Pulmonary Vascular Structure Research Articles

Pulmonary Vascular Structure and Function Are Related to Exercise Capacity in Health and COPD

Although it is generally accepted that aerobic exercise training does not change lung structure or function, some work suggests that greater pulmonary vascular structure and function is associated with higher exercise capacity (VO2peak). Is there a cross-sectional association between the pulmonary vasculature and VO2peak? We hypothesized that those with higher computed tomography (CT) blood vessel volumes, and pulmonary diffusing capacity for carbon monoxide (DLCO) would have higher VO2peak, independent of airflow limitation. Participants from the CanCOLD study were categorized as: never-smokers with normal spirometry (n=263); ever-smokers with normal spirometry (n=407); and chronic obstructive pulmonary disease (COPD): individuals with spirometric airflow obstruction (n=334). Total vessel volume (TVV), the volume for all vessels with a cross-sectional area ≤5 mm2 (BV5), and between 5-10 mm2 (BV5-10) were generated from CT scans and used as indices of pulmonary vascular structure. DLCO was used as an index of pulmonary microvascular function. VO2peak was evaluated via incremental cardiopulmonary exercise testing. General linear regression models revealed that even after controlling for FEV1, emphysema severity and body morphology, DLCO, TVV, BV5 and BV5-10, were independently associated with VO2peak. Interaction effects were observed between COPD and TVV, BV5, and BV5-10 indicating a weaker association between pulmonary vascular volumes and VO2peak in COPD. Our results suggest that pulmonary vascular structure and DLCO is independently associated with VO2peak, regardless of severity of airflow limitation and emphysema, suggesting that these associations are not limited to COPD.

Sex-related differences in pulmonary vascular volume distribution.

Pulmonary arterial hypertension affects females more frequently than males, and there are known sex-related differences in the lungs. However, normal sex-related differences in pulmonary vascular structure remain incompletely described. We aimed to contrast computed tomography-derived pulmonary vascular volume and its distribution within the lungs of healthy adult females and males. From the CanCOLD Study, we retrospectively identified healthy never-smokers. We analyzed full-inspiration computed tomography images, using vessel and airway segmentation to generate pulmonary vessel volume, vessel counts, and airway counts. Vessels were classified by cross-sectional area >10, 5-10, and <5 mm2 into bins, with volume summed within each area bin and in total. We included 46 females and 36 males (62 ± 9 years old). Females had lower total lung volume, total airway counts, total vessel counts, and total vessel volume (117 ± 31 vs. 164 ± 28 mL) versus males (all p < 0.001). Females also had lower vessel volume >10 mm2 (14 ± 8 vs. 27 ± 9 mL), vessel volume 5-10 mm2 (35 ± 11 vs. 55 ± 10 mL), and vessel volume <5 mm2 (68 ± 18 vs. 82 ± 19 mL) (all p < 0.001). Normalized to total vessel volume, vessel volume >10 mm2 (11 ± 4 vs. 16 ± 4%, p < 0.001) and 5-10 mm2 (30 ± 6 vs. 34 ± 5%, p = 0.001) remained lower in females but vessel volume <5 mm2 relative to total volume was 18% higher (59 ± 8 vs. 50 ± 7%, p < 0.001). Among healthy older adults, pulmonary vessel volume is distributed into smaller vessels in females versus males.

Iron deficiency in pulmonary vascular disease: pathophysiological and clinical implications.

Iron deficiency is common in pulmonary hypertension, but its clinical significance and optimal definition remain unclear. Phenotypic data for 1028 patients enrolled in the Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics study were analyzed. Iron deficiency was defined using the conventional heart failure definition and also based upon optimal cut-points associated with impaired peak oxygen consumption (peakVO2), 6-min walk test distance, and 36-Item Short Form Survey (SF-36) scores. The relationships between iron deficiency and cardiac and pulmonary vascular function and structure and outcomes were assessed. The heart failure definition of iron deficiency endorsed by pulmonary hypertension guidelines did not identify patients with reduced peakVO2, 6-min walk test, and SF-36 (P > 0.208 for all), but defining iron deficiency as transferrin saturation (TSAT) <21% did. Compared to those with TSAT ≥21%, patients with TSAT <21% demonstrated lower peakVO2 [absolute difference: -1.89 (-2.73 to -1.04) mL/kg/min], 6-min walk test distance [absolute difference: -34 (-51 to -17) m], and SF-36 physical component score [absolute difference: -2.5 (-1.3 to -3.8)] after adjusting for age, sex, and hemoglobin (all P < 0.001). Patients with a TSAT <21% had more right ventricular remodeling on cardiac magnetic resonance but similar pulmonary vascular resistance on catheterization. Transferrin saturation <21% was also associated with increased mortality risk (hazard ratio 1.63, 95% confidence interval 1.13-2.34; P = 0.009) after adjusting for sex, age, hemoglobin, and N-terminal pro-B-type natriuretic peptide. The definition of iron deficiency in the 2022 European Society of Cardiology (ESC)/European Respiratory Society (ERS) pulmonary hypertension guidelines does not identify patients with lower exercise capacity or functional status, while a definition of TSAT <21% identifies patients with lower exercise capacity, worse functional status, right heart remodeling, and adverse clinical outcomes.

