Effects Of Bosentan Research Articles

Effects of bosentan on nondigital ulcers in patients with systemic sclerosis

Bosentan is an oral dual endothelin receptor antagonist, which has been shown to be efficacious for preventing new digital ulcers in patients with systemic sclerosis (SSc) in two high-quality randomized controlled trials. However, its efficacy for nondigital ulcers in SSc remains unknown. To evaluate the efficacy of bosentan on nondigital ulcers in patients with SSc. Bosentan was administered to five patients with SSc with pulmonary arterial hypertension, who also had nondigital ulcers refractory to conventional treatments. The efficacy of bosentan on nondigital ulcers and its association with clinical features of ulcers were analysed. The nondigital ulcers refractory to conventional treatments were significantly improved by the administration of bosentan in cases surrounded with severe cyanosis. In contrast, nondigital ulcers without cyanosis were still refractory to bosentan therapy. Bosentan may be efficacious for accelerating the healing of nondigital ulcers with severe cyanosis, suggesting that nondigital ulcers caused by severely impaired peripheral circulation are highly responsive to this treatment.

The Anti-Proliferative Effect of Bosentan in Occlusive Pulmonary Hypertension Involves a Reduction in Both Oxidative and Nitrosative Stress

The Anti-Proliferative Effect of Bosentan in Occlusive Pulmonary Hypertension Involves a Reduction in Both Oxidative and Nitrosative Stress

The Effect of the ET-1 Receptor Antagonist, Bosentan, on Patients With Poorly Controlled Asthma: A 17 Week, Double-blind, Placebo-Controlled Crossover Pilot Study

PURPOSE: Endothelin-1 (ET-1) is a highly potent bronchoconstrictor, 100 times more so than methacholine. In asthmatics, BAL and circulating ET-1 levels are elevated, and are further elevated during acute exacerbations. This pilot study was performed to assess the effect of bosentan on patients with poorly controlled asthma.

Bosentan inhibits cigarette smoke-induced endothelin receptor expression in pulmonary arteries

The endothelin (ET) system contributes to lung vascular tension and remodelling in smokers and chronic obstructive pulmonary disease (COPD) patients. This study examined the effect of cigarette smoke (CS) on ET receptor A (ET(A)) and B (ET(B)) expression in human pulmonary artery smooth muscle cells (HPASMCs) and human small intrapulmonary arteries, as well as their functional consequences. CS extract (CSE) increased ET(A) and ET(B) expression in HPASMCs and small intrapulmonary arteries, which was attenuated by bosentan, the ET(A) antagonist BQ123 and the ET(B) antagonist BQ788, and by blocking ET-1 with a monoclonal antibody against ET-1, suggesting a feed-forward mechanism mediated by ET-1 release. ET receptor (ETR) antagonism attenuated the CSE-induced HPASMC proliferation. Furthermore, CSE exposure increased the acute ET-1-induced small intrapulmonary artery contraction, which was attenuated by bosentan, BQ123 and BQ788. Pulmonary arteries from smokers and COPD patients showed a higher expression of ET(A) and ET(B) than those of nonsmoker patients. These results show a novel mechanism by which ETR blockade attenuates CS-induced ETR overexpression and, subsequently, small intrapulmonary artery tension. These data may be of potential value to explain therapeutic effects of bosentan in some forms of disproportionate pulmonary hypertension in COPD patients.

Therapy for pulmonary arterial hypertension due to congenital heart disease and Down's syndrome

