Effect of menthol on hypobaric hypoxia-induced pulmonary arterial hypertension in mice and its mechanism / 中国药理学通报

Aim To study the effect of menthol on hypobaric hypoxia-induced pulmonary arterial hypertension and explore the underlying mechanism in mice. Methods 10 to 12 weeks old wild type (WT) mice and TRPM8 gene knockout (TRPM8

Value of CT pulmonary vascular quantitative parameters in diagnosis of chronic obstructive pulmonary disease patients and high-risk groups / 中华放射学杂志

Objective:To explore the diagnostic value of CT pulmonary vascular quantitative parameters in patients with chronic obstructive pulmonary disease (COPD) and high-risk groups.Methods:A retrospective study of 1 126 patients who underwent chest CT examination and pulmonary function test in Shanghai Tongji Hospital from January 2015 to August 2020. According to lung function, they were divided into COPD group (471 cases), high-risk group (454 cases), and normal control group (201 cases). Pulmonary vascular parameters on chest CT, including the total number of vessels (N total), the number cross-sectional area of vessels under 5 mm 2 (N CSA<5), lung surface area (LSA), number of pulmonary blood vessels per unit lung surface area (N total/LSA) and the total area of vessels (VA total) at a 9, 15, 21 mm depth from the pleural surface, and the total blood vessel volume (TBV), blood vessel volume under 5 mm 2 and 10 mm 2(BV5 and BV10) were measured quantitatively. Kruskal-Wallis H test was used to compare the differences of quantitative parameters of pulmonary vascular in the three groups; Spearman rank test was used to analyze the correlation between CT pulmonary vascular parameters and pulmonary function. Results:There were significant differences in N total/LSA at a 9, 15, 21 mm depth from the pleural surface among three groups ( P<0.05). There were significant differences in N CSA<5, N total at a 9 mm depth from the pleural surface among three groups ( P<0.05). There were significant differences in LSA at a 9 mm depth from the pleural surface, N CSA<5, N total, LSA, VA total at a 15, 21 mm depth from the pleural surface and TBV, BV5 and BV10 among three groups ( P<0.05). In high-risk group, there were positive correlation between N total/LSA, VA total at a 9 mm depth from the pleural surface and some pulmonary function parameters ( r=0.095-0.139, P<0.05). N CSA<5, N total, LSA, N total/LSA, TBV, BV5 and BV10 at different depth from pleural surface were negatively correlated with some pulmonary function parameters ( r=-0.110--0.215, P<0.05). In COPD group, number of vessels at a 9 mm depth from the pleural surface was positively correlated with the diffusion capacity for carbon monoxide of the lung single breath ( r=0.105, 0.103, P<0.05). In addition to N total/LSA were positively correlated with lung function parameters ( r=0.181-0.324, P<0.05), the remaining pulmonary vascular parameters were negatively correlated with some pulmonary function parameters ( r=-0.092--0.431, P<0.05). Conclusion:Quantitative chest CT imaging are able to effectively evaluate pulmonary vascular changes in COPD patients and high-risk groups, and the quantitative parameters of pulmonary vascular CT may distinguish COPD from high-risk groups, providing a novel means for early diagnosis of COPD and prediction of high-risk groups.

Enhanced MR features of central chronic pulmonary artery thromboembolism and the clinical application value / 中华放射学杂志

Objective:To explore the relationship between the imaging features of enhanced MRI in patients with central chronic pulmonary artery thromboembolism (CPTE) and pulmonary vascular resistance (PVR).Methods:Thirty-nine patients with CPTE who had contrast-enhanced MRI examination were retrospectively enrolled this study from January 2018 to December 2020. And 33 patients who received right heart catheterization were divided into two groups based on PVR=1 000 dyn·s·cm -5. The differences of imaging features of CPTE in enhanced MRI between the two groups were compared. The relationship between gender, duration of disease, age, pleural thickening, bilateral bronchial artery dilation, number of the involved vascular segments, number of thrombosis, number of the thrombus-related delayed enhancement of artery wall and PVR was analyzed by binary logistic regression. Results:In 39 patients with central CPTE, the dilated lumen (168, 43.30%) and delayed enhancement of wall (122, 31.52%) were found in most of pulmonary arteries. The rate of the lumen dilatation associated with thrombus was the highest among that of the lumen abnormality (66, 52.80%). There were more thrombi in PVR<1 000 dyn·s·cm -5 group than those in PVR≥1 000 dyn·s·cm -5 group (χ 2=9.55, P=0.002). There was no significant difference in the incidence of wall delayed enhancement associated the thrombus between the two groups (χ 2=0.90, P=0.344). The incidence of bilateral bronchial arterial dilatation in PVR<1 000 dyn·s·cm -5 group was higher than that in PVR≥1 000 dyn·s·cm -5 group ( P=0.019). Logistic regression analysis showed that female, the less number of involved vascular segments and bilateral bronchial artery dilation were correlated with the lower PVR. Conclusions:Enhanced MRI is helpful to accurately evaluate the lumen abnormality of pulmonary artery and wall remodeling in central CPTE, which is of great value for the assessment of patients′ conditions and treatment effect.