Ground-glass opacity in a patient with right aortic arch and no left pulmonary artery

BackgroundHere we report a case of patients with mixed ground glass opacity in the left lung combined with congenital right aortic arch, which is only present in 0.01–0.1% of adults.Case presentationA 60-year-old woman was referred to our department with a mixed ground-glass opacity (GGO) in the upper lobe of her left lung. She had congenital right aortic arch, and the left pulmonary artery was absent. Enhanced chest computed tomography, pulmonary perfusion imaging, and three-dimensional reconstruction were performed to confirm the blood supply in the left lung and the exact location of the GGO. Because of the unusual left pulmonary vascular structure, wedge resection was performed to prevent massive hemorrhage. The final pathological examination revealed that the mixed GGO was a well-differentiated pulmonary adenocarcinoma.ConclusionThe surgical options should be evaluated carefully in view of the complications and the prognosis of the patient, when ground glass opacity is combined with congenital cardiovascular anomalies.

Effects of panax notoginseng saponins on pulmonary vascular remodeling in rats with pulmonary hypertension and its mechanisms

Objective: To investigate the effects of panax notoginseng saponins (PNS) on pulmonary vascular remodeling and SIRT1/FOXO3a/p27 pathway in pulmonary arterial hypertension (PAH) rats. Methods: Male SD rats weighing 200~250g were randomly divided into control group, monocrotaline group (MCT) and monocrotaline + panax notoginseng saponins group (MCT+PNS), with 10 rats in each group. The rats in control group were injected intraperitoneally with normal saline 3 ml/kg on the first day, then injected intraperitoneally with normal saline 2.5 ml/kg every day. The rats in MCT group were injected intraperitoneally with MCT 60 mg/kg on the first day, followed by daily injection of normal saline 2.5 ml/kg. In MCT+PNS group, 60 mg/kg MCT was injected intraperitoneally on the first day, and 50 mg/kg PNS was injected intraperitoneally every day. The above models were fed conventionally for 4 weeks. After the modeling was completed, the mean pulmonary artery pressure (mPAP) and right ventricular systolic pressure (RVSP) of rats in each group were detected by right heart catheter method, weighed and calculated right ventricular hypertrophy index (RVHI), and the pulmonary vascular structure and morphological changes were observed by HE and Masson staining. The protein and gene expressions of SIRT1, FOXO3a, p27, PCNA and Caspase-3 were detected by qPCR and Western blot. Results: Compared with control group, mPAP, RVSP and RVHI in MCT group were increased significantly (P＜0.01), pulmonary vessels were thickened significantly and collagen fibers were increased, protein and gene expressions of SIRT1, FOXO3a, p27 and Caspase-3 were decreased (P＜0.05 or P＜0.01). The protein and gene expressions of PCNA were increased (P＜0.05). Compared with MCT group, the levels of mPAP, RVSP and RVHI in MCT+PNS group were decreased significantly (P＜0.05 or P＜0.01), pulmonary vascular thickening was alleviated and collagen fibers were reduced. The protein and gene expressions of SIRT1, FOXO3a, p27 and Caspase-3 were increased (P＜0.05 or P＜0.01), while the protein and gene expressions of PCNA were decreased (P＜0.05 or P＜0.01). Conclusion: Panax notoginseng saponins can relieve pulmonary vascular remodeling in rats with pulmonary hypertension by activating SIRT1/FOXO3a/p27 pathway.

Novel p38 Mitogen-Activated Protein Kinase Inhibitor Reverses Hypoxia-Induced Pulmonary Arterial Hypertension in Rats.

