sildenafil-citrate and Pulmonary-Fibrosis

The combination of pulmonary fibrosis and emphysema (CPFE) has been recently defined as a syndrome, it is radiologically recognized and is characterized by the simultaneous coexistence of emphysema of superior pulmonary location and fibrosis predominantly in lower lobes.. We present three patients with CPFE, who underwent right cardiac catheterization for pulmonary hemodynamic assessment, finding mean pulmonary artery pressure (mPAP) between 37-52 mm Hg (mean 45 mm Hg), who received treatment with specific vasodilators for pulmonary arterial hypertension (PAH).. The three patients had higher mPAP than expected for Group III (Pulmonary hypertension due to lung disease and/or hypoxia) of the classification of pulmonary hypertension (PH) by the World Health Organization (WHO), in whom the use of Sildenafil was justified by the presence of progressive dyspnea, and no symptoms suggestive of infectious exacerbation associated with right ventricular failure.

Topics: Cardiac Catheterization; Humans; Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Pulmonary Emphysema; Pulmonary Fibrosis; Sildenafil Citrate; Vasodilator Agents

Inhaled treprostinil was recently developed for the treatment of pulmonary arterial hypertension (PAH). We investigated the safety and acute haemodynamic effects of the combination oral sildenafil and inhaled treprostinil in an open label study in patients with precapillary pulmonary hypertension.. Inhaled nitric oxide (20ppm; n=50), sildenafil (50mg; n=50) and inhaled treprostinil (15microg; n=25 or 30microg; n=25) were applied in subsequent order during right heart catheter investigation to consecutive patients with pulmonary arterial hypertension (PAH; n=28), non-operable chronic thromboembolic pulmonary hypertension (CTEPH; n=17) and pulmonary fibrosis associated pulmonary hypertension (n=5).. Inhaled nitric oxide reduced pulmonary vascular resistance (PVR) to 87.3+/-5.1% of baseline values, reduced mean pulmonary arterial pressure (PAP) to 89.7+/-3.5% and increased cardiac output (CO) to 102.4+/-2.9%. Sildenafil reduced PVR to 80.1+/-5.0%, mPAP to 86.5+/-2.9% and increased CO to 103.8+/-3.2%. Treprostinil, inhaled 1h after sildenafil, reduced PVR to 66.3+/-3.8%, mPAP to 77.8+/-3.3%, and increased CO to 107.1+/-3.3% (mean+/-95% confidence interval). Subgroup analysis showed similar acute haemodynamic effects in PAH and CTEPH patients. Ventilation/perfusion distribution measurement in six patients with pre-existing gas exchange limitations was not changed by sildenafil and treprostinil. Relevant side effects were not observed.. The combination of sildenafil and inhaled treprostinil was well tolerated and induced additive, pulmonary selective vasodilatation in pulmonary hypertension patients. This could be of relevance also for long-term treatment of PAH and CTEPH patients.

Topics: Administration, Inhalation; Administration, Oral; Antihypertensive Agents; Area Under Curve; Blood Pressure; Cough; Drug Synergism; Drug Therapy, Combination; Epoprostenol; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Fibrosis; Pulmonary Gas Exchange; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vascular Resistance

Pulmonary hypertension is a common finding in patients with idiopathic pulmonary fibrosis (IPF), and is associated with increased morbidity and mortality. Therapy with sildenafil has been shown to decrease pulmonary vascular resistance in patients with pulmonary fibrosis and may improve functional status. Patients with IPF and documented pulmonary hypertension were followed up in an open-label study of sildenafil. The 6-min walk test distance (6MWD) was obtained before and after 3 months of sildenafil therapy. Fourteen patients were followed up in the study; 11 patients completed both 6-min walk tests. The mean improvement in walk distance was 49.0 m (90% confidence interval, 17.5 to 84.0 m). When all 14 patients were dichotomized into groups of "responders" (ie, >/= 20% improvement in 6MWD) or "nonresponders" (ie, < 20% change or unable to complete), 57% were classified as responders. Sildenafil is a promising and well-tolerated therapeutic agent for use in patients with IPF and pulmonary hypertension, and should be studied in a large, well-controlled trial.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Aged; Aged, 80 and over; Cyclic Nucleotide Phosphodiesterases, Type 5; Exercise Test; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Fibrosis; Pulmonary Wedge Pressure; Purines; Sildenafil Citrate; Sulfones; Vascular Resistance; Vasodilator Agents; Walking