BackgroundOral bosentan is effective in pulmonary arterial hypertension (PAH) related to congenital heart disease (CHD). In patients with Down's syndrome, the effect of bosentan is largely unknown. Aim of the study was to evaluate the long-term effects of bosentan in adult patients with CHD-related PAH with and without Down's syndrome. MethodsWHO functional class, resting oxygen saturation, 6-minute walk test (6MWT) and hemodynamics were assessed at baseline and after 12months of bosentan therapy in patients with CHD-related PAH with and without Down's syndrome. ResultsSeventy-four consecutive patients were enrolled: 18 with and 56 without Down's syndrome. After 12months of bosentan therapy, both with and without Down's syndrome patients showed an improvement in WHO functional class (Down: 2.5±0.5 vs 2.9±0.6, p=0.005; controls: 2.5±0.5 vs 2.9±0.5, p=0.000002), 6-minute walk distance (Down: 288±71 vs 239±74m, p=0.0007; controls: 389±80 vs 343±86m, p=0.00003), and hemodynamics (pulmonary flow, Down: 4.0±1.6 vs 3.5±1.4l/m/m2, p=0.006; controls: 3.5±1.4 vs 2.8±1.0l/m/m2, p=0.0005; pulmonary to systemic flow ratio, Down: 1.4±0.7 vs 1.0±0.4, p=0.003; controls: 1.1±0.7 vs 0.9±0.3, p=0.012; pulmonary vascular resistance index, Down: 15±9 vs 20±13WUm2, p=0.007; controls: 20±10 vs 26±15WUm2, p=0.002). No differences in the efficacy of therapy were observed between the two groups. ConclusionsBosentan was safe and well tolerated in adult patients with CHD-related PAH with and without Down's syndrome during 12months of treatment. Clinical status, exercise tolerance, and pulmonary hemodynamics improved, regardless of the presence of Down's syndrome.

Successful Treatment with Bosentan for Pulmonary Hypertension and Reduced Peripheral Circulation in Juvenile Systemic Sclerosis

Pulmonary arterial hypertension (PAH) when associated with systemic sclerosis (SSc) (SSc-PAH) is one of the leading causes of mortality and is found in 10-15% of adult patients with SSc. The ET receptor antagonist bosentan has been shown to be effective in the treatment of adult patients with SSc-PAH. Furthermore, it has been shown that bosentan ameliorates decreased skin perfusion and digital ulceration secondary to SSc. However, the effectiveness and safety of bosentan for treatment of juvenile SSc still remains unclear. We describe a case of juvenile SSc-PAH successfully treated with bosentan. The present case shows that bosentan ameliorated PAH and peripheral circulation as evaluated by cold stress thermography. No bosentan-related adverse events such as liver dysfunction were observed. Prospective randomized trials are required to validate the effectiveness of bosentan for patients with juvenile SSc; however, bosentan might be useful for the management of patients with juvenile SSc.

BUILD-3: A Randomized, Controlled Trial of Bosentan in Idiopathic Pulmonary Fibrosis

A previous trial of bosentan in idiopathic pulmonary fibrosis (IPF) showed a trend to delayed IPF worsening or death. Also, improvements in some measures of dyspnea and health-related quality of life were observed. To demonstrate that bosentan delays IPF worsening or death. Prospective, randomized (2:1), double-blind, placebo-controlled, event-driven, parallel-group, morbidity-mortality trial of bosentan in adults with IPF of less than 3 years' duration, confirmed by surgical lung biopsy, and without extensive honeycombing on high-resolution computed tomography. The primary endpoint was time to IPF worsening (a confirmed decrease from baseline in FVC ≥ 10% and diffusing capacity of the lung for carbon monoxide ≥ 15%, or acute exacerbation of IPF) or death up to End of Study. Effects of bosentan on health-related quality of life, dyspnea, and the safety and tolerability of bosentan were investigated. Six hundred sixteen patients were randomized to bosentan (n=407) or placebo (=209). No significant difference between treatment groups was observed in the primary endpoint analysis (hazard ratio, 0.85; 95% confidence interval, 0.66-1.10; P=0.2110). No treatment effects were observed on health-related quality of life or dyspnea. Some effects of bosentan treatment were observed in changes from baseline to 1 year in FVC and diffusing capacity of the lung for carbon monoxide. The safety profile for bosentan was similar to that observed in other trials. The primary objective in the Bosentan Use in Interstitial Lung Disease-3 trial was not met. Bosentan was well tolerated. Clinical trial registered with www.clinicaltrials.gov (NCT 00391443).

