Animals ; Humans ; Hydrogen Sulfide ; Hypertension, Pulmonary ; etiology ; pathology ; physiopathology ; Pulmonary Artery ; physiopathology ; Pulmonary Circulation

OBJECTIVEPulmonary hypertension (PH) is a common complication of congenital heart defects with a left-to-right shunt characterized by high pulmonary blood flow. Pulmonary vascular structural remodeling (PVSR) is the pathological basis of PH. However, the pathophysiologic features and mechanisms responsible for PH and PVSR induced by increased pulmonary blood flow have not been fully understood. The present study was designed to explore the possible effect and mechanism of hydrogen sulfide (H(2)S) on the regulation of PVSR induced by high pulmonary flow in rats.

METHODSThirty-two male SD rats, weighing 120 - 140 g, were randomly divided into shunt group (n = 8), shunt + NaHS group (n = 8), control group (n = 8) and control + NaHS group (n = 8). Rats in shunt group and shunt + NaHS group were subjected to an abdominal aorta-inferior vena cava shunt to create an animal model of high pulmonary flow. Rats in the control and control + NaHS groups underwent the same experimental protocol as mentioned above except for the shunt procedure. Rats in the shunt + NaHS and control + NaHS groups were intraperitoneally injected with NaHS at 56 micromol/(kgxd), and rats in the shunt and control groups were injected with the same volume of physiological saline. After 11 weeks of experiment, rats were sacrificed and lung tissues were obtained. The percentage of muscularized artery (MA) was calculated. The changes in relative medial thickness (RMT) in small pulmonary arteries and median pulmonary arteries were examined. Proliferative cell nuclear antigen (PCNA), extracellular signal-regulated kinase (ERK1) and phosphorylation extracellular signal-regulated kinase (P-ERK1) protein expression were examined by Western blot, and at the same time, PCNA protein expression by pulmonary artery smooth muscle cells was observed by immunohistochemistry.

RESULTSAfter 11 weeks of shunt, compared with control group, the percentage of MA increased significantly (25.12 +/- 2.26 vs 14.42 +/- 3.41, P < 0.05), and RMT in small pulmonary arteries and median pulmonary arteries increased significantly in rats of shunt group (23.6 +/- 3.5 vs 12.6 +/- 2.1, 24.8 +/- 1.9 vs 13.5 +/- 2.2, P < 0.05 for all). PCNA protein expression in small and median pulmonary arteries increased significantly (0.49 +/- 0.04 vs 0.39 +/- 0.07, 0.46 +/- 0.08 vs 0.36 +/- 0.05, P < 0.01 for all), and the ratio of PERK/ERK1 protein expression of pulmonary arteries increased significantly (P < 0.01) in rats of shunt group compared with those of control group. After the administration of exogenous H(2)S donor, NaHS, for 11 weeks, in contrast to rats in shunt group, the percentage of MA decreased significantly (21.5 +/- 2.0 vs 25.1 +/- 2.3, P < 0.05), and RMT in small and median pulmonary arteries decreased significantly (20.2 +/- 2.8 vs 23.6 +/- 3.5, 20.8 +/- 3.1 vs 20.8 +/- 3.1, P < 0.05 for all) in rats of shunt + NaHS group. PCNA protein expression in small and median pulmonary artery smooth muscle cells decreased significantly (0.32 +/- 0.06 vs 0.49 +/- 0.04, 0.29 +/- 0.07 vs 0.46 +/- 0.08, P < 0.01 for all), and the ratio of PERK/ERK1 protein expression of pulmonary arteries decreased significantly (P < 0.01) in rats of shunt + NaHS group compared with that of shunt group.

CONCLUSIONH(2)S may play a regulatory role in pulmonary vascular structural remodeling induced by high pulmonary blood flow via mitogen-activated protein kinase (MAPK)/ERK signal transduction pathway.

Animals ; Hydrogen Sulfide ; pharmacology ; Hypertension, Pulmonary ; pathology ; physiopathology ; Lung ; pathology ; Male ; Pulmonary Artery ; drug effects ; physiopathology ; Rats ; Rats, Sprague-Dawley

UNLABELLEDTo explore the changes of time-dependent pulmonary artery structural remodeling in pulmonary hypertension induced by high pulmonary flow in rats.