Role of FoxO1/p38MAPK signaling pathway in acute lung injury induced by LPS / 中国药理学通报

Aim To investigate the effect of forkhead transcription factors of O classl (FoxO1) on lipopolysaccharide (LPS) -induced acute lung injury and its regulatory mechanism. Methods The model of acute lung injury (ALI) was simulated by LPS. HE staining was used to observe the pathological changes of lung tissues. The contents of tumor necrosis factor a (TNF-a) and interleukin-6 (IL-6) in lung tissues were determined by ELISA. The expression of FoxOl in mouse lung tissues was observed by immunohistochemical staining. The phosphorylation levels of FoxOl, DNA methyltransferase and p38 MAPK were detected by Western blot. The mRNA levels of FoxOl, IL-6, TNF-a and DNA methyltransferase were detected by qRT-PCR. DNA methylation in FoxOl promoter region in lung tissues was detected by nested methylation specific PCR (nMS-PCR). Pulmonary vascular endothelial cells (PVECs) were cultured and transfected with FoxOl siRNA, and the phosphorylation of p38 MAPK was detected by Western blot. The correlation between FoxOl methylation level and inflammatory factors was analyzed by Pearson method. Results Compared with control group, alveolar inflammatory cells increased significantly in LPS group, and pulmonary edema and hyperemia were obvious. TNF-α and IL-6 levels increased by 52. 2% and 150. 4% (P < 0. 05), respectively. The phosphorylation level of p38 MAPK and FoxOl expression increased by 134. 1% and 61. 8% (P < 0. 05), respectively, while the DNA methylation level of Fox0l promoter region decreased by 17. 2% (P < 0. 05). After transfection of FoxOl siRNA in vitro, the phosphorylation level of p38 decreased. Pearson analysis showed that FoxOl methylation level was negatively correlated with inflammatory factors. Conclusion The regulation of FoxOl/p3 8 MAPK signaling pathway by hypomethylation of FoxOl promoter is an important mechanism of LPS-induced acute lung injury.

The preventive effect and mechanism of Dayuanyin in hypoxic pulmonary hypertension through NF-κB signaling pathway / 药学学报

Dayuanyin (DYY) has been shown to reduce lung inflammation in both coronavirus disease 2019 (COVID-19) and lung injury. This experiment was designed to investigate the efficacy and mechanism of action of DYY against hypoxic pulmonary hypertension (HPH) and to evaluate the effect of DYY on the protection of lung function. Animal welfare and experimental procedures are approved and in accordance with the provision of the Animal Ethics Committee of the Institute of Materia Medica, Chinese Academy of Medical Science. Male C57/BL6J mice were randomly divided into 4 groups: control group, model group, DYY group (800 mg·kg-1), and positive control sildenafil group (100 mg·kg-1). The animals were given control solvents or drugs by gavage three days in advance. On day 4, the animals in the model group, DYY group and sildenafil group were kept in a hypoxic chamber containing 10% ± 0.5% oxygen, and the animals in the control group were kept in a normal environment, and the control solvent or drugs continued to be given continuously for 14 days. The right ventricular systolic pressure, right ventricular hypertrophy index, organ indices and other metrics were measured in the experimental endpoints. Meantime, the expression levels of the inflammatory factors in mice lung tissues were measured. The potential therapeutic targets of DYY on pulmonary hypertension were predicted using network pharmacology, the expression of nuclear factor kappa B (NF-κB) signaling pathway-related proteins were measured by Western blot assay. It was found that DYY significantly reduced the right ventricular systolic pressure, attenuated lung injury and decreased the expression of inflammatory factors in mice. It can also inhibit hypoxia-induced activation of NF-κB signaling pathway. DYY has a protective effect on lung function, as demonstrated by DYY has good efficacy in HPH, and preventive administration can slow down the disease progression, and its mechanism may be related to inhibit the activation of NF-κB and signal transducer and activator of transcription 3 (STAT3) by DYY.