Mitogen-activated protein kinase (MAPK) signaling is strongly implicated in cardiovascular remodeling in pulmonary hypertension (PH) and right ventricle (RV) failure. The effects of a newly designed p38 inhibitor, LASSBio-1824, were investigated in experimentally induced PH. Male Wistar rats were exposed to hypoxia and SU5416 (SuHx), and normoxic rats were used as controls. Oral treatment was performed for 14 days with either vehicle or LASSBio-1824 (50 mg/kg). Pulmonary vascular resistance and RV structure and function were assessed by echocardiography and catheterization. Histological, immunohistochemical and Western blot analysis of lung and RV were performed to investigate cardiovascular remodeling and inflammation. Treatment with LASSBio-1824 normalized vascular resistance by attenuating vessel muscularization and endothelial dysfunction. In the heart, treatment decreased RV systolic pressure, hypertrophy and collagen content, improving cardiac function. Protein content of TNF-α, iNOS, phosphorylated p38 and caspase-3 were reduced both in lung vessels and RV tissues after treatment and a reduced activation of transcription factor c-fos was found in cardiomyocytes of treated SuHx rats. Therefore, LASSBio-1824 represents a potential candidate for remodeling-targeted treatment of PH.

Mouse model of experimental pulmonary hypertension: Lung angiogram and right heart catheterization.

Pulmonary arterial hypertension is a progressive and fatal disease and rodents with experimental pulmonary hypertension (PH) are often used to study pathogenic mechanisms, identify therapeutic targets, and develop novel drugs for treatment. Here we describe a hands-on set of experimental approaches including ex vivo lung angiography and histology and in vivo right heart catheterization (RHC) to phenotypically characterize pulmonary hemodynamics and lung vascular structure in normal mice and mice with experimental PH. We utilized Microfil polymer as contrast in our ex vivo lung angiogram to quantitatively examine pulmonary vascular remodeling in mice with experimental PH, and lung histology to estimate pulmonary artery wall thickness. The peripheral lung vascular images were selected to determine the total length of lung vascular branches, the number of branches and the number of junctions in a given area (mm−2). We found that the three parameters determined by angiogram were not significantly different among the apical, middle, and basal regions of the mouse lung from normal mice, and were not influenced by gender (no significant difference between female and male mice). We conducted RHC in mice to measure right ventricular systolic pressure, a surrogate measure for pulmonary artery systolic pressure and right ventricle (RV) contractility (RV ± dP/dtmax) to estimate RV function. RHC, a short time (4–6 min) procedure, did not alter the lung angiography measurements. In summary, utilizing ex vivo angiogram to determine peripheral vascular structure and density in the mouse lung and utilizing in vivo RHC to measure pulmonary hemodynamics are reliable readouts to phenotype normal mice and mice with experimental PH. Lung angiogram and RHC are also reliable approaches to examine pharmacological effects of new drugs on pulmonary vascular remodeling and hemodynamics.

Echocardiographic, Biochemical, and Electrocardiographic Correlates Associated With Progressive Pulmonary Arterial Hypertension.

Background: Pulmonary arterial hypertension (PAH) is a progressive proliferative vasculopathy associated with mechanical and electrical changes, culminating in increased vascular resistance, right ventricular (RV) failure, and death. With a main focus on invasive tools, there has been an underutilization of echocardiography, electrocardiography, and biomarkers to non-invasively assess the changes in myocardial and pulmonary vascular structure and function during the course of PAH.Methods: A SU5416-hypoxia rat model was used for inducing PAH. Biventricular functions were measured using transthoracic two-dimensional (2D) echocardiography/Doppler (echo/Doppler) at disease onset (0 week), during progression (3 weeks), and establishment (5 weeks). Similarly, electrocardiography was performed at 0, 3, and 5 weeks. Invasive hemodynamic measurements and markers of cardiac injury in plasma were assessed at 0, 3, and 5 weeks.Results: Increased RV systolic pressure (RVSP) and rate of isovolumic pressure rise and decline were observed at 0, 3, and 5 weeks in PAH animals. EKG showed a steady increase in QT-interval with progression of PAH, whereas P-wave height and RS width were increased only during the initial stages of PAH progression. Echocardiographic markers of PAH progression and severity were also identified. Three echocardiographic patterns were observed: a steady pattern (0–5 weeks) in which echo parameter changed progressively with severity [inferior vena cava (IVC) expiratory diameter and pulmonary artery acceleration time (PAAT)], an early pattern (0–3 weeks) where there is an early change in parameters [RV fractional area change (RV-FAC), transmitral flow, left ventricle (LV) output, estimated mean PA pressure, RV performance index, and LV systolic eccentricity index], and a late pattern (3–5 weeks) in which there is only a late rise at advanced stages of PAH (LV diastolic eccentricity index). RVSP correlated with PAAT, PAAT/PA ejection times, IVC diameters, RV-FAC, tricuspid systolic excursion, LV systolic eccentricity and output, and transmitral flow. Plasma myosin light chain (Myl-3) and cardiac troponin I (cTnI) increased progressively across the three time points. Cardiac troponin T (cTnT) and fatty acid-binding protein-3 (FABP-3) were significantly elevated only at the 5-week time point.Conclusion: Distinct electrocardiographic and echocardiographic patterns along with plasma biomarkers were identified as useful non-invasive tools for monitoring PAH progression.