METHODSEighty male SD rats were randomly divided into control group (n =40) and shunt group (n = 40). Rats in shunt group were subjected to an abdominal aorta-inferior vena cava shunt to create an animal model of high pulmonary flow. In the control group, rats experienced the same experimental processes except the shunting procedure. After 1 day, 3 days, 1 week, 4 weeks, and 8 weeks of experiment, systolic pulmonary artery pressure (SPAP) and mean pulmonary artery pressure (MPAP) of each rat were evaluated by using a right cardiac catheterization procedure. Heart tissues were separated as right ventricle (RV) and left ventricle plus septum (LV+SP), and the ratio of RV to LV+SP [RV/ (LV+ SP)] was calculated. The morphologic changes including micro- and ultra-structural changes of pulmonary arteries of rats were observed under optical microscope and electro-microscope, respectively. The percentages of muscularized artery (MA), partial muscularized artery (PMA) and non-muscularized artery (NMA) in small pulmonary arteries and median pulmonary arteries were calculated. The changes of relative medial thickness (RMT) and relative medial area (RMA) of pulmonary arteries were examined.

RESULTSCompared with control group, SPAP and MPAP did not change on day 1, day 3, and week 4. However, in week 1 and week 8 of experiment, SPAP and MPAP increased significantly (P < 0.01). Meanwhile, in week 8 of experiment, RV/ (LV+SP) increased significantly (P < 0.05). In contrast to control group, the percentages of MA, PMA, and NMA did not change in day 1, day 3 and week 1. But in week 4 and week 8, the percentages of MA and PMA increased significantly (P < 0.01) but that of NMA decreased significantly (P < 0.01). RMT and RMA did not change in day 1, day 3, week 1 and even week 4 in shunt group as compared with those of control group, but they increased significantly in week 8 (P < 0.05). The changes of ultra-structure of pulmonary arteries included that endothelial cells became swollen and large in size on day 3, smooth muscular cells increased in size besides the change of endothelial cells in week 1, and they changed from contractile phenotype to synthetic phenotype in week 4. Collagen deposited in pulmonary arteries markedly in week 8.

CONCLUSIONPulmonary artery structural remodeling develops in a time-dependent manner. Endothelial cells of pulmonary arteries become swollen firstly, followed by the proliferation of smooth muscular cells and finally by remodeling of extra cellular matrix.

Animals ; Blood Pressure ; Hypertension, Pulmonary ; pathology ; physiopathology ; Male ; Pulmonary Artery ; pathology ; ultrastructure ; Pulmonary Circulation ; Random Allocation ; Rats ; Rats, Sprague-Dawley

Pulmonary arterial hypertension (PAH) is a clinical hemodynamic syndrome characterized by elevated pulmonary arterial pressure and pulmonary vascular resistance leading to right heart failure and death. Vascular remodeling is the most prominent histopathological feature of PAH, which is regulated by many factors. Endoplasmic reticulum stress, calcium disorder and mitochondrial dysfunction are involved in the vascular cell proliferation and apoptosis by regulating intracellular calcium homeostasis and cellular metabolism. Epigenetic phenomenon such as DNA damage and abnormal expression of miRNA are also involved in the regulation of abnormal proliferation of vascular cells. Vascular cell phenotype switching including endothelial-mesenchymal transition and smooth muscle cell phenotype switching play an important role in abnormal proliferation of vascular cells. Vascular remodeling is produced by a variety of cells and molecular pathways, and aiming at multiple targets which is expected to find a new breakthrough in the treatment of PAH,and to improve abnormal vascular remodeling, delay or even reverse the progression of PAH.
Cell Proliferation ; Cells, Cultured ; Humans ; Hypertension, Pulmonary ; physiopathology ; MicroRNAs ; genetics ; Myocytes, Smooth Muscle ; pathology ; Pulmonary Artery ; pathology ; Vascular Remodeling ; genetics