Effects of atorvastatin in suppressing pulmonary vascular remodeling in rats with chronic obstructive pulmonary disease

Abstract Objective To investigate the effects of atorvastatin calcium on pulmonary vascular remodeling, the authors explored the regulatory mechanism of Histone Deacetylation Enzyme-2 (HDAC2) in rats with Chronic Obstructive Pulmonary Disease (COPD), and provided a new direction for drug treatment in the progression of vascular remodeling. Methods Eighteen female SD rats were randomly divided into control (Group S1), COPD (Group S2), and atorvastatin calcium + COPD (Group S3) groups. A COPD rat model was established by passive smoking and intratracheal injection of Lipopolysaccharide (LPS). Haematoxylin and eosin staining and Victoria Blue + Van Gibson staining were used to observe pathological changes in the lung tissue. The pulmonary vascular inflammation score was calculated, and the degree of pulmonary vascular remodeling was evaluated. The ratio of Muscular Arteries in lung tissue (MA%), the ratio of the vessel Wall Area to the vessel total area (WA%), and the ratio of the vessel Wall Thickness to the vascular outer diameter (WT%) were measured using imaging software. The expression of HDAC2 was measured using western blotting, ELISA (Enzyme-Linked Immunosorbent Assay), and qPCR (Real-time PCR). Results Compared with the control group, the degree of pulmonary vascular inflammation and pulmonary vascular remodeling increased in rats with COPD. The WT%, WA%, and lung inflammation scores increased significantly; the expression of HDAC2 and HDAC2mRNA in the serum and lung tissue decreased, and the level of Vascular Endothelial Growth Factor (VEGF) in the lung tissues increased (p< 0.05). Compared with the COPD group, the lung tissues from rats in the atorvastatin group had fewer inflammatory cells, and the vascular pathological changes were significantly relieved. The WT%, WA%, and lung inflammation scores decreased significantly; the expression of HDAC2 and HDAC2mRNA in the serum and lung tissues increased, and the level of VEGF in the lung tissues decreased (p< 0.05). Conclusion The present study revealed that atorvastatin calcium could regulate the contents and expression of HDAC2 in serum and lung tissues and inhibit the production of VEGF, thereby regulating pulmonary vascular remodeling in a rat model with COPD.

Reverse Potts for the Treatment of Severe Idiopathic Pulmonary Hypertension in Children

ABSTRACT Idiopathic pulmonary arterial hypertension is a rare and progressive disease with poor prognosis. Many patients progressively worsen even when using combinations of specific drugs for its treatment. Herein, we present our experience in the management of three children with severe pulmonary arterial hypertension refractory to clinical treatment who underwent Potts surgery in addition to clinical treatment.

Revisión Sistemática Exploratoria sobre Uso de Óxido Nítrico Inhalado para Evaluación de Reactividad Vascular Pulmonar en Laboratorio de Hemodinamia en Sujetos Pediátricos con Hipertensión Pulmonar / Exploratory Systematic Review on the Use of Inhaled Nitric Oxide for Evaluation of Pulmonary Vascular Reactivity in Hemodynamics Laboratory in Pediatric Subjects with Pulmonary Hypertension

Introducción. La hipertensión arterial pulmonar (HAP) es una enfermedad que presenta un elevado índice de mortalidad en la población pediátrica. Para su diagnóstico, el gold standard es la prueba de reactividad vascular pulmonar (PRVP), debido a que permite medir la respuesta vasodilatadora del lecho vascular pulmonar frente a la administración de moléculas con acción terapéutica, como el óxido nítrico inhalado (iNO). Esta prueba al ser positiva se asocia a un mejor pronóstico. En la actualidad existe incertidumbre y falta de consenso sobre la indicación y administración de iNO durante la PRVP. Objetivo. Describir el uso reportado en la literatura sobre iNO en PRVP en sujetos pediátricos con HAP. Métodos. Revisión sistemática exploratoria sensible en bases de datos PubMed, Epistemonikos, Cochrane, Scopus, Lilacs y Scielo, que describen el uso de iNO durante la PRVP en sujetos pediátricos con HAP. Resultados. se identificaron 8.906 artículos, de los cuales se seleccionaron 5 para la revisión cualitativa. La PRVP se realizó durante el cateterismo cardiaco derecho (CCD) en sujetosentre 2 semanas y 18 años de edad. Los diagnósticos fueron HAP primaria, idiopática y asociada a patología cardiaca congénita, cardiomiopatía y enfermedad pulmonar. Esta prueba fue realizada en sujetos sólo con soporte de oxígeno o con sedación profunda en ventilación mecánica invasiva, con dosis variables de oxígeno (21 y 100%) e iNO (3 y 80 ppm), o asociado a otras moléculas como iloprostol®, dilitiazem, sildenafil y/o epoprostenol. La administración de iNO disminuyó presión de arteria pulmonar y la resistencia vascular pulmonar, con mantención de presión arterial sistémica y gasto cardiaco y sin complicaciones asociadas a su uso. Conclusiones. Existen escasos estudios sobre iNO en PRVP pediátrica y con calidad metodológica limitada. El iNO se utiliza como método diagnóstico de vaso reactividad en sujetos pediátricos con HAP asociada a cardiopatía congénita, primaria o secundaria. Los protocolos para su uso son variables con dosis entre 20 y 40 ppm, con o sin uso de oxigeno adicional, con tiempos poco precisos y sin consenso en equipos de administración.

