Functional and structural changes in pulmonary vasculature characterize pulmonary arterial hypertension (PAH) and the prognosis of advanced PAH remains poor despite progress in pharmacotherapy. Adipose-derived regenerative cells (ADRCs) promote cell regeneration at pathological sites and comprise a novel therapy for ailments of various organs. We investigated the effects of ADRC therapy in rat models of monocrotaline (MCT)-induced pulmonary hypertension (PH) and the underlying mechanisms. Rats were assigned to Control and MCT groups without and with (M/A) intravenous transfusion of seven million ADRCs on day 7. We echocardiographically evaluated pulmonary hypertension as pulmonary artery flow acceleration time (PAAT) and deceleration (PADc). Right ventricular (RV) systolic pressure was measured by catheterization on day 28 and then pathological changes in pulmonary vessels were assessed. We analyzed PAH-associated gene expression on day 14 using real-time RT-PCR. Echocardiography and RV catheterization showed that ADRC therapy inhibited PH development (assessed as PAAT, PADc, and RV systolic pressure) at day 28 (MCT vs. M/A, P < 0.05). Pulmonary vascular remodeling was also inhibited (vessel wall thickness: MCT vs. M/A, P < 0.01). Messenger RNA levels of endothelin (ET) A and B receptors, ET-1 and transforming growth factor (TGF)-β increased in the lungs by MCT were suppressed by ADRCs (MCT vs. M/A, P < 0.05). The development of PH was inhibited by ADRCs through suppressing changes in the expression of genes associated with ET and TGF-β systems. We believe that ADRC therapy could serve as a novel strategy for treating PH.
Electrocardiography (ECG) is used to screen for pulmonary hypertension (PH). However, it is unclear which parameters of ECG are the most useful for screening.ECG parameters related to right ventricular hypertrophy criteria were examined in 145 ECGs of subjects who were suspected to have PH and underwent right heart catheterization (RHC) (age 58.4 ± 17.5 years, 112 women, mean pulmonary arterial pressure [MPAP] 35.4 ± 13.3 mmHg). Based on the results of RHC, 108 subjects had PH (56 pulmonary arterial hypertension [PAH] and 52 chronic thromboembolic pulmonary hypertension [CTEPH]).Fourteen of 17 ECG parameters in the present study were significantly associated with PH on univariate analysis. On multivariable logistic regression analysis, S wave depth in lead V5 (odds ratio [OR] 1.25, 95% confidence interval [CI] 1.10-1.47) and depth of T wave inversion in lead V4 (OR 1.21, 95% CI 1.03-1.46) were independent predictors of MPAP ≥ 25 mmHg, and the cut-off values determined by receiver operating characteristic curve analyses were 0.42 mV and -0.28 mV, respectively.In conclusion, a deeper S wave in lead V5 and the presence of a wider extent of negative T waves in the precordial leads may be clinically simple and useful ECG parameters for screening for PH.
Background: Right heart catheterization (RHC) is the gold standard for the diagnosis of pulmonary hypertension (PH) and a useful tool for monitoring PH. However, there are some disadvantages in the regular use of RHC because it is invasive. Noninvasive methods for monitoring hemodynamics are needed to manage patients with PH. In this study, we aimed to evaluate the reliability of noninvasive hemodynamic assessment with whole-body impedance cardiography (Non-Invasive Cardiac System [NICaS]) for PH. Methods and Results: We investigated 65 consecutive patients undergoing RHC. Two-thirds of them had pulmonary arterial hypertension and one-third had chronic thromboembolic PH; 25% of the patients were receiving medical therapy. Cardiac output (CO) was estimated by NICaS (NI-CO), thermodilution (TD-CO), and the Fick method (Fick-CO). There was a strong correlation between NI-CO and TD-CO (r=0.715, P<0.0001) and Fick-CO (r=0.653, P<0.0001). Noninvasive pulmonary vascular resistance (PVR) was estimated using a conventional invasive equation with NI-CO, mean pulmonary arterial pressure was calculated by echocardiographic measurement, and pulmonary capillary wedge pressure was estimated at 10mmHg in all cases. NICaS-derived PVR was very strongly correlated with invasive PVR (TD-PVR: r=0.704, P<0.0001; Fick-PVR: r=0.702, P<0.0001). Conclusions: Noninvasive measurement of CO and PVR using NICaS and echocardiography is a useful tool for the assessment of PH. (Circ J 2013; 77: 2383-2389)
AimBalloon pulmonary angioplasty (BPA) has recently been established as an effective therapy for peripheral-type chronic thromboembolic pulmonary hypertension (CTEPH). However, the safety and effectiveness of BPA in elderly patients with CTEPH have not been clarified. MethodsA total of 19 patients with CTEPH who underwent BPA were recruited. The patients were assigned to groups by age, <70 years (non-elderly; n = 11) and 70 years (elderly; n = 8). Hemodynamic parameters, right ventricular function and plasma N-terminal pro-brain natriuretic peptide were assessed before and after BPA, and complications arising after BPA were also evaluated. ResultsHemodynamic parameters and right heart function did not differ significantly between the two groups at baseline. BPA significantly improved pulmonary arterial pressure, pulmonary