The hemodynamic findings related to the histologic changes in the small pulmonary arteries in congenital heart disease were analyzed with a left-to-right shunt. A lung biopsy was performed during the repair because of pulmonary arterial (PA) hypertension (mean PA pressure > or = 15 mmHg) in 38 patients. There were 13 patients whose age ranged from 2 years to 25 years old. A preoperative cardiac catheterization was performed to locate the site of the defect and to determine the preoperative hemodynamic findings. Among them, 29 patients had pulmonary vascular resistance (PVR) > 2.5 unit/m2. The lung biopsy specimens were investigated microscopically for the Heath- Edward grade, morphometric analysis of medial wall thickness (MWT) and the rate of the decrease in the pulmonary arteriolar concentration (PAC) obtained by the alvoelo-arterial ratio divided by patients' age. All patients were in the Heath-Edward grade I to III (29 patients in grade I). This grade correlated with the MWT, but did not correlate with a decrease in the PAC. The MWT and the rate of the decrease in the PAC did not accompany each other, but either one had the tendency dominate the pattern in individual patients. The MWT had a close correlation with the mean PA pressure and PVR, and an even closer correlation in patients with a high PVR and those older than 2 years of age. The rate of the decreased in the PAC showed a weak correlation with the shunt volume in patients over 2 years of age or with a large shunt. In the high flow group (PVR < 2.5 unit/m2, Qp/Qs > 2.0, n=14) the MWT was significantly thinner and the rate of the decrease in the PAC was significantly higher than the high resistance group (PVR > 2.5 unit/m2, Qp/Qs2 < 2.0, n=13). The rate of the decrease in the PAC correlated with the patients' age, but the MWT did not. The lung biopsy results in patients who had both left-to-right shunts and pulmonary hypertension showed that the rate of the decrease in the PAC was weakly related to the shunt volume and the MWT was related to the PA pressure and PVR. Either an increased MWT or the rate of the decrease in the PAC tended to dominate. These phenomena were prominent in patients older than 2 in whom a wide range of individual variations were noted in the morphometric pattern. The medial hypertrophy and the rate of the decrease in the PAC may be induced by different stimuli or that medial hypertrophy may play a role in preventing PAC decrease.
Adolescent ; Adult ; Child ; Child, Preschool ; Female ; Heart Defects, Congenital/*pathology/physiopathology/surgery ; Hemodynamics ; Human ; Infant ; Male ; Pulmonary Artery/*pathology/physiopathology

OBJECTIVETo investigate the relationship between pulmonary pathological features and clinical physiology of congenital heart defects (CHD) with decreased pulmonary artery blood flow.

METHODSBetween July 2001 and May 2006, 18 patients with CHD with decreased pulmonary artery blood flow undergoing palliative or definitive repair and having lung biopsy intraoperatively were enrolled in this study. The patients' age was 0.4 - 8.0 years, and body weight was 6.0 - 20.0 kg. The method of semi-quantitative morphometric technique and an image analyzer were applied to measure the following indices of pulmonary microvessels: the percentage of media thickness (MT%), the percentage of media section area (MS%) and numbers of microvessels per square centimeter (VPSC). The diameters of left pulmonary artery (LPA) and right pulmonary artery (RPA) were measured with two-dimensional echocardiography. The percutaneous oxygen saturation (SpO(2)), hemoglobin concentration (HB) and hematocrit value (HCT) were examined and recorded preoperatively.

RESULTSThere was a significant negative correlation between SpO(2) and HCT or Hb (R(2) = 0.4914, P = 0.001 and R(2) = 0.5505, P < 0.001), the variation trend of these three variables was linked. There was a negative correlation between SpO(2) and the body weight (R(2) = 0.2208, P = 0.049), which is in accordance with clinical features of aggravated process of cyanosis and hypoxia. The morphological observation of lung biopsy specimens indicated that most of peripheral pulmonary arteries were distended, irregular and their walls were uneven, and "lake" type of pulmonary AV malformations were observed. There was a positive correlation between VPSC and the body weight or BSA (R(2) = 0.5472, P < 0.001 and R(2) = 0.5233, P = 0.001). There was a significant correlation between VPSC and LPA or RPA (R(2) = 0.4312, P = 0.003 and R(2) = 0.2463, P = 0.036). It was shown that the diameter of central pulmonary arteries could be a reflection of peripheral pulmonary artery growth. The diameter of LPA also correlated with the diameter of RPA (R(2) = 0.286, P = 0.022).