The expression and significance of heparinase, MMP‐9 in lung tissue of rat pulmonary hypertension model

Objective To investigate the relationship between heparinase and matrix metalloproteinase (MMP 9) and pulmonary hypertension by comparing their expression characteristics in pulmonary hypertension model rats and normal rats, and to study their possible mechanisms in pulmonary hypertension and pulmonary vascular structure reconstruction in rats. Methods Pulmonary hypertension model was established by single intraperitoneal injection of Monocrotaline. Twenty rats were randomly divided into normal control group and pulmonary hypertension model group (model group) with 10 rats in each group. Color Doppler ultrasonography was used to measure the changes of pulmonary artery peak velocity and inner diameter of pulmonary artery root. The changes of mean pulmonary artery pressure (mPAP), right ventricular hypertrophy index and mean carotid artery pressure (mCAP) were measured. HE staining was used to observe the pathological morphological changes of pulmonary vessels. The expression of heparinase and MMP 9 in the lung tissues of rats in the two groups was determined by immunohistochemical SABC method. Results The peak velocity of pulmonary artery, inner diameter of pulmonary artery root, mPAP, MMP 9 and right ventricular hypertrophy index in model group were significantly higher than those in control group (P<0.01). There was no significant difference in mean carotid pressure and heparinase expression between the two groups (P>0.05). Conclusion The establishment of pulmonary hypertension model by single intraperitoneal injection of Lilipine has the characteristics of simple operation, low damage to animals and high success rate. Inhibition of MMP 9 synthesis or reduction of MMP 9 activity may be one of the mechanisms by which MMP 9 inhibits wilylin-induced pulmonary hypertension and pulmonary vascular structural reconstruction in rats.

TMEM16A Regulates Pulmonary Arterial Smooth Muscle Cells Proliferation via p38MAPK/ERK Pathway in High Pulmonary Blood Flow-Induced Pulmonary Arterial Hypertension

Objective: Pulmonary arterial hypertension (PAH) is a complex disease of the small pulmonary arteries that is mainly characterized by vascular remodeling. It has been demonstrated that excessive proliferation of pulmonary arterial smooth muscle cells (PASMCs) plays a pivotal role in vascular remodeling during PAH. The present study was undertaken to explore the role of TMEM16A in regulating PASMCs proliferation in high pulmonary blood flow-induced PAH. Methods: Aortocaval shunt surgery was undertaken to establish an animal model. Pulmonary artery pressure and pulmonary vascular structure remodeling (PVSR) were tested. Immunohistochemical staining and Western blot were performed to investigate the expression of TMEM16A. The proliferation of PASMCs was tested by the MTT assay. After treating PASMCs with TMEM16A-siRNA, the expression of proliferating cell nuclear antigen (PCNA), phosphorylated p38 mitogen-activated protein kinase (p-p38MAPK), and phosphorylated extracellular signal-regulated kinase (p-ERK) signaling in PASMCs were tested. Results: PAH and PVSR developed 11 weeks postoperation. Elevated expression of TMEM16A accompanied by high expression of PCNA in pulmonary arteries of the shunt group was observed. The increased proliferation of PASMCs and increased expression of TMEM16A and PCNA, along with activated p-p38MAPK and p-ERK signaling in PASMCs of the shunt group, were all attenuated by siRNA-specific TMEM16A knockdown. Conclusion: TMEM16A regulates PASMCs proliferation in high pulmonary blood flow-induced PAH, and the p38MAPK/ERK signaling pathway is probably involved.

PDGF mediates pulmonary arterial smooth muscle cell proliferation and migration by regulating NFATc2.