Sildenafil offers potential to treat patients with pulmonary hypertension by selectively inhibiting phosphodiesterase type five pathways in the lung. It is recommended for selected patients with pulmonary arterial hypertension, but its role in the management of pulmonary hypertension associated with parenchymal lung disease is unclear.. Seven patients (68-86 years) with end stage chronic obstructive pulmonary disease (COPD, 4) and idiopathic pulmonary fibrosis (IPF, 3) were referred to our unit. All patients had a long-term history of chronic lung disease and were on maximal appropriate therapy prescribed by their referring pulmonologist. Thromboembolic disease was excluded by pulmonary angiography and all patients had had high resolution thoracic CT scan. At assessment right heart catheterisation, 2D echocardiography and 6-min walk test were performed prior to commencement of sildenafil 50mg tds. Their medication was otherwise unchanged. After 8 weeks treatment, right heart catheterisation, 2D echocardiography and 6-min walk test were repeated.. The pulmonary vascular resistance was reduced in six patients (from 13, 3, 3, 6.5, 3.5 and 10.5 wood units to 9.7, 2.5, 2.8, 4.4, 2.5 and 5.4 wood units, respectively). Six-minute walk test increased in six patients (from 110 m, 210 m, 80 m, 30 m, 210 m and 80 m to 130 m, 312 m, 120 m, 82 m, 244 m and 100 m, respectively). One patient with COPD did not demonstrate a favourable response although their cardiac output increased on sildenafil therapy. 2D echocardiography showed a reduction in estimated PA pressure in six patients with an improvement in right ventricular systolic function in two COPD patients.. Our results suggest that sildenafil may have a role for selected patients with COPD and IPF who have pulmonary hypertension.

Topics: Aged; Aged, 80 and over; Cardiac Catheterization; Echocardiography; Exercise Test; Female; Humans; Hypertension, Pulmonary; Male; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Disease, Chronic Obstructive; Pulmonary Fibrosis; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Walking

Lung fibrosis can be complicated by pulmonary hypertension, limiting exercise tolerance and life expectancy. Furthermore, vasodilators might cause deterioration in gas exchange. Our aim was to compare acute effects of sildenafil, nitric oxide, and epoprostenol in individuals with pulmonary hypertension secondary to lung fibrosis.. We did a randomised controlled, open-label trial, in 16 individuals admitted to our hospital with pulmonary hypertension secondary to lung fibrosis. After inhalation of nitric oxide (10-20 ppm), we assigned patients to either maximum tolerated dose of intravenous epoprostenol (mean 8.0 ng/kg per min; n=8) or oral sildenafil (50 mg; n=8). Our primary objective was to assess pulmonary vasodilative potency (decrease in pulmonary vascular resistance index) of sildenafil by comparison with inhaled nitric oxide and infused epoprostenol. Analyses were by intention to treat.. Pulmonary vascular resistance index was reduced by nitric oxide (-21.9%, 95% CI -14.1 to -36.2), epoprostenol (-36.9%, -24.4 to -59.6), and sildenafil (-32.5%, -10.2 to -54.1). However, ratio of pulmonary to systemic vascular resistance decreased only in individuals who received nitric oxide and sildenafil. Baseline measurement of multiple-inert-gas elimination showed right-to-left shunt flow (4.8%, 0.0-28.2) and little perfusion of low ventilation(V)/perfusion(Q) areas (0.1%, 0.0-13.0). Prostacyclin increased V/Q mismatch (shunt 16.8%, 10.8-35.9; low V/Q 3.8%, 0.0-13.0) and decreased arterial oxygenation. By contrast, nitric oxide (4.5%, 0.0-18.0; 0.0%, 0.0-17.3) and sildenafil (3.3%, 0.0-11.3; 0.0%, 0.0-12.4) maintained V/Q matching, with raised arterial partial pressure of oxygen (14.3 mm Hg, -1.7 to 31.3) noted for sildenafil. We recorded no adverse events.. Sildenafil causes preferential pulmonary vasodilation and improves gas exchange in patients with severe lung fibrosis and secondary pulmonary hypertension.