CONCLUSIONSFor patients with congenital heart defects with decreased pulmonary blood flow, the pulmonary pathological changes are the bases of their clinical physiologic features. It is suggested that they should be treated in their earlier stage of life.

Child ; Child, Preschool ; Female ; Heart Defects, Congenital ; pathology ; physiopathology ; Humans ; Infant ; Lung ; blood supply ; Male ; Pulmonary Artery ; abnormalities ; pathology ; physiopathology

OBJECTIVEHypoxic pulmonary hypertension is an important pathophysiologic process of various cardiovascular diseases. Sulfur dioxide (SO2) was considered as a kind of toxic gas previously, but recent studies suggested that SO2 could act as a key bioactive molecule in the pathogenesis of cardiovascular diseases. Therefore, this study was designed to examine the effect of sulfur dioxide on pulmonary vascular structure of hypoxic pulmonary hypertensive rats treated with SO2 donor substances.

METHODSThe rats were randomly divided into 3 groups: control group(n = 8), hypoxic group(n = 8) and hypoxic + SO2 group (n = 10, treated with SO2 donor Na2SO3/NaHSO3). The rats of hypoxic group and hypoxic + SO2 group were under a hypoxic condition for 21 days, while the rats of control group were exposed to room air. The mean pulmonary artery pressure was tested by means of right cardiac catheterization and the content of SO2 in plasma was investigated by high performance liquid chromatography (HPLC). The change in relative medial thickness (RMT) of pulmonary arteries was examined under optical microscope. The ultra-structural changes were observed under a transmission electron microscope. The data were analyzed through one-way analysis of variance (ANOVA) by SPSS 13.0 software.

RESULTSCompared with control group [(2.25 +/- 0.50) kPa], the mean pulmonary artery pressure of hypoxic group [(5.12 +/- 0.51) kPa] raised significantly (t = 5.091, P < 0.01) and RMT of hypoxic group (9.66 +/- 1.27) compared with control group (6.83 +/- 1.57) significantly raised (t = 3.392, P < 0.01). Ultrastructural observation showed the proliferation and degeneration of endothelial cells in small pulmonary arteries in rats with pulmonary hypertension. The internal elastic lamina was irregular. The proliferation of medial smooth muscle cells of arteries was shown at the level of respiratory bronchioles. The collagens also increased. Meanwhile, compared with control group [(33.36 +/- 5.62) micromol/L], the content of SO2 in plasma of hypoxic group [(27.01 +/- 4.17) micromol/L] declined (t = 2.067, P < 0.05). Whereas compared with that of hypoxic group [(5.12 +/- 0.51) kPa], the mean pulmonary artery pressure of hypoxic + SO2 group [(3.94 +/- 0.33) kPa] declined (t = 2.712, P < 0.01) and RMT of hypoxic + SO2 group (6.97 +/- 1.83) decreased compared with hypoxic group (9.66 +/- 1.27) (t = 3.009, P < 0.01). Compared with those of hypoxic group, the pulmonary artery ultrastructural changes in hypoxic group ameliorated obviously after using exogenous sulfur dioxide donor. The endothelial cells became flat and the smooth muscle cells of arteries slightly enlarged and arranged regularly. At the same time, compared with hypoxic group [(27.01 +/- 4.17) micromol/L], the content of SO2 in plasma of hypoxic + SO2 group [(29.89 +/- 4.52) micromol/L] raised (t = 1.263, P > 0.05).

CONCLUSIONSulfur dioxide plays an important role in the regulation of small pulmonary artery structural changes in hypoxic pulmonary hypertensive rats. The hypoxic pulmonary hypertensive damages can be ameliorated significantly after using exogenous SO2 donor.

Animals ; Hypertension, Pulmonary ; blood ; pathology ; physiopathology ; Hypoxia ; blood ; pathology ; physiopathology ; Male ; Pulmonary Artery ; drug effects ; pathology ; Rats ; Rats, Wistar ; Sulfur Dioxide ; adverse effects ; blood

AIMTo study the effect of aspirin on chronic hypoxia and hypercapnic pulmonary hypertension.