Prolonged beneficial effect of bosentan treatment and 4-year survival rates in adult patients with pulmonary arterial hypertension associated with congenital heart disease

Pulmonary arterial hypertension (PAH) associated with congenital heart disease (CHD) due to systemic to pulmonary shunting is associated with a high risk of morbidity and mortality. In this study we evaluated 4years treatment effect of bosentan on exercise capacity and quality of life and survival rates in 64 adult patients with PAH associated with CHD, including patients with Down syndrome (DS). All patients were evaluated at baseline and during follow-up with laboratory tests, 6-minute walk test, quality of life questionnaires, and Doppler echocardiography. In total, 13 patients (20%) died during 4-years of follow-up; 4 patients with DS and 9 patients without DS. Mean follow-up of all patients treated with bosentan was 3.5±1.2year. We analyzed treatment efficacy separately within patients without DS (n=34) and patients with DS (n=30). Mean 6-minute walking distance (6MWD) in patients without DS significantly increased at 6months from 417±108 to 458±104m (+41m; p=0.002) and significant improvement continued to exist during at least 2.5years of follow-up (p=0.003). Moreover, stroke volume increased significantly (p=0.02). In the patients with DS, 6-MWD, stroke volume and quality of life remained stable during treatment. In this study we demonstrate a prolonged beneficial effect of bosentan treatment on exercise capacity, stroke volume and quality of life in patients without DS. However the mortality rate of 20% of patients after 4years of follow-up remains high.

Effectiveness of bosentan in the treatment of ischemic lesions in a case of thromboangiitis obliterans (Buerger disease): A case report

Buerger disease or thromboangiitis obliterans (TAO) is a thrombotic occlusive, non-atherosclerotic segmental inflammatory disease that affects the small and medium-sized arteries and veins in the extremities of the limbs, frequently requiring amputation. Cessation of tobacco use is the only known effective treatment, though preliminary results from the use of pharmacological therapy implicated in pathogenesis of TAO have demonstrated noticeable clinical improvement of patients. We report the case of a 35-year-old woman with active TAO, refractory to smoking cessation and conventional therapy, who exhibited a favorable clinical response to treatment with bosentan, an oral dual endothelin receptor antagonist, administered on a compassionate-use basis. Six months after starting bosentan therapy, the pain and trophic lesions in the patient's toes had completely disappeared. Bosentan was well tolerated, without any observed adverse reaction. The findings of this case report suggest that bosentan may be considered a therapeutic option for patients with active disease, despite quitting smoking, or for those who fail in absolute abstention from smoking.

Long-Term (5 Years) Effects of Bosentan in Patients With Pulmonary Arterial Hypertension

Introduction and objectives Bosentan has proven efficacy in pulmonary hypertension in the short term. Little is known about its effects beyond 2 to 3 years. Our objective was to analyze the efficacy and safety of bosentan in the long term (5 years) in patients treated in our center. Methods This retrospective study sequentially analyzed clinical, functional, and laboratory parameters in a series of patients treated initially with bosentan as monotherapy from 2002 to 2009 in a single hospital. Treatment success was defined as survival without clinical worsening that required additional pulmonary vasodilators. Results We included 20 patients (70% women, mean age 46 ± 14 years, 65% congenital heart disease), with a median follow-up of 64 months. One patient required withdrawal of bosentan due to adverse effects. At 4 months, significant improvements were achieved in hemodynamic, clinical and functional parameters. Clinical and functional benefits persisted at 5-year follow-up. Overall 5-year survival after beginning bosentan therapy was 95% (84%-100%). Treatment success at 1, 2, 3, 4 and 5 years was 95% (84%-100%), 83% (65%-100%), 78% (58%-98%), 61% (38%-84%), and 41% (16%-66%), respectively. The group with better outcomes had NT-proBNP levels at 1 year < 400 pg/mL ( P = .013). Conclusions In our series, treatment success with bosentan in monotherapy was maintained in 78% at 3-year follow-up and 41% at 5-year follow-up. The group with long-term success showed significantly lower NT-proBNP levels at 1-year follow-up. Survival at 5 years in our series was 95%.

Pharmacoeconomic evidence of bosentan for pulmonary arterial hypertension

In this article, we review randomized controlled trials, open-label trials and pharmacoeconomic models of bosentan for the management of patients with pulmonary arterial hypertension. Bosentan consistently improves WHO functional class and quality of life, slows clinical worsening and is associated with improved survival compared with historical treatment. Although head-to-head trials are scarce, data directly comparing bosentan with sildenafil indicate no clinically significant differences between treatments as measured by the 6-min walk distance alone. Compared with historical care, bosentan treatment, over a 15–30-year period, increases the number of quality-adjusted life years (3.49 years). Economic modeling suggests that the cost–effectiveness of bosentan is similar to that of ambrisentan (US$43,725–57,778 per quality-adjusted life year), not as cost effective as sildenafil (at 20 mg three-times daily) and more cost effective than iloprost. More randomized controlled trials of longer duration are required to confirm the results from these economic models.