Topics: Adult; Aged; Antihypertensive Agents; Epoprostenol; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Nitric Oxide; Piperazines; Pulmonary Fibrosis; Pulmonary Gas Exchange; Purines; Sildenafil Citrate; Sulfones; Vascular Resistance; Vasodilator Agents

Combined pulmonary fibrosis and emphysema (CPFE) is a relatively new entity within the spectrum of cigarette smoke induced lung disorders. Currently there is no consensus about its treatment. We hypothesized that caveolin-1 critically determines the parenchymal and vascular remodeling leading to the development of CPFE. We assessed the effect of therapeutic targeting of caveolin-1 in mesenchymal and endothelial cells by the phosphodiesterase-5 inhibitor, sildenafil.. Male Wistar rats (n = 168) were exposed to; room air (control); bleomycin (7 U/kg), bleomycin+sildenafil (50 mg/kg/day P.O.), cigarette smoke (CS) (4 Gold Flake 69 mm/day), CS + sildenafil, CS + bleomycin, CS + bleomycin+sildenafil. Animals were euthanized at 8, 9, 11, 12 weeks and lung histopathological changes, collagen deposition, ROS, Xanthine oxidase, caveolin-1 determined.. Cigarette smoke causes progressive ROS accumulation, caveolin-1 up-regulation in alveolar epithelial cells, alveolar macrophages, peribronchiolar fibroblasts, endothelial and vascular smooth muscle cells, interstitial inflammation and emphysema. Sildenafil reduces oxidative stress, parenchymal caveolin-1 and attenuates emphysema caused by CS. Bleomycin increases lung ROS and downregulates caveolin-1 leading to fibroblast proliferation and fibrosis. Combined cigarette smoke and bleomycin exposure, results in differential caveolin-1 expression and heterogeneous parenchymal remodeling with alternating areas of emphysema and fibrosis. Increased caveolin-1 induces premature senescence of lung fibroblasts and emphysema. Decreased caveolin-1 is associated with propagation of EMT and fibrosis. Sildenafil attenuates the parenchymal remodeling however it is not effective in reducing VSMC hypertrophy in combined group.. CPFE is characterized by heterogenous parenchymal remodeling and differential caveolin-1 expression. Sildenafil therapy attenuates parenchymal pathologies in CPFE. Additional therapy is however needed for attenuating VSMC remodeling.

Topics: Animals; Bleomycin; Caveolin 1; Cigarette Smoking; Collagen; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Endothelial Cells; Fibroblasts; Gene Expression Regulation; Humans; Lung; Male; Mesenchymal Stem Cells; Phosphodiesterase 5 Inhibitors; Pulmonary Emphysema; Pulmonary Fibrosis; Rats; Rats, Wistar; Reactive Oxygen Species; Sildenafil Citrate; Xanthine Oxidase

Current treatment with vasodilators for pulmonary hypertension associated with respiratory diseases is limited by their inhibitory effect on hypoxic pulmonary vasoconstriction (HPV) and uncoupling effects on ventilation-perfusion (V'/Q'). Hypoxia is also a well-known modulator of the nitric oxide (NO) pathway, and may therefore differentially affect the responses to phosphodiesterase 5 (PDE5) inhibitors and soluble guanylyl cyclase (sGC) stimulators. So far, the effects of the sGC stimulator riociguat on HPV have been poorly characterized.. Contraction was recorded in pulmonary arteries (PA) in a wire myograph. Anesthetized rats were catheterized to record PA pressure. Ventilation and perfusion were analyzed by micro-CT-SPECT images in rats with pulmonary fibrosis induced by bleomycin.. The PDE5 inhibitor sildenafil and the sGC stimulator riociguat similarly inhibited HPV in vitro and in vivo. Riociguat was more effective as vasodilator in isolated rat and human PA than sildenafil. Riociguat was ≈3-fold more potent under hypoxic conditions and it markedly inhibited HPV in vivo at a dose that barely affected the thromboxane A2 (TXA2) mimetic U46619-induced pressor responses. Pulmonary fibrosis was associated with V'/Q' uncoupling and riociguat did not affect the V'/Q' ratio.. PDE5 inhibitors and sGC stimulators show a different vasodilator profile. Riociguat was highly effective and potentiated by hypoxia in rat and human PA. In vivo, riociguat preferentially inhibited hypoxic than non-hypoxic vasoconstriction. However, it did not worsen V'/Q' coupling in a rat model of pulmonary fibrosis.