Background. Pulmonary arterial hypertension (PAH) is a disease that has a high mortality rate among the pediatric population. For its diagnosis, the pulmonary vascular reactivity test (PVRT) is considered the "Gold Standard", because it allows to measure the vasodilator response of pulmonary vascular circulation with the administration of molecules with therapeutic action, such as inhaled nitric oxide (iNO). This test, when positive, is associated with a better prognosis of the disease. Currently, there's uncertainty and lack of consensus on the indication and administration of iNO during the PVRT. Objetives. to describe use of iNO in PVRT in pediatric users with PAH reported in the literature. Methods. Scoping review of studies published between 1992 and 2021 in PubMed, Epistemonikos, Cochrane, Scopus, Lilacs and Scielo databases, which describe the use of iNO during PVRT in pediatric users with PAH, in English and Spanish. Primary and secondary studies with a sensitive search strategy were considered. Results. 8,906 articles were identified, 40 were selected by title, 8 by full text, and 5 for final qualitative review. Of the total of articles selected, 3 were primary and 2 secondary studies. PVRT was performed during right heart catheterization (RHC) in a population between 2 weeks and 18 years old. Diagnoses were primary PAH, idiopathic PAH and PAH associated with congenital heart disease, cardiomyopathy and pulmonary disease. This test was carried out in subjects on spontaneous ventilation with oxygen support or with deep sedation in invasive mechanical ventilation, with variable oxygen doses between 21 and 100%, with exclusive use of iNO between 3 and 80 ppm, being more used between 20 and 40 ppm, or associated with other molecules such as iloprostol®, dilithiazim, sildenafil and / or epoprostenol. In all selected studies, administration of iNO decreased PAP (pulmonary artery pressure) and PVR (pulmonary vascular resistance), with maintenance of SBP (systemic arterial blood pressure) and cardiac output. The primary studies were made up of pre and post-test of serial or parallel interventions. The selected studies of iNO in PVRT did not report complications associated with its use. Conclusions. studies on iNO in pediatric PVRT are scarce in number of publications and methodological quality. iNO is used as a diagnostic method of vasoreactivity in pediatric users with PAH associated with congenital, primary, or secondary heart disease. The protocols for its use are variable with recommended doses between 20 and 40 ppm, with or without the use of additional O2, with imprecise times and without consensus in administration equipment. The response to PVRT serves as a guide for the treatment and prognosis of pediatric users with PAH.

Clinical efficacy and safety of Treprostinil in the treatment of children with early decompensation after the Fontan procedure / 中华实用儿科临床杂志

Objective:To investigate the efficacy and safety of Treprostinil in the treatment of children with early decompensation after the Fontan procedure.Methods:A retrospectively analysis was performed on the clinical data of 16 children with early decompensation after the Fontan procedure treated with Treprostinil injection from December 2017 to June 2020 at Fuwai Central China Cardiovascular Hospital.A total of 16 patients were included, including 5 boys (31.2%) and 11 girls (68.8%). The age was (4.6 ±1.2) years, the weight was (16.0±2.1) kg.The changes of central venous pressure (CVP), heart rate (HR), systolic blood pressure (SBP), central venous oxygen saturation (ScvO 2), lactic acid (Lac), oxygenation index and B-type natriuretic peptide (BNP) were recorded at the infusion of Treprostinil and 3 hours, 24 hours, 48 hours and 72 hours after the infusion.The short-term efficacy of Treprostinil was observed[mortality, mechanical ventilation time, and length of intensive care unit (ICU) stay]; paired t-test was used to analyze the above indexes at different time points.The adverse reactions during the administration were also recorded. Results:Of the 16 children, the median mechanical ventilation time was 9 (5, 22) h, and the median ICU stay time was 2 (1, 12)days.After 72 hours of drug administration, CVP, Lac, BNP and HR decreased: CVP decreased from(16±5) mmHg (1 mmHg=0.133 kPa) to (11±2) mmHg ( P<0.001), Lac decreased from(6.8±3.2) mmol/L to (3.2±1.2) mmol/L ( P=0.002), BNP decreased from(980±223) ng/L to (250±120) ng/L( P<0.001), HR decreased from(150±20) times/min to (125±16) times/min( P=0.002); SBP, ScvO 2 and oxygenation index increased: SBP increased from(83±10) mmHg to (98±12) mmHg( P<0.001), ScvO 2 increased from 0.53±0.13 to 0.65±0.11 ( P=0.003), oxygenation index increased from (200±72) mmHg to (298±13) mmHg ( P<0.001), and the differences were statistically significant(all P< 0.05). One case died (6.3%), 2 cases (12.5%) had transient blood pressure drop and 1 case (6.3%) had nausea and vomiting.Besides, no other treatment-related complications were observed. Conclusions:As for children with early decompensation after the Fontan procedure, the intravenous application of Treprostinil can reduce pulmonary artery pressure rapidly, effectively improve circulatory status and oxygenation and ultimately improve the prognosis.