The reconstruction of pulmonary vascular structure caused by the proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs) is the central link in the formation of pulmonary arterial hypertension (PAH). Platelet-derived growth factor (PDGF) can regulate the proliferation and migration of PASMCs. At the same time, nuclear factor of activated T cells (NFATs) plays an important role in the development of PAH. To the best of our knowledge, there are no reports yet regarding whether PDGF regulates NFATc2 to increase the proliferation of PASMCs. The present study aimed to investigate whether PDGF affects the proliferation and migration of PASMCs by regulating NFAT, and to study the pathogenesis of PAH. PASMCs were treated with recombinant PDGF; Cell Counting Kit-8 and clone formation experiments showed that PDGF enhanced the cell viability and proliferation of PASMCs. Cell cycle distribution and molecular markers related to cell proliferation (cyclin D1, CDK4 and Proliferating Cell Nuclear Antigen) were detected by flow cytometry, and the results indicated that PDGF promoted the division of PAMSCs. The scratch migration and Transwell migration assays showed that the migratory ability of PASMCs was enhanced following PDGF treatment. Changes in NFATs (NFATc1-5) after PDGF treatment were evaluated by reverse transcription-quantitative PCR and western blotting; NFATc2 showed the most significant results. Finally, PDGF-treated cells were treated with an NFAT pathway inhibitor, cyclosporin A, or a small interfering RNA targeting NFATc2, and changes in cell proliferation and migration were evaluated to assess the role of NFATc2 in PDGF-induced cell proliferation and migration. In conclusion, PDGF may regulate PASMC proliferation and migration by regulating the expression of NFAT, further leading to the occurrence of PAH. It is proposed that NFATc2 could be used as a potential target for PAH treatment.

Reversal of Hypoxic Pulmonary Hypertension by Hypoxia-Inducible Overexpression of Angiotensin-(1-7) in Pulmonary Endothelial Cells

Hypoxia-induced pulmonary vascular constriction and structure remodeling are the main causes of hypoxic pulmonary hypertension. In the present study, an adeno-associated virus vector, containing Tie2 promoter and hypoxia response elements, was designed and named HTSFcAng(1-7). Its targeting, hypoxic inducibility, and vascular relaxation were examined in vitro, and its therapeutic effects on hypobaric hypoxia-induced pulmonary hypertension were examined in rats. Transfection of HTSFcAng(1-7) specifically increased the expression of angiotensin-(1-7) in endothelial cells in normoxia. Hypoxia increased the expression of angiotensin-(1-7) in HTSFcAng(1-7)-transfected endothelial cells. The condition medium from HTSFcAng(1-7)-transfected endothelial cells inhibited the hypoxia-induced proliferation of pulmonary artery smooth muscle cells, relaxed the pulmonary artery rings, totally inhibited hypoxia-induced early contraction, enhanced maximum relaxation, and reversed phase II constriction to sustained relaxation. In hypoxic pulmonary hypertension rats, treatment with HTSFcAng(1-7) by nasal drip adeno-associated virus significantly reversed hypoxia-induced hemodynamic changes and pulmonary artery-wall remodeling, accompanied by the concomitant overexpression of angiotensin-(1-7), mainly in the endothelial cells in the lung. Therefore, hypoxia-inducible overexpression of angiotensin-(1-7) in pulmonary endothelial cells may be a potential strategy for the gene therapy of hypoxic pulmonary hypertension.

Using Pulmonary Angiogram to Estimate Vascular Remodeling in Mice

BackgroundPulmonary vascular remodeling is a major cause for the elevated pulmonary vascular resistance in patients with pulmonary arterial hypertension (PAH) and animals with experimental pulmonary hypertension (PH). Utilizing pulmonary angiography technique, we are able to visualize vascular blockade and structural changes in the lung vasculature of patients with PAH and animals with experimental PH. Given the differences in ventilation (V), perfusion (Q) and V/Q relationship in different regions of the lung, it is important to know whether vascular structure and density are different in various areas of the lung. In this study, we aimed to examine whether pulmonary vascular structure and density are different in the upper (apical), middle and lower (basal) regions of the lung in mice and whether pulmonary hemodynamic measurement via right heart catheterization affects the angiographic measurement.MethodsA polyethylene tube was cannulated into the pulmonary artery (PA) via the right ventricle in anesthetized mice to perfuse microfilm polymer (yellow) into the lung vasculature using an automated pump. The lungs filled with microfil were dehydrated using ethanol and placed in methyl salicylate for overnight to show only the vasculature. Lungs were then photographed with a digital camera. The peripheral lung vascular images from the upper, middle and lower regions were selected and converted to binary images for quantitative analysis.ResultsIn the skeletonized images (showing only the vasculature), the length of branches, the number of branches, and the number of junctions were first measured and compared among the upper, middle and lower regions of normal mouse lungs. The data showed that there was no significant difference among different regions in terms of the length of branches as well as the numbers of branches and junctions. Furthermore, we compared these three parameters in different regions between the lungs isolated from mice in which we measured right ventricular pressure using right heart catheterization and the lungs isolated from control mice. The data indicated that the length of branches (22±3, 20±3 and 21±1 vs. 21±1, 22±1 and 19±2 mm/mm2, respectively), the number of branches (420±70, 364±83 and 411±44 vs. 388±50, 426±26 and 353±27 per mm2, respectively, and the number of junctions (186±34, 186±14 and 212±38 vs. 183±35, 191±13 and 155±18 per mm2, respectively) in the upper, middle and lower regions of the lungs from mice with right heart catheterization were not significantly different from the lungs of control mice.ConclusionPeripheral vascular structure and density in the mouse lung, determined by the length of branches and the numbers of branches and junctions, are not significantly different among the apical, middle and basal regions of the mouse lung. Lung hemodynamic measurement or invasive right heart catheterization has little effect on the peripheral vascular density. These results suggest that lung angiogram on the peripheral vasculature is a reliable experimental tool to evaluate lung vascular structural changes in small animals.Support or Funding InformationNational Natural Science Foundation of China (81800035)