Topics: Aged; Animals; Disease Models, Animal; Enzyme Activators; Female; Humans; Hypertension, Pulmonary; Hypoxia; In Vitro Techniques; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Pulmonary Artery; Pulmonary Fibrosis; Pyrazoles; Pyrimidines; Rats; Rats, Wistar; Sildenafil Citrate; Soluble Guanylyl Cyclase; Vasoconstriction; Vasodilator Agents; Ventilation-Perfusion Ratio

Sildenafil improves the 6-min walking distance in patients with idiopathic pulmonary fibrosis (IPF) and right-sided ventricular systolic dysfunction.We analysed the previously unexplored role of sildenafil on vasoconstriction and remodelling of pulmonary arteries from patients with IPF and pulmonary hypertension (PH) ex vivo Pulmonary arteries from 18 donors without lung disease, nine IPF, eight PH+IPF and four PH patients were isolated to measure vasodilator and anti-contractile effects of sildenafil in isometric organ bath. Ventilation/perfusion was explored in an animal model of bleomycin lung fibrosis.Sildenafil relaxed serotonin (5-HT) pre-contracted pulmonary arteries in healthy donors and IPF patients and, to a lesser extent, in PH+IPF and PH. Sildenafil inhibited 5-HT dose-response contraction curve mainly in PH+IPF and PH, but not in healthy donors. Sildenafil did not impair the ventilation/perfusion mismatching induced by bleomycin. Pulmonary arteries from PH+IPF patients showed a marked expression of phosphodiesterse-5 and extracellular matrix components. Sildenafil inhibited pulmonary artery endothelial and smooth muscle cell to mesenchymal transition by inhibition of extracellular regulated kinases 1 and 2 (ERK1/2) and SMAD3 phosphorylation.These results suggest an absence of direct relaxant effect and a prominent anti-contractile and anti-remodelling role of sildenafil in PH+IPF pulmonary arteries that could explain the beneficial effects of sildenafil in IPF with PH phenotype.

Topics: Animals; Bleomycin; Disease Models, Animal; Endothelium, Vascular; Extracellular Matrix; Fibroblasts; Humans; Hypertension, Pulmonary; Lung; Male; Myocytes, Smooth Muscle; Myofibroblasts; Pulmonary Artery; Pulmonary Disease, Chronic Obstructive; Pulmonary Fibrosis; Rats; Rats, Wistar; Serotonin; Signal Transduction; Sildenafil Citrate; Transforming Growth Factor beta1; Vasoconstriction; Vasodilator Agents

Topics: Herbicides; Humans; Paraquat; Pulmonary Fibrosis; Sildenafil Citrate

To describe clinical canine patients with naturally occurring pulmonary hypertension and radiographic pulmonary alveolar infiltrates before and after treatment with sildenafil.. Ten client-owned dogs.. A retrospective analysis of dogs with echocardiographically-determined pulmonary hypertension and pulmonary alveolar infiltrates on thoracic radiographs was performed before (PRE) and after (POST) sildenafil therapy. Clinical scores, pulmonary alveolar infiltrate scores and tricuspid regurgitation gradients were analyzed PRE and POST sildenafil.. Pulmonary alveolar infiltrates associated with pulmonary hypertension developed in a diffusely patchy distribution (10/10). Sixty percent of dogs had a suspected diagnosis of interstitial pulmonary fibrosis as the etiology of pulmonary hypertension. Median PRE clinical score was 4 (range: 3-4) compared to POST score of 0 (0-2) (p = 0.005). Median alveolar infiltrate score PRE was 10 (5-12) compared to POST score of 4 (0-6) (p = 0.006). Median tricuspid regurgitation gradient PRE was 83 mmHg (57-196) compared to 55 mmHg POST (33-151) (p = 0.002).. A subset of dogs with moderate to severe pulmonary hypertension present with diffuse, patchy alveolar infiltrates consistent with non-cardiogenic pulmonary edema. The typical clinical presentation is acute dyspnea and syncope, often in conjunction with heart murmurs suggestive of valvular insufficiency. This constellation of signs may lead to an initial misdiagnosis of congestive heart failure or pneumonia; however, these dogs clinically and radiographically improve with the initiation of sildenafil.