Progress on the mechanism of PDGF-BB signaling pathway in the pulmonary vascular remodeling of neonatal hypoxic pulmonary hypertension / 国际儿科学杂志

Neonatal hypoxic pulmonary hypertension(HPH)is a common acute critical disease in NICU, and is one of the diseases leading to neonatal death.At present, the specific pathogenesis is still unclear.Current studies have shown that pulmonary vascular remodeling is an important pathological feature of pulmonary hypertension, and the excessive proliferation and migration of pulmonary artery smooth muscle cell is the main cause of pulmonary vascular remodeling.Platelet-derived growth factor(PDGF-BB)is a powerful mitogenic factor which involved in cell proliferation and migration.Currently, plenty of studies have found that PDGF-BB plays an important role in multiple diseases, including tumor, atherosclerosis, pulmonary hypertension and pulmonary fibrosis.In view of the mechanism of PDGF-BB, this article reviews the possible mechanism of PDGF-BB in pulmonary vascular remodeling with neonatal HPH, aiming to provide a new direction for the therapies of reversing pulmonary vascular remodeling with neonatal HPH.

Overview of miRNA involved in PASMCs phenotypic switching in pulmonary hypertension / 中国药理学通报

Pulmonary hypertension ( PH) is occult, with no distinctive clinical manifestations and poor prognosis.Pulmonary vascular remodelling is an important pathological feature in which pulmonary artery smooth muscle cell ( PASMCs) pheno- typic switching plays a crucial role.MicroRNA (miRNA) is a class of evolutionary highly conserved single-stranded small non-coding RNA.Recently, an increasing number of scholars have found that miRNA can play an important role in the occurrence and development of PH by regulating the phenotypic switching of PASMCs, which is expected to be a potential target for the prevention and treatment of PH.It has been found that miR NA such as miR-221 , miR-24, miR-15b, miR-96, miR-23a.miR-9, miR-214, miR-20a can promote the phenotypic switching of PASMCs, while miRNA such as miR-21, miR-132, miR-182, miR-449, miR-206 .miR-124, miR-30c, miR-140.miR-17-92 cluster can inhibit it.This article aims to review the research progress on miRNA that mediates PASMCs phenotypic switching in PH from both growth factor-related miRNA and hy- poxia-related miRNA.

Research progress on hypoxia-induced imbalance of calcium homeostasis in pulmonary artery smooth muscle cells and its treatment / 中国药理学通报

Chronic hypoxic lung diseases are major causes of disability and mortality worldwide, which are typically aggravated by hypoxic pulmonary hypertension.The pathogenesis of hypoxic pulmonary hypertension is complex, and its mechanism has not been fully elucidated.The previous studies have shown abnormally elevated levels of free Ca + in the cytoplasm of pulmonary artery smooth muscle cells to be the predominant drivers of pulmonary hypertension , causing continuous contraction and remodeling of the pulmonary vessels.This article briefly summarizes the mechanism of hypoxia-induced imbalance in calcium homeostasis in pulmonary artery smooth muscle cells, together with its related drug research, based on the existing literature.Hypoxia induces an imbalance in calcium homeostasis in pulmonary artery smooth muscle cells by regulating hypoxia-inducible factor-1, K+ , store-operated calcium channel, receptor-operated calcium channel, the Ca +-sensing myosin contractile mechanism by binding to calmodulin, leading to pulmonary vasoconstriction.Ca + can also activate PKC/ MAPKs and PI3K/Akt/mTOR pathways, leading to pulmonary vascular remodeling.

Research progress on mechanisms and therapeutic drugs of hypoxic pulmonary hypertension / 中国药理学通报

Hypoxic pulmonary hypertension ( HPH) is a complex mechanism of HPH is complex, and it has a high mortality rate cardiopulmonary disease eaused by hypoxia.The pathological of disability.Clinically the diug of treatment for HPH is unspe-cialized, mainly relying on traditional vasomotor dnrgs, inclu¬ding prostaglandin 12 receptor agonists, endothelin receptor an¬tagonists and phosphodiesterase-5 inhibitors, but their efficacy cannot be achieved.To meet the clinical need, it is of great sig¬nificance to develop targeted anti-HPH dnigs.To provide ideas for the discovery of HPH treatment drugs, the pathophysiological mechanism of HPH and the current status of dmg development are reviewed in the paper.