vascular resistance and fractional area change in both groups (all P < 0.05), although the differences were comparable. No fatal complications developed, but the frequency of minor complications, such as transient hemoptysis, was higher in the elderly group than in the non-elderly group (median 0.45 [interquartile range 0.27-0.63] vs 0 [0-0.33], respectively; P = 0.021). The frequency of such complications was also higher in patients with a psychiatric disorder than in those without (0.50 [0.44-1.00] vs 0.14 [0-0.33], respectively; P = 0.006). Multivariate regression analysis identified higher age, baseline N-terminal pro-brain natriuretic peptide values and an underlying psychiatric disorder as significant predictors of complications of BPA. ConclusionsBPA is an effective treatment for peripheral-type CTEPH regardless of age; however, higher age, N-terminal pro-brain natriuretic peptide values before treatment and an underlying psychiatric disorder might be associated with minor complications. Geriatr Gerontol Int 2018; 18: 678-684
To elucidate whether the pharmacokinetics (PK) and pharmacodynamics (PD) of sildenafil are influenced differently when it is coadministered with bosentan (S+B) or with ambrisentan (S+A), we evaluated the PK and PD profiles of sildenafil before and after 4–5 weeks of S+A or S+B treatment in patients with pulmonary arterial hypertension. The area under the plasma concentration–time curve of sildenafil was significantly higher in S+A treatment than in S+B treatment (165.8 ng•h/mL vs. 396.8 ng•h/mL, P = 0.018) and the oral clearance of sildenafil was significantly lower after S+A treatment than after S+B treatment (120.6 L/h/kg vs. 50.4 L/h/kg, P = 0.018). In the PD study, incremental shuttle walking distance was superior during treatment with S+A than during treatment with S+B (S+B; 280 m vs. S+A; 340 m, P = 0.042). There were no concerns about safety with either combination therapy regime.
Ventilator-induced lung injury (VILI) is associated with inflammatory responses in the lung. Thrombomodulin (TM), a component of the coagulation system, has anticoagulant and anti-inflammatory effects. We hypothesized that the administration of recombinant human soluble TM (rhsTM) would block the development of lung injury. Lung injury was induced by high tidal volume ventilation for 2 h with 100% oxygen in rats. Rats were ventilated with a tidal volume of 35 ml/kg with pretreatment via a subcutaneous injection of 3 mg/kg rhsTM (HV (high tidal volume)/TM) or saline (HV/SAL) 12 h before mechanical ventilation. Rats ventilated with a tidal volume of 6 ml/kg under 100% oxygen with rhsTM (LV (low tidal volume)/TM) or saline (LV/SAL) were used as controls. Lung protein permeability was determined by Evans blue dye (EBD) extravasation. Lung injury was successfully induced in the HV/SAL group compared with the LV/SAL group, as shown by the significant decrease in arterial oxygen pressure (PaO2), increased protein permeability, and increase in mean pulmonary artery pressure (mPAP) and ratio of mean pulmonary artery pressure to mean artery pressure (Pp/Ps). Treatment of rats with lung injury with rhsTM (HV/TM) significantly attenuated the decrease in PaO2 and the increase in both mPAP and Pp/Ps, which was associated with a decrease in the lung protein permeability. Lung tissue mRNA expressions of interleukin (IL)-1α, IL-1β, IL-6, tumor necrosis factor-α, and macrophage inflammatory protein (MIP)-2 were significantly higher in HV than in LV rats. Rats with VILI treated with rhsTM (HV/TM) had significantly lower mRNA expressions of IL-1α, IL-1β, IL-6, and MIP-2 than those expressions in HV/SAL rats. Administration of rhsTM may prevent the development of lung injury created by high level of oxygen with large tidal volume mechanical ventilation, which has concomitant decrease in proinflammatory cytokine and chemokine expression in the lung.
The aim of this study was to evaluate the efficacy of mesenchymal stem cells (MSCs) in a nitrofen-induced congenital diaphragmatic hernia (CDH) rat model.Pregnant rats were exposed to nitrofen on embryonic day 9.5 (E9.5). MSCs were isolated from the enhanced green fluorescent protein (eGFP) transgenic rat lungs. The MSCs were transplanted into the nitrofen-induced E12.5 rats via the uterine vein, and the E21 lung explants were harvested. The study animals were divided into three: the control group, the nitrofen-induced left CDH (CDH group), and the MSC-treated nitrofen-induced left CDH (MSC-treated CDH group). The specimens were morphologically analyzed using HE and immunohistochemical staining with proliferating cell nuclear antigen (PCNA), surfactant protein-C (SP-C), and α-smooth muscle actin.The alveolar and medial walls of the pulmonary arteries were significantly thinner in the MSC-treated CDH group than in the CDH group. The alveolar air space areas were larger, while PCNA and the SP-C positive cells were significantly higher in the MSC-treated CDH group, than in the CDH group. MSC engraftment was identified on immunohistochemical staining of the GFP in the MSC-treated CDH group.MSC transplantation potentially promotes alveolar and pulmonary artery development, thereby reducing the severity of pulmonary hypoplasia.