Topics: Animals; Dog Diseases; Dogs; Hypertension, Pulmonary; Phosphodiesterase 5 Inhibitors; Pulmonary Alveoli; Pulmonary Fibrosis; Sildenafil Citrate

Recent imaging studies demonstrated the usefulness of quantitative computed tomographic (CT) analysis assessing pulmonary hypertension (PH) in patients with chronic obstructive lung disease (COPD-PH). The aim of this study was to investigate whether it would be also valuable for predicting and evaluating the effect of pulmonary vasodilators in patients with COPD-PH.. We analyzed a correlation between the extent of cystic destruction (LAA%) and total cross-sectional areas of small pulmonary vessels less than 5 mm(2) (%CSA <5) in many CT slices from each of four COPD-PH patients before and after the initiation of pulmonary vasodilator. To evaluate those generalized data from patients with COPD, we evaluated multiple slices from 42 patients whose PH was not clinically suspicious. We also selected five PH patients with idiopathic interstitial pneumonia (IIP-PH) and analyzed serial changes of pulmonary artery enlargement (PA:A ratio).. In 42 COPD patients without PH, LAA% had a statistically significant negative correlation with %CSA <5. However, three of four COPD-PH patients manifested no such correlation. In two patients, clinical findings were dramatically improved after the initiation of pulmonary vasodilator. Notably, LAA% and %CSA <5 in those patients correlated significantly after its treatment. In COPD-PH, the PA:A ratio was significantly decreased after the initiation of pulmonary vasodilator therapy (1.25 ± 0.13 vs. 1.13 ± 0.11, p = 0.019), but not in IIP-PH.. Our study demonstrates that the use of quantitative CT analysis is a plausible and beneficial tool for predicting and evaluating the effect of pulmonary vasodilators in patients with COPD-PH.

Topics: Aged; Bosentan; Endothelin Receptor Antagonists; Exercise Test; Female; Forced Expiratory Volume; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pulmonary Artery; Pulmonary Diffusing Capacity; Pulmonary Disease, Chronic Obstructive; Pulmonary Fibrosis; Sildenafil Citrate; Sulfonamides; Tadalafil; Tomography, X-Ray Computed; Vasodilator Agents; Vital Capacity

We report a rare case of diffuse systemic sclerosis (SSc) evolving into diffuse SSc/systemic lupus erythematosus (SLE) overlap syndrome. A 15-year-old boy was diagnosed as diffuse SSc with initial presentations of Raynaud's phenomenon and skin tightening. He underwent Chinese herbal treatment and clinical symptoms deteriorated in the following 3 years. On admission to our ward, serositis with pleural effusion, severe pulmonary fibrosis with moderate pulmonary hypertension, swallowing difficulty, and polyarthritis were observed. Autoantibody profiles revealed concurrence of anti-double-stranded DNA, anti-Smith, anti-topoisomerase I, and anti-ribonucleoprotein antibodies. The patient fulfills the criteria for both diffuse SSc and SLE. After drainage for pleural effusion accompanied by oral prednisolone and sildenafil, there were improvement of respiratory distress, swallowing difficulty, and pulmonary hypertension. In conclusion, connective tissue diseases may overlap with each other during the disease course. Serial follow-up for clinical symptoms as well as serological changes is recommended.

Topics: Adolescent; Antihypertensive Agents; Arthritis; Autoantibodies; Biomarkers; Deglutition Disorders; Disease Progression; Drainage; Drugs, Chinese Herbal; Glucocorticoids; Humans; Hypertension, Pulmonary; Lupus Erythematosus, Systemic; Male; Piperazines; Pleural Effusion; Prednisolone; Pulmonary Fibrosis; Purines; Raynaud Disease; Scleroderma, Diffuse; Serositis; Sildenafil Citrate; Sulfones; Treatment Outcome

Previous studies in rats have suggested a causal relationship between progressive pulmonary inflammation and lung fibrosis induced by crystalline silica particles. We report here that, in NMRI mice, the lung response to silica particles is accompanied by a mild and non progressive pulmonary inflammation which is dispensable for the development of lung fibrosis. We found that glucocorticoid (dexamethasone) dramatically reduced lung injury, cellular inflammation and pro-inflammatory cytokine expression (TNF-α, IL-1β and KC) but had no significant effect on silica-induced lung fibrosis and expression of the fibrogenic and suppressive cytokines TGF-β and IL-10 in mice. Other anti-inflammatory molecules such as the COX inhibitor piroxicam or the phosphodiesterase 5 inhibitor sildenafil also reduced lung inflammation without modifying collagen, TGF-β or IL-10 lung content. Our findings indicate that the development of lung fibrosis in silica-treated NMRI mice is not driven by inflammatory lung responses and suggest that suppressive cytokines may represent critical fibrotic factors and potential therapeutic targets in silicosis.