Research progress on therapeutic strategies for improving pulmonary vascular remodeling in pulmonary hypertension / 中国药理学通报

Pulmonary hypertension(PH)is a chronic,progressive,high-mortality disease characterized by a continuous increase in pulmonary vascular pressure. All types of PH have the same characteristics,i.e.,the excessive proliferation,anti-apoptosis and inflammation of pulmonary artery endothelial cells and smooth muscle cells,which leads to progressive thickening of pulmonary small vessels,resulting in pulmonary vascular remodeling and increased pulmonary vascular resistance,ultimately leading to right ventricular hypertrophy,heart failure,and death. The drugs used to treat PH mainly include L-type calcium channel blockers,phosphodiesterase 5 inhibitors,guanosine cyclase activators,endothelin receptor antagonists,and synthetic prostacyclin and its analogues. These drugs reduce pulmonary artery pressure by relaxing pulmonary blood vessels but do not cure the patient,and their prognosis remains poor. Therefore,the development of drugs that can effectively improve or even reverse pulmonary vascular remodeling is the key to treating PH. In recent years,studies on pulmonary vascular remodeling mainly included(1)the synthesis of new small-molecule compounds;(2)the transformation of mature drugs,such as the use of drug combinations and dosage form transformation,etc.;(3)the pharmacodynamic evaluation of traditional Chinese medicines and derived compounds based on the theory of "lung distension";(4)research into monomers of traditional Chinese medicine; and(5)research into new targets.

The substitution of SERCA2 redox cysteine 674 promotes pulmonary vascular remodeling by activating IRE1α/XBP1s pathway

Pulmonary hypertension (PH) is a life-threatening disease characterized by pulmonary vascular remodeling, in which hyperproliferation of pulmonary artery smooth muscle cells (PASMCs) plays an important role. The cysteine 674 (C674) in the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2 (SERCA2) is the critical redox regulatory cysteine to regulate SERCA2 activity. Heterozygous SERCA2 C674S knock-in mice (SKI), where one copy of C674 was substituted by serine to represent partial C674 oxidative inactivation, developed significant pulmonary vascular remodeling resembling human PH, and their right ventricular systolic pressure modestly increased with age. In PASMCs, substitution of C674 activated inositol requiring enzyme 1 alpha (IRE1α) and spliced X-box binding protein 1 (XBP1s) pathway, accelerated cell cycle and cell proliferation, which reversed by IRE1α/XBP1s pathway inhibitor 4μ8C. In addition, suppressing the IRE1α/XBP1s pathway prevented pulmonary vascular remodeling caused by substitution of C674. Similar to SERCA2a, SERCA2b is also important to restrict the proliferation of PASMCs. Our study articulates the causal effect of C674 oxidative inactivation on the development of pulmonary vascular remodeling and PH, emphasizing the importance of C674 in restricting PASMC proliferation to maintain pulmonary vascular homeostasis. Moreover, the IRE1α/XBP1s pathway and SERCA2 might be potential targets for PH therapy.

Increasing angiotensin-converting enzyme (ACE) 2/ACE axes ratio alleviates early pulmonary vascular remodeling in a porcine model of acute pulmonary embolism with cardiac arrest / 世界急诊医学杂志（英文）

@#BACKGROUND: Acute pulmonary embolism (APE) with cardiac arrest (CA) is characterized by high mortality in emergency due to pulmonary arterial hypertension (PAH). This study aims to determine whether early pulmonary artery remodeling occurs in PAH caused by massive APE with CA and the protective effects of increasing angiotensin-converting enzyme (ACE) 2-angiotensin (Ang) (1-7)-Mas receptor axis and ACE-Ang II-Ang II type 1 receptor (AT1) axis (ACE2/ACE axes) ratio on pulmonary artery lesion after return of spontaneous circulation (ROSC). METHODS: To establish a porcine massive APE with CA model, autologous thrombus was injected into the external jugular vein until mean arterial pressure dropped below 30 mmHg (1 mmHg=0.133 kPa). Cardiopulmonary resuscitation and thrombolysis were delivered to regain spontaneous circulation. Pigs were divided into four groups of five pigs each: control group, APE-CA group, ROSC-saline group, and ROSC-captopril group, to examine the endothelial pathological changes and expression of ACE2/ACE axes in pulmonary artery with or without captopril. RESULTS: Histological analysis of samples from the APE-CA and ROSC-saline groups showed that pulmonary arterioles were almost completely occluded by accumulated endothelial cells. Western blotting analysis revealed a decrease in the pulmonary arterial ACE2/ACE axes ratio and increases in angiopoietin-2/angiopoietin-1 ratio and expression of vascular endothelial growth factor (VEGF) in the APE-CA group compared with the control group. Captopril significantly suppressed the activation of angiopoietin-2/angiopoietin-1 and VEGF in plexiform lesions formed by proliferative endothelial cells after ROSC. Captopril also alleviated endothelial cell apoptosis by increasing the B-cell lymphoma-2 (Bcl-2)/Bcl-2-associated X (Bax) ratio and decreasing cleaved caspase-3 expression. CONCLUSION: Increasing the ACE2/ACE axes ratio may ameliorate pulmonary arterial remodeling by inhibiting the apoptosis and proliferation of endothelial cells after ROSC induced by APE.