Rationale and design of a trial on the role of bosentan in Fontan patients: Improvement of exercise capacity?

Background The Fontan circulation is a palliative procedure performed in patients with complex congenital heart disease (CHD), making transpulmonary blood flow dependent on the systemic venous pressure. In a Fontan circulation a low pulmonary vascular resistance (PVR) is crucial, as is epitomized by the observation that a high PVR is a strong predictor of mortality. Long-term follow-up has shown that PVR may rise many years after the Fontan procedure has been performed, possibly due to micro-emboli from a dilated right atrium or from the venous system. Other mechanisms of increased PVR might be aging, obstructed airways caused by lymphatic dysfunction, lack of pulsatile pulmonary flow causing a release of endothelium-derived vasoactive molecules, and prolonged overexpression of vasoconstrictors such as endothelin-1. Mean plasma level of endothelin-1 has been shown to be significantly higher in Fontan patients compared to healthy controls. In patients with pulmonary arterial hypertension (PAH), therapy with bosentan, an endothelin-1 receptor antagonist, has demonstrated to improve exercise capacity and to reduce the elevated PVR. In addition, reduction of PVR is shown early and late after the Fontan procedure on treatment with exogenous NO, another advanced PAH therapy. However, the long term effect of reducing the PVR by bosentan treatment on exercise capacity in Fontan patients is still unknown. Methods We designed a prospective, multicenter, randomized open label trial to study the effect of bosentan in Fontan patients. The primary endpoint will be the change in maximum exercise capacity (peak V'O2). Conclusion We hypothesize that treatment with bosentan, an endothelin-1 receptor antagonist, improves maximum exercise capacity and functional capacity in adult Fontan patients.

312 Early Effects of Bosentan in Patients with Pulmonary Hypertension Due to Leftheart Failure Awaiting Heart Transplantation

312 Early Effects of Bosentan in Patients with Pulmonary Hypertension Due to Leftheart Failure Awaiting Heart Transplantation

Bosentan Effects on Hemodynamics and Clinical Outcome in Heart Failure Patients with Pulmonary Hypertension Awaiting Cardiac Transplantation

In heart failure (HF) patients, pulmonary hypertension (PH) is associated with a poor prognosis. We assessed whether low dose treatment with the dual endothelin-1 receptor antagonist bosentan is associated with improved hemodynamics and clinical outcome in these patients. We performed a retrospective data analysis in 82 end-stage heart failure patients on the waiting list for cardiac transplantation since January 2006. All patients had pulmonary arterial pressure >35 mmHg, pulmonary vascular resistance >240 dyn × s × cm-5, and/or a transpulmonary gradient (TPG) >15 mmHg. Fifty-four patients received a median dose of 125 mg bid bosentan (BOS group), and 28 patients received standard medical treatment (CON group). Data were assessed until June 2009. Hemodynamic parameters improved significantly in the BOS group but remained unchanged in the CON group. The percentage of patients who fell below the thresholds of PAP, PVR, and TPG for cardiac transplantation increased significantly by 20.3%, 34.5%, and 20.8%, respectively (p = 0.007-0.013) in the BOS group, but did not change significantly in the CON group. One-year survival on the waiting list was approximately 20% higher in the BOS group than in the CON group (p = 0.020). Bosentan treatment remained an independent predictor of reduced mortality risk on the waiting list after propensity score adjustment (relative risk = 0.107; 95% CI: 0.013-0.869; p = 0.036). Treatment with the endothelin-1 antagonist bosentan is associated with improvements in hemodynamics and clinical outcome in end-stage heart failure patients with PH. If these results can be confirmed by randomized controlled trials, bosentan may represent a treatment option in these patients.

