for 2 wk 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 cotreated 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 RV 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.
Hemnes
Anna R
AR
Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, 720 Rutland Ave., Ross 850, Baltimore, MD 21205, USA.
Zaiman
Ari
A
Champion
Hunter C
HC
D000818:Animals; D001761:Bleomycin / Q000009:adverse effects*; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004789:Enzyme Activation; D006976:Hypertension, Pulmonary / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use*; D010879:Piperazines / Q000627:therapeutic use*; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D011687:Purines / Q000627:therapeutic use; D017382:Reactive Oxygen Species / Q000378:metabolism*; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000627:therapeutic use*; D018497:Ventricular Dysfunction, Right / Q000139:chemically induced / Q000517:prevention & control*; D054460:rho-Associated Kinases / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D017382:Reactive Oxygen Species; D013450:Sulfones; D001761:Bleomycin; D000068677:Sildenafil Citrate; D054460:rho-Associated Kinases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517382:Pde5a protein, mouse; D020742:rhoA GTP-Binding Protein