Treatment of pulmonary hypertension based on inhibition of pulmonary vascular cell proliferation / 药学学报

Pulmonary hypertension is a rapidly progressing disease of the lung vasculature with poor prognosis, ultimately leading to right heart failure and death. The remodeling of small pulmonary arteries represents an important pathological characteristic of pulmonary hypertension. Pulmonary arterial smooth muscle cells (PASMCs) located in the middle layer of pulmonary artery exhibit hyperproliferation and resistance to apoptosis, which is the main initiator of pulmonary vascular remodeling and similar to that seen in tumor cells. In this review we focus on the signaling pathways that play a key role in PASMCs proliferation and the latest research progress on inhibitors targeting cell proliferation pathways to provide a new perspective for the treatment of PH．

An observational study of correlation of cardiac manifestations with severity of COPD.

Introduction: Various systemic manifestations and complications have been observed throughout the course of Chronic Obstructive Pulmonary Disease. Out of those manifestations one of the important manifestations is cardiac involvement. The major and well-known cardiac complications of COPD are pulmonary vascular disease and its impact on right ventricular function, higher incidence of myocardial infarction and arrhythmias. These complications correlate inversely with survival. Aim: To study cardiac manifestations in COPD patients and its correlation with severity of the disease. Methodology: This observational study was conducted in the department of medicine at a tertiary care hospital in Solapur, Maharashtra. Data of 80 patients diagnosed and their cardiac status assessed on the basis of clinical findings, radiological changes and spirometry, electrocardiography and echocardiography. All patients were analyzed for cardiac involvement based on symptomatology, ECG and 2D-ECHO results. Results: Out of 80 COPD patients 6 patients were GOLD class 1 (mild), 28 in class 2 (moderate), 36 in class 3 (severe) and 10 patients belonged to GOLD class 4 (very severe). Cardiovascular complications were found in 40 patients out of 80. Of these, pulmonary hypertension was found in 45%, IHD in 30%, cor-pulmonale in 20% and arrhythmias were found in 10% of which supraventricular arrhythmias were seen in 75% and ventricular arrhythmia in25%. Conclusion:Our study concluded that patients with mild to moderate COPD may also have cardiac complications. Due to common symptomatology, they are difficult to diagnose. Hence, it is necessary at the time of initial diagnosis to carry out ECG and 2DECHO for early detection and for better management of these patients

Manifestaciones pulmonares y sistémicas de la hipertensión arterial pulmonar: Un enfoque panvascular

La hipertensión arterial pulmonar (HAP) es una grave enfermedad cuyo resultado final de la interacción entre el tono vascular y la alteración progresiva de la remodelación de las arterias pulmonares provoca insuficiencia cardíaca derecha y muerte. El remodelado vascular pulmonar es la alteración estructural clave en la hipertensión pulmonar. Este proceso implica cambios en la íntima, media, adventicia y espacio perivascular, a menudo con la interacción de células inflamatorias. Los mecanismos fisiopatológicos de la HAP abarcan una serie de modificaciones vasculares que producen un aumento de la resistencia vascular pulmonar. Las modificaciones vasculares que se producen en la HAP incluyen: la vasoconstricción, la proliferación del músculo liso, la inflamación, la apoptosis endotelial, la proliferación endotelial resistente a la apoptosis, la fibrosis, la trombosis in-situ, y finalmente, las lesiones plexiformes. Hasta hace poco, la HAP se consideraba una enfermedad restringida a la circulación pulmonar. Sin embargo, existe una creciente evidencia de que los pacientes con HAP también exhiben disfunción vascular sistémica, como lo demuestra la alteración de la dilatación mediada por el flujo de la arteria braquial, el flujo sanguíneo cerebral anormal, la miopatía esquelética y la enfermedad renal intrínseca. Los datos recientes apoyan un vínculo con los eventos genéticos y moleculares detrás de la patogénesis de la HAP. Esta revisión sirve de introducción a los principales hallazgos sistémicos en la HAP y la evidencia que apoya un vínculo común con la fisiopatología de la HAP. Sobre la base de la evidencia disponible, proponemos un paradigma en el que las anomalías metabólicas, la lesión genética y la disfunción vascular sistémica contribuyen a las manifestaciones sistémicas de la HAP. Este concepto no sólo abre interesantes posibilidades de investigación, sino que también anima a considerar las manifestaciones extrapulmonares en el tratamiento de los pacientes con HAP, pues la disfunción vascular sistémica contribuiría a las manifestaciones sistémicas de la HAP.