Expression of pulmonary arterial elastin in rats with hypoxic pulmonary hypertension using H2S

Object: This study analyses the changes of pulmonary arterial elastin expression inhibited by hydrogen sulfide (H2S) in rats with hypoxic pulmonary hypertension.Method: The research used 30 healthy rats and randomly divided them into control group, hypoxia group, and hypoxia + sodium hydrosulfide group. Each group contains 10 samples. The right catheterization was selected to measure the mean pulmonary artery pressure (mPAP). The RV/LV + S ratio was calculated through separating the right ventricle and the left ventricle plus the interventricular septum. Optical microscopy was used to observe the changes of pulmonary vascular structure. The research used immunohistochemistry to express the levels of elastin and transforming growth factor beta (TGF-β).Results: The ratios of Mpap and RV/LV + S in the hypoxic group exceed the control group. The hypoxia + sodium hydrosulfide group (hypoxia + NaHS) is lower than the hypoxic group. In the hypoxic group, the elastic expressions of medium and small pulmonary artery smooth muscle cells exceed the control group. The expression of elastin in hypoxic + NaHS medium and small pulmonary artery smooth muscle cells is lower than that of the control group.The protein expression levels of α-SM-actin in muscle arterial smooth muscle of pulmonary arterioles in hypoxic group, control group and hypoxic + NaHS group were 49.84% + 6.27%, 56.84% + 6.38%, 23.82% + 3.84%, 27.51% + 3.24%, 29.00% + 4.05%, 34.72% + 3.38%.Conclusion: Hydrogen sulfide in rats with hypoxic pulmonary hypertension can inhibit the expression of elastin in its extracellular matrix, which also has remarkable regulation function in forming HPH and remodeling hypoxic pulmonary vascular structure.

TRPV4 channel mediates adventitial fibroblast activation and adventitial remodeling in pulmonary hypertension.

Pulmonary arterial adventitial fibroblasts (PAF), the most abundant cellular constituent of adventitia, act as a key regulator of pulmonary vascular wall structure and function from the outside-in. Previous studies indicate that transient receptor potential vanilloid 4 (TRPV4) channel plays an important role in the development of pulmonary hypertension (PH), but no attention has been given so far to its role in adventitial remodeling. In this study, we thus investigated TRPV4 implication in PAF activation occurring in PH. First, we isolated and cultured PAF from rat adventitial intrapulmonary artery. RT-PCR, Western blot, immunostaining, and calcium imaging (fluo-4/AM) showed that PAF express functional TRPV4 channels. In extension of these results, using pharmacological and siRNA approaches, we demonstrated TRPV4 involvement in PAF proliferation (BrdU incorporation) and migration (wound-healing assay). Then, Western blot experiments revealed that TRPV4 activation upregulates the expression of extracellular matrix protein synthesis (collagen type I and fibronectin). Finally, we explored the role of TRPV4 in the adventitial remodeling occurring in PH. By means of Western blot, we determined that TRPV4 protein expression was upregulated in adventitia from chronically hypoxic and monocrotaline rats, two animal models of PH. Furthermore, morphometric analysis indicated that adventitial remodeling is attenuated in PH-induced trpv4-/- mice. These data support the concept that PAF play an essential role in hypertensive pulmonary vascular remodeling and point out the participation of TRPV4 channel activity in PAF activation leading to excessive adventitial remodeling.

Antenatal sildenafil treatment improves neonatal pulmonary hemodynamics and gas exchange in lambs with diaphragmatic hernia.