Endothelin receptor expression in idiopathic pulmonary arterial hypertension: effect of bosentan and epoprostenol treatment

Endothelin receptor antagonists are used to treat idiopathic pulmonary arterial hypertension (IPAH), but human pulmonary arterial endothelin receptor expression is not well defined. We hypothesised that disease and treatment would modify normal receptor distribution in pulmonary resistance arteries of children. Using immunohistochemistry and semiquantitative analysis, we investigated endothelin receptor subtypes A and B (ET(A) and ET(B), respectively), and endothelial nitric oxide synthase (eNOS) expression in peripheral pulmonary arteries of tissue from untreated children with IPAH (n=7), following extended combined bosentan and epoprostenol therapy (n=5) and from normal subjects (n=5). Clinical, haemodynamic and pathological abnormalities were severe and advanced in all IPAH cases. ET(A) was detected in pulmonary arterial endothelial cells of all normal and diseased tissue and cultured cells. Endothelial ET(A), ET(B) and eNOS expression was reduced in patent, plexiform and dilatation lesions of untreated cases, but in treated cases, ET(A) and ET(B) were normal and eNOS increased. In smooth muscle, ET(A) expression was reduced in treated cases but ET(B) expression increased in all arteries of both treated and untreated cases. In summary, ET(A) is expressed on human pulmonary arterial endothelium. In IPAH, combination treatment with bosentan and epoprostenol had a more marked influence on endothelin receptor expression of endothelial than smooth muscle cells.

Effects of bosentan on collagen type I synthesis on in vitro culture of scleroderma skin fibroblasts

The present study evaluated the effects of a non-selective endothelin (ETA/B) receptors antagonist, on collagen type I (COLI) synthesis on in vitro culture of scleroderma (SSc) skin fibroblasts (Fb). Fb were obtained from skin biopsies of 6 female SSc patients (mean age 64. 1±6 years), after informed consent and Ethical Committee Approval. Cells were treated with endothelin-I [ET-I, 100nM] for 24 and 48 hrs, pre-treated for I hr with ETA/B receptors antagonist [10nM] alone or followed by ET-I for 24 and 48 hrs. Untreated Fb were used as controls. Immunocytochemistry and western blot analysis were performed to evaluate COLI synthesis. ET-I increased COLI synthesis both at 24 and 48 hrs when compared to controls. ETA/B receptor antagonost blocks the increased COLI synthesis ET-I-mediated both at 24 and 48 hrs vs. ET-I. Results showed that ET-I receptors blockage by ETA/B receptors antagonist might prevent the excessive synthesis of COLI, supporting its positive action in the management of skin fibrosis.

Effects of bosentan on collagen type I synthesis on in vitro culture of scleroderma skin fibroblasts

The present study evaluated the effects of a non-selective endothelin (ET A/B ) receptors antagonist, on collagen type I (COLI) synthesis on in vitro culture of scleroderma (SSc) skin fibroblasts (Fb). Fb were obtained from skin biopsies of 6 female SSc patients (mean age 64. 1 ± 6 years), after informed consent and Ethical Committee Approval. Cells were treated with endothelin-I [ET-I, 100nM] for 24 and 48 hrs, pre-treated for I hr with ET A/B receptors antagonist [10nM] alone or followed by ET-I for 24 and 48 hrs. Untreated Fb were used as controls. Immunocytochemistry and western blot analysis were performed to evaluate COLI synthesis. ET-I increased COLI synthesis both at 24 and 48 hrs when compared to controls. ET A/B receptor antagonost blocks the increased COLI synthesis ET-I-mediated both at 24 and 48 hrs vs. ET-I. Results showed that ET-I receptors blockage by ET A/B receptors antagonist might prevent the excessive synthesis of COLI, supporting its positive action in the management of skin fibrosis.

Effects of Bosentan Treatment on Angiotensin Converting Enzyme in Monocrotaline Induced Pulmonary Hypertension Rats

❙ABSTRACT❙ Background: Pulmonary artery hypertension is characterized by persistent increase of vascular resistance, and is associated with right ventricle failure. We investigated changes of plasma renin, serum aldosterone, angiotensin converting enzyme (ACE) concentrations, ACE gene expressions and protein contents after bosentan treatment. Methods: Six-week-old male Sprague-Dawley rats were divided into three groups: control (C) group, monocrotaline (M) group, and bosentan (B) group. Groups M and B were subcutaneously administered with 60 mg/kg of monocrotaline. In group B, 20 mg/kg/day of bosentan was administered by gavage twice a day. The rats were sacrificed after 1, 5, 7, 14, and 28 days. Changes of ACE gene expressions were analyzed by reverse transcription-polymerase chain reaction. Also, plasma renin, serum aldosterone, and ACE levels were measured. Results: Serum aldosterone levels were significantly increased in group M compared with group C and significantly decreased after bosentan treatment on day 28. Serum ACE concentrations were significantly decreased compared with group M after bosentan treatment on day 28. Gene expressions of ACE were significantly increased in group M compared with group C on day 5 and significantly decreased after bosentan treatment on day 7 and 14. ACE protein contents significantly increased in group M compared with group C in week 2 and 4. It significantly decreased after bosentan treatment in week 2. Conclusions: The renin-angiotensin system is associated with pulmonary artery hypertension. To investigate the effects of bosentan on the renin-angiotensin system in pulmonary artery hypertension, further studies on the effects of bosentan according to different doses are required in the future. (J Korean Soc Hypertens 2011;17(1):28-36)