Pulmonary arterial hypertension (PAH) is a serious disease whose end result of the interaction between vascular tone and the progressive alteration of the remodeling of the pulmonary arteries causes right heart failure and death. Pulmonary vascular remodeling is the key structural alteration in pulmonary hypertension. This process involves changes in the intima, media, adventitia, and perivascular space, often with the interaction of inflammatory cells. The pathophysiological mechanisms of PAH include a series of vascular modifications that produce an increase in pulmonary vascular resistance. Vascular modifications that occur in PAH include: vasoconstriction, proliferation of smooth muscle, inflammation, Endothelial apoptosis, apoptosis-resistant endothelial proliferation, fibrosis, in-situ thrombosis, and finally, plexiform lesions. Until recently, PAH was considered a disease restricted to the pulmonary circulation. However, there is growing evidence that patients with PAH also exhibit systemic vascular dysfunction, as evidenced by impaired brachial artery flow-mediated dilation, abnormal cerebral blood flow, skeletal myopathy, and intrinsic kidney disease. Recent data support a link to the genetic and molecular events behind the pathogenesis of PAH. This review serves as an introduction to the main systemic findings in PAH and the evidence supporting a common link with the pathophysiology of PAH. Based on the available evidence, we propose a paradigm in which metabolic abnormalities, genetic injury, and systemic vascular dysfunction contribute to the systemic manifestations of PAH. This concept not only opens up interesting research possibilities, but also encourages consideration of extrapulmonary manifestations in the treatment of patients with PAH, since systemic vascular dysfunction would contribute to the systemic manifestations of PAH.

A hipertensão arterial pulmonar (HAP) é uma doença grave cujo resultado final da interação entre o tônus vascular e a alteração progressiva da remodelação das artérias pulmonares causa insuficiência cardíaca direita e morte. A remodelação vascular pulmonar é a principal alteração estrutural na hipertensão pulmonar. Esse processo envolve mudanças na íntima, média, adventícia e espaço perivascular, muitas vezes com a interação de células inflamatórias. Os mecanismos fisiopatológicos da HAP incluem uma série de modificações vasculares que produzem um aumento na resistência vascular pulmonar. As modificações vasculares que ocorrem na HAP incluem: vasoconstrição, proliferação do músculo liso, inflamação, apoptose endotelial, proliferação endotelial resistente à apoptose, fibrose, trombose in situ e, finalmente, lesões plexiformes. Até recentemente, a HAP era considerada uma doença restrita à circulação pulmonar. No entanto, há evidências crescentes de que os pacientes com HAP também apresentam disfunção vascular sistêmica, conforme evidenciado pela dilatação prejudicada mediada pelo fluxo da artéria braquial, fluxo sanguíneo cerebral anormal, miopatia esquelética e doença renal intrínseca. Dados recentes suportam uma ligação com os eventos genéticos e moleculares por trás da patogênese da HAP. Esta revisão serve como uma introdução aos principais achados sistêmicos em HAP e as evidências que apoiam uma ligação comum com a fisiopatologia da HAP. Com base nas evidências disponíveis, propomos um paradigma em que anormalidades metabólicas, lesão genética e disfunção vascular sistêmica contribuem para as manifestações sistêmicas da HAP. Esse conceito não apenas abre possibilidades interessantes de pesquisa, mas também incentiva a consideração das manifestações extrapulmonares no tratamento de pacientes com HAP, uma vez que a disfunção vascular sistêmica contribuiria para as manifestações sistêmicas da HAP.

Role of secretory protein GREM1 in systemic-to-pulmonary shunt associated pulmonary arterial hypertension / 中国胸心血管外科临床杂志

@#Objective    To explore the possibility that GREM1, a bone morphogenetic protein (BMP) antagonist, is a mechanical explanation for BMP signal suppression in congenital heart disease associated pulmonary arterial hypertension (CHD/PAH) patients. Methods    Systemic-to-pulmonary shunt induced PAH was surgically established in rats. At the postoperative 12th week, right heart catheterization and echocardiography evaluation were performed to evaluate hemodynamic indexes and morphology of right heart system. Right heart hypotrophy index and pulmonary vascular remodeling were evaluated. Changes of BMP signal pathway related proteins and GREM1 in lungs and plasma GREM1 concentration were detected. The effect of GREM1 on the proliferation and apoptosis of pulmonary arterial endothelial cells (PAECs) was also explored. Results    The hypertensive status was successfully reproduced in rats with systemic-to-pulmonary shunt model. BMP signal pathway was suppressed but GREM1 was up-regulated with no change in hypoxia inducible factor-1 in lungs exposed to systemic-to-pulmonary shunt, while this trend was reversed by systemic-to-pulmonary shunt correction (P<0.05). Immunohistochemical staining demonstrated enhanced staining of GREM1 in remodeled pulmonary arteries. In vitro experiments found that BMP signal was down-regulated but GREM1 expression and secretion were up-regulated in proliferative PAECs (P<0.05). Furthermore, BMP2 significantly inhibited PAECs proliferation and promoted PAECs apoptosis (P<0.05), which could be antagonized by GREM1. In addition, plasma level of GREM1 in rats with systemic-to-pulmonary shunt was also increased and positively correlated with pulmonary hemodynamic indexes. Conclusion    Systemic-to-pulmonary shunt induces the up-regulation of GREM1 in lungs, which promotes pulmonary vascular remodeling via antagonizing BMP cascade. These results present a new mechanical explanation for BMP pathway suppression in lungs of CHD/PAH patients.