Background: Gastric carcinoma remains the second commonest cause of cancer deaths worldwide. Presence of the carcinoma cell in the pulmonary artery is serious condition that might cause remodeling of the pulmonary artery. The present study conducted detailed histopathological analyses to elucidate how gastric carcinoma cells may affect the structure and hemodynamics of pulmonary arteries. Methods: Remodeling of the pulmonary artery was assessed based on measurements of arterial diameters and stenosis rates from the autopsies, and their correlation were also validated. We additionally calculated 95 percent confidential intervals (CIs) for the rate of stenosis in groups of pulmonary arteries of different caliber zones (under 100, 100 to 300, and over 300 micrometer). The right ventricular thickness was measured and examined whether it correlated with the rate of pulmonary arterial stenosis. Results: A total of 4612 autopsy cases were recorded at our institute, among which 168 had gastric carcinoma. Finally, 51 cases of the gastric carcinoma were employed for the study which had carcinoma cells in the lumen of the pulmonary artery. The mean right ventricular wall thickness of these cases was 3.14 mm. There were significant positive associations between the rates of pulmonary arterial stenosis and right ventricular thickness from pulmonary arteries of diameter under 100, 100 to 300, and over 300 micrometer. In these zones, 31, 31, and 33 cases had rates of pulmonary arterial stenosis that were below the lower limit of the 95 percent CI values, respectively. On the other hand, among cases with significant pulmonary stenosis, 17 of 18 cases with stenosis in the over 300 micrometer zone involved pulmonary arteries of both in the under 100 and 100 to 300 micrometer zones. Conclusion: One-third of autopsy with advanced gastric carcinoma had carcinoma cells in lumen of pulmonary artery, but implantation and proliferation may be essential to induce intimal thickening that causes an increasing of pulmonary arterial pressure, because our study revealed a significant positive association between the rate of pulmonary arterial stenosis and right ventricular thickness. In addition, diffuse type gastric carcinoma may be apt to cause the remodeling of the pulmonary artery.
Severe pulmonary arterial hypertension (PAH) is an incurable disease whose exact mechanisms remain unknown. However, growing evidence highlights the role of inflammation and endothelin (ET) signaling. The lack of reliable models makes it difficult to investigate the pathophysiology of this disease. Our aim was therefore to develop a mouse model of severe PAH closely mimicking the human condition to explore the role of interleukin-6 (IL-6), and ET signaling in advanced PAH progression. Young male SV129 mice received vascular endothelial growth factor receptor inhibitor (SU5416) three times a week and were exposed to hypoxia (10% O ) for three weeks. Molecular analysis and histological assessment were examined using real-time PCR, Western blot and immunostaining, respectively. The developed murine model presented important characteristics of severe PAH in human: concentric neointimal wall thickening, plexogenic lesions, recruitment of macrophages, and distal arteriolar wall muscularization. We detected an increase of IL-6 production and a stronger macrophage recruitment in adventitia of remodeled arterioles developing plexogenic lesions. Moreover, ET-1 and ET receptor A were up-regulated in lung lysates and media of remodeled arterioles. Recombinant IL-6 stimulated the proliferation and regulated endothelial cells in increasing ET-1 and decreasing ET receptor B. These data describe a murine model, which displays the most important features of human severe PAH. We assume that inflammation, particularly IL-6 regulating ET signaling, plays a crucial role in forming plexogenic lesions. This model is thus reliable and might be used for a better understanding of severe PAH progression and treatment.
Background: Idiopathic pulmonary arterial hypertension (IPAH) is a rare, fatal disease of unknown pathogenesis. Evidence from our recent study suggests that IPAH pathogenesis is related to upregulation of the Wnt/planar cell polarity (Wnt/PCP) pathway. We used microscopic observation and immunohistochemical techniques to identify expression patterns of cascading proteins-namely Wnt-11, dishevelled-2 (Dvl-2), and dishevelled-associated activator of morphogenesis 1 (Daam-1)-in pulmonary arteries. Methods: We analyzed sections of formalin-fixed and paraffin-embedded autopsied lung tissues obtained from 9 IPAH cases, 7 associated pulmonary arterial hypertension cases, and 16 age-matched controls without pulmonary arterial abnormalities. Results of microscopic observation were analyzed in relation to the cellular components and size of pulmonary arteries. Results: Varying rates of positive reactivity to Dvl-2 and Daam-1 were confirmed in all cellular components of pulmonary arteries, namely, endothelial cells, myofibroblasts, and medial smooth muscle cells. In contrast, none of these components was reactive to Wnt-11. No specific expression patterns were observed for endothelial cells or myofibroblasts under any experimental conditions. However, marked expression of Dvl-2 and Daam-1 was confirmed in smooth muscle cells. In addition, Dvl-2 was depleted while Daam-1 expression was elevated in IPAH, in contrast with specimens from associated pulmonary arterial hypertension cases and controls. Conclusions: High Daam-1 expression may upregulate the Wnt/PCP pathway and cause IPAH.