Potent anti-inflammatory and antinociceptive activity of the endothelin receptor antagonist bosentan in monoarthritic mice

IntroductionEndothelins are involved in tissue inflammation, pain, edema and cell migration. Our genome-wide microarray analysis revealed that endothelin-1 (ET-1) and endothelin-2 (ET-2) showed a marked up-regulation in dorsal root ganglia during the acute phase of arthritis. We therefore examined the effects of endothelin receptor antagonists on the development of arthritis and inflammatory pain in monoarthritic mice.MethodsGene expression was examined in lumbar dorsal root ganglia two days after induction of antigen-induced arthritis (AIA) using mRNA microarray analysis. Effects of drug treatment were determined by repeated assessment of joint swelling, pain-related behavior, and histopathological manifestations during AIA.ResultsDaily oral administration of the mixed ETA and ETB endothelin receptor antagonist bosentan significantly attenuated knee joint swelling and inflammation to an extent that was comparable to dexamethasone. In addition, bosentan reduced inflammatory mechanical hyperalgesia. Chronic bosentan administration also inhibited joint swelling and protected against inflammation and joint destruction during AIA flare-up reactions. In contrast, the ETA-selective antagonist ambrisentan failed to promote any detectable antiinflammatory or antinociceptive activity.ConclusionsThus, the present study reveals a pivotal role for the endothelin system in the development of arthritis and arthritic pain. We show that endothelin receptor antagonists can effectively control inflammation, pain and joint destruction during the course of arthritis. Our findings suggest that the antiinflammatory and antinociceptive effects of bosentan are predominantly mediated via the ETB receptor.

Bosentan and improved pulmonary endothelial function in pulmonary arterial hypertension: Figure 1–

To the Editors: Pulmonary arterial hypertension (PAH) is characterised by pulmonary endothelial dysfunction and smooth muscle cell proliferation 1. Miniaturised catheter-based technology has recently enabled in vivo assessment of both endothelial dysfunction and pulmonary artery thickening in vivo 2, 3. Bosentan, an oral dual endothelin-1 receptor antagonist, has been shown to improve clinical outcomes in PAH 4. In vitro , bosentan has been shown to improve human endothelial cell function 5 and reduce neointimal and smooth muscle proliferation. In pigs in vivo , bosentan has been shown to partially restore hypoxia-induced reductions in nitric oxide 6. The effect of bosentan on human pulmonary artery structure and function in vivo , however, has not been studied. We hypothesised that bosentan therapy might improve pulmonary microvascular endothelial function and pulmonary artery remodelling in patients with established PAH. Therefore, we assessed the effect of 6 months of clinically indicated bosentan therapy in patients with advanced PAH on: 1) pulmonary microvascular function, assessed by Doppler-derived pulmonary blood flow responses to vasoactive agents; and 2) segmental pulmonary artery structure, measured by pulmonary intravascular ultrasound (IVUS). Eight bosentan-naive subjects (three males and five females; five subjects with idiopathic and three with scleroderma-related PAH; mean±sem age 66±4 yrs; weight 79±5 kg) were studied. The institutional review board (Royal Prince Alfred Hospital, Sydney, NSW, Australia) approved the study protocol and informed consent was obtained from all subjects. All patients were in New York Heart Association (NYHA) functional class III, had mean pulmonary arterial pressure ( P pa) >25 mmHg at rest (without demonstrable reversibility) and had pulmonary capillary wedge pressure ≤15 mmHg. Clinically indicated right heart catheterisation, assessing suitability for bosentan prescription, was performed. Thereafter, pulmonary artery IVUS assessment was performed in a distal segmental pulmonary artery of both upper and lower lobes …