Topics: Animals; Bronchoalveolar Lavage Fluid; Cell Count; Collagen; Cyclooxygenase Inhibitors; Female; Interleukin-10; L-Lactate Dehydrogenase; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Phosphodiesterase 5 Inhibitors; Piperazines; Piroxicam; Pneumonia; Pulmonary Fibrosis; Purines; Sildenafil Citrate; Silicon Dioxide; Sulfones; Transforming Growth Factor beta

Sildenafil, a selective and potent inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase (PDE)5, has a relaxant effect on the smooth muscle cells of the arterioles supplying the human corpus cavernosum acting via nitric oxide (NO)-dependent mechanism. This study aimed to investigate the possible protective effect of sildenafil citrate on the extent of tissue integrity, oxidant-antioxidant status and neutrophil infiltration to the inflamed organ in a rat model of bleomycin-induced lung fibrosis. Lung fibrosis was induced by intratracheal administration of 0.1 ml of bleomycin hydrochloride (5 mg/kg in 0.9% NaCl) under anesthesia to Sprague-Dawley rats (200-250 g; n = 7-8 per group). Control rats received an equal volume of saline intratracheally. In the treatment groups, the rats were treated with either sildenafil citrate (10 mg/kg per day; subcutaneously) or saline for 14 days. Another group of rats were administered subcutaneously with N(G)-nitro-l-arginine methyl ester (l-NAME; 20 mg/kg in 0.9% NaCl) 5 min after sildenafil injections. After decapitation, the lungs were excised and taken for microscopic evaluation or stored for the measurement of malondialdehyde (MDA) and glutathione (GSH) levels, and myeloperoxidase (MPO) activity, and for the assessment of apoptosis. Trunk blood was collected for the assessment of serum tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta levels. In the group with lung fibrosis, the lung tissue was characterized by microscopic lesions, increased lipid peroxidation with a concomitant reduction in GSH content, increased MPO activity and apoptosis. Serum TNF-alpha and IL-1beta levels were higher in the lung fibrosis group compared to control values. Sildenafil reversed tissue MDA levels, MPO activity and serum pro-inflammatory cytokine levels, and preserved GSH content although its effect on the extent of tissue lesion and apoptosis was not statistically significant. Treatment with l-NAME reversed the effect of sildenafil on GSH content. In conclusion, sildenafil citrate administration to rats with bleomycin-induced lung fibrosis seems to be beneficial via prevention of lipid peroxidation, cytokine production and/or release and neutrophil accumulation.

Topics: Animals; Apoptosis; Bleomycin; Disease Models, Animal; Female; Glutathione; Interleukin-1beta; Lung; Male; Malondialdehyde; Neutrophils; NG-Nitroarginine Methyl Ester; Peroxidase; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Fibrosis; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfones; Tumor Necrosis Factor-alpha

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.

Topics: Animals; Bleomycin; Cyclic Nucleotide Phosphodiesterases, Type 5; Enzyme Activation; Hypertension, Pulmonary; Male; Mice; Mice, Inbred C57BL; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Fibrosis; Purines; Reactive Oxygen Species; rho-Associated Kinases; rhoA GTP-Binding Protein; Sildenafil Citrate; Sulfones; Ventricular Dysfunction, Right

Topics: Cardiac Catheterization; Follow-Up Studies; Humans; Hypertension, Pulmonary; Phosphodiesterase Inhibitors; Piperazines; Prognosis; Pulmonary Diffusing Capacity; Pulmonary Fibrosis; Pulmonary Wedge Pressure; Purines; Sildenafil Citrate; Sulfones; Survival Rate

Topics: Humans; Hypertension, Pulmonary; Oxygen; Piperazines; Pulmonary Fibrosis; Pulmonary Gas Exchange; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Aged; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Natriuretic Peptide, Brain; Piperazines; Pulmonary Fibrosis; Purines; Raynaud Disease; Scleroderma, Systemic; Sildenafil Citrate; Sulfones

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Aged; Aged, 80 and over; Erectile Dysfunction; Fatal Outcome; Hemorrhage; Humans; Lung Diseases; Male; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Alveoli; Pulmonary Fibrosis; Purines; Sildenafil Citrate; Sulfones