Infants with congenital diaphragmatic hernia (CDH) are predisposed to pulmonary hypertension after birth, owing to lung hypoplasia that impairs fetal pulmonary vascular development. Antenatal sildenafil treatment attenuates abnormal pulmonary vascular and alveolar development in rabbit and rodent CDH models, but whether this translates to functional improvements after birth remains unknown. We aimed to evaluate the effect of antenatal sildenafil on neonatal pulmonary hemodynamics and lung function in lambs with diaphragmatic hernia (DH). DH was surgically induced at approximately 80 days' gestation in 16 lamb fetuses (term in lambs is approximately 147 days). From 105 days' gestation, ewes received either sildenafil (0.21 mg/kg/h intravenously) or saline infusion until delivery (n = 8 fetuses in each group). At approximately 138 days' gestation, all lambs were instrumented and then delivered via Cesarean section. The lambs were ventilated for 120 min with continuous recording of physiological (pulmonary and carotid artery blood flow and pressure; cerebral oxygenation) and ventilatory parameters, and regular assessment of arterial blood gas tensions. Only lambs that survived until delivery and with a confirmed diaphragmatic defect at postmortem examination were included in the analysis; these comprised six DH-sildenafil lambs and six DH-saline control lambs. Lung-to-body-weight ratio (0.016 ± 0.001 vs 0.013 ± 0.001; P = 0.06) and dynamic lung compliance (0.8 ± 0.2 vs 0.7 ± 0.2 mL/cmH2 O; P = 0.72) were similar in DH-sildenafil lambs and controls. Pulmonary vascular resistance decreased following lung aeration to a greater degree in DH-sildenafil lambs, and was 4-fold lower by 120 min after cord clamping than in controls (0.6 ± 0.1 vs 2.2 ± 0.6 mmHg/(mL/min); P = 0.002). Pulmonary arterial pressure was also lower (46 ± 2 vs 59 ± 2 mmHg; P = 0.048) and pulmonary blood flow higher (25 ± 3 vs 8 ± 2 mL/min/kg; P = 0.02) in DH-sildenafil than in DH-saline lambs at 120 min. Throughout the 120-min ventilation period, the partial pressure of arterial carbon dioxide tended to be lower in DH-sildenafil lambs than in controls (63 ± 8 vs 87 ± 8 mmHg; P = 0.057), and there was no significant difference in partial pressure of arterial oxygen between the two groups. Sustained maternal antenatal sildenafil infusion reduced pulmonary arterial pressure and increased pulmonary blood flow in DH lambs for the first 120 min after birth. These findings of improved pulmonary vascular function are consistent with improved pulmonary vascular structure seen in two previous animal models. The data support the rationale for a clinical trial investigating the effect of antenatal sildenafil in reducing the risk of neonatal pulmonary hypertension in infants with CDH. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

A Review of Exercise Interventions in Pulmonary Arterial Hypertension and Recommendations for Rehabilitation Programing.

Pulmonary arterial hypertension (PAH) is characterized by impaired pulmonary vascular structure and function and is commonly associated with symptoms of dyspnea, fatigue, and potentially syncope. With chronic exposure to elevated pulmonary pressures, dramatic right ventricular dysfunction is common, thereby compromising cardiorespiratory fitness and increasing the risk of mortality. Collective investigative efforts, both at the preclinical and clinical levels, have established the safety and efficacy of regular exercise training in improving quality of life, cardiorespiratory fitness, and the physiologic profile of patients with PAH. Although the total volume of exercise training studies in patients with PAH pales in comparison with other chronic conditions, evidence for the optimal training recommendations is emerging. This review aims to provide a synopsis of the current exercise training literature in patients with PAH and provide preliminary training recommendations that can be implemented in rehabilitation programs.

Sequelae Tuberkulosis dengan Hemoptisis Rekurens

Background: Various sequelae and complications can occur in treated or untreated tuberculosis (TB). One of complications in the lungs is hemoptysis, due to alterations of pulmonary vascular structure. Hemoptysis as TB sequelae can happen recurrently and massively. Case: We present the case of 31 year old man with recurrent hemoptysis since 1 year before admitted to hospital. Patient had a history of receiving antituberculosis drugs (ATD) before. Chest xray showed pleural thickening and opacity in right hemithorax with signs of loss of volume. Bronchoscopy showed active bleeding in lateral segment of right lung middle lobe. Chest CT showed destroyed right lung. Hemoptysis still existed despite the given conventional therapy, thus patient underwent pulmonary arteriography. The result showed extensive vascular abnormality in the right lung with arteriovenous fistula on right bronchial artery and aneurysmatic branch of superior bronchial and inner intercostal arteries. During the procedure, there was no active bleeding, so bronchial artery embolization was adjourned. Patient then experienced recurrent and massive hemoptysis, thus right pneumonectomy was done. During the surgery, there was uncontrolled active bleeding that caused the patient’s death. Conclusion: This case illustrates recurrent hemoptysis as one of severe TB sequelae. In extensive pulmonary vascular abnormality, pneumonectomy can cause uncontrolled active bleeding. Bronchial artery embolization can be used as an alternative to treat patients with recurrent homptysis.

Berberine attenuates hypoxia-induced pulmonary arterial hypertension via bone morphogenetic protein and transforming growth factor-β signaling.

Hypoxia-induced excessive pulmonary artery smooth muscle cell (PASMC) proliferation plays an important role in the pathology of pulmonary arterial hypertension (PAH). Berberine (BBR) is reported as an effective antiproliferative properties applied in clinical. However, the effect of BBR on PAH remains unclear. In the present study, we elucidated the protective effects of BBR against abnormal PASMC proliferation and vascular remodeling in chronic hypoxia-induced hearts. Furthermore, the potential mechanisms of BBR were investigated. For this purpose, C57/BL6 mice were exposed to chronic hypoxia for 4 weeks to mimic severe PAH. Hemodynamic and pulmonary pathomorphology data showed that chronic hypoxia significantly increased the right ventricular systolic pressure (RVSP), the right ventricle/left ventricle plus septum RV/(LV + S) weight ratio, and the median width of pulmonary arterioles. BBR attenuated the elevations in RVSP and RV/(LV + S) and mitigated pulmonary vascular structure remodeling. BBR also suppressed the hypoxia-induced increases in the expression of proliferating cell nuclear antigen (PCNA) and of α-smooth muscle actin. Furthermore, administration of BBR significantly increased the expression of bone morphogenetic protein type II receptor (BMPR-II) and its downstream molecules P-smad1/5 and decreased the expression of transforming growth factor-β (TGF-β) and its downstream molecules P-smad2/3. Moreover, peroxisome proliferator-activated receptor γ expression was significantly decreased in the hypoxia group, and this decrease was reversed by BBR treatment. Our study demonstrated that the protective effect of BBR against hypoxia-induced PAH in a mouse model may be achieved through altered BMPR-II and TGF-β signaling.

Relation of Macrophage Migration Inhibitory Factor to Pulmonary Hemodynamics and Vascular Structure and Carbamyl-Phosphate Synthetase I Genetic Variations in Pediatric Patients with Congenital Cardiac Shunts.

Macrophage migration inhibitory factor (MIF) plays an important pathophysiological role in pulmonary hypertension (PHT). Previously, we demonstrated that serum MIF is increased in pediatric PHT associated with congenital heart disease (CHD). In the present study, we determined possible associations between MIF levels, hemodynamic and histological parameters, and mitochondrial carbamyl-phosphate synthetase I (CPSI) T1405N polymorphism in a similar population. The asparagine 1405 variant (related to A alleles in the C-to-A transversion) has been shown to be advantageous in pediatric PHT compared to the threonine 1405 variant (C alleles). Forty-one patients were enrolled (aged 2-36 months) and subsequently divided into 2 groups after diagnostic evaluation: the high-pulmonary blood flow (high PBF) group (pulmonary-to-systemic blood flow ratio 2.58 (2.21-3.01), geometric mean with 95% CI) and the high-pulmonary vascular resistance (high PVR) group (pulmonary vascular resistance 6.12 (4.78-7.89) Wood units × m2). Serum MIF was measured using a chemiluminescence assay. The CPSI polymorphism was analyzed by polymerase chain reaction followed by high-resolution melting analysis. Medial hypertrophy of pulmonary arteries was assessed by the histological examination of biopsy specimens. Serum MIF was elevated in patients compared to controls (p = 0.045), particularly in the high-PVR group (n = 16) (p = 0.022) and in subjects with the AC CPSI T1405N genotype (n = 16) compared to those with the CC genotype (n = 25) (p = 0.017). Patients with high-PVR/AC-genotype profile (n = 9) had the highest MIF levels (p = 0.030 compared with the high-PBF/CC-genotype subgroup, n = 18). In high-PVR/AC-genotype patients, the medial wall thickness of intra-acinar pulmonary arteries was directly related to MIF levels (p = 0.033). There were no patients with the relatively rare AA genotype in the study population. Thus, in the advantageous scenario of the asparagine 1405 variant (AC heterozygosity in this study), heightened pulmonary vascular resistance in CHD-PHT is associated with medial hypertrophy of pulmonary arteries where MIF chemokine very likely plays a biological role.