METHODSSD rats were randomly divided into normal control group (A), hypoxic hypercapnic group (B), hypoxic hypercapnia + aspirin group (C). The concentration of TXB2 and 6-keto-PGF1alpha in plasma and in lung were detected by the technique of radioimmunology.

RESULTS(1) mPAP was significantly higher in B group than those of A and C group. Differences of mCAP were not significant in three groups. (2) Light microscopy showed that WA/TA (vessel wall area/total area) and PAMT (the thickness of medial smooth cell layer) were significantly higher in B group than those of A and C group. (3) The concentration of TXB2 and 6-keto-PGF1alpha in plasma and lung as well as the ratio of TXB2/6-keto-PGF1alpha were significantly higher in rats of B group than those of A and C group.

CONCLUSIONAspirin may inhibit hypoxic hypercapnia pulmonary hypertension and pulmonary vessel remodeling.

6-Ketoprostaglandin F1 alpha ; metabolism ; Animals ; Aspirin ; pharmacology ; Carotid Arteries ; pathology ; physiopathology ; Epoprostenol ; metabolism ; Hypercapnia ; physiopathology ; Hypertension, Pulmonary ; metabolism ; pathology ; physiopathology ; Hypoxia ; physiopathology ; Male ; Pulmonary Artery ; pathology ; physiopathology ; Rats ; Rats, Sprague-Dawley ; Thromboxane A2 ; metabolism

OBJECTIVE: To explore the relationship between main pulmonary artery diameter and process of chronic pulmonary disease.
 METHODS: We retrospectively reviewed 9 cases without pulmonary diseases (control group) and 100 cases with chronic pulmonary diseases, which were divided into 3 groups: the simple chronic pulmonary disease (A group, 37 cases), the compensatory period of chronic cor pulmonale (B group, 20 cases) and the decompensatory period of chronic cor pulmonale (C group, 43 cases). Main pulmonary artery diameter (MPAD) was measured by chest CT. The differences of MPAD among these 4 groups were analyzed.
 RESULTS: There was a strong positive correlation between pulmonary artery diameter and process of chronic pulmonary disease. Mean MPAD in the group C was higher than that in the group B (P<0.05), and mean MPAD in the group B was higher than that in the group A (P<0.05). Mean MPAD in control group was the smallest one among all groups (P<0.05).
 CONCLUSION Main pulmonary artery diameter could reflect the process of chronic pulmonary disease.
Case-Control Studies ; Chronic Disease ; Humans ; Hypertension, Pulmonary ; physiopathology ; Pulmonary Artery ; pathology ; Retrospective Studies ; Tomography, X-Ray Computed

AIMTo investigate the expression of heme oxygenase-1 gene and production of endogenous carbon monoxide in the rat lung tissue at different time points of chronic hypoxic pulmonary hypertension and the effect of hemin, an inducer of heme oxygenase, on the expression of HO-1 gene and production of endogenous carbon monoxide and pulmonary hypertension.

METHODSWe recreated a rat model of hypoxic pulmonary hypertension by intermittent normal pressure hypoxia (10% O2). The following assays were carried out: Reverse transcriptase polymerase chain reaction (RT-PCR) were performed to determine the level of HO-1 mRNA in rat lung tissue, double wave length spectrophotometry was used to evaluate the quantity of COHb in arterial blood, cardiac catheterization was used to measure the right ventricular systolic pressure (RVSP) and HE staining was performed in dissected lung tissue to observe the pathologic changes of the intra-acinar pulmonary arteries(IAPA).

RESULTS(DT here was low level of HO-1 mRNA in normal rat lung tissue, but the level of HO-1 mRNA increased by 2-4 times in the lung tissue of hypoxic rats (P < 0.01). The quantity of COHb was 2-3 times as those of control group (P < 0.01 or P < 0.05). These were accompanied by the increase of RVSP and the thickness of IAPA. (2) Hemin could maintain the HO-1 mRNA and COHb in the hypoxic rat lung tissue at a high level, and partially suppressed the increase of rat RVSP, ameliorated the pathologic changes of IAPA.

CONCLUSIONThe upregulation of the expression of HO-1 gene and production of CO in the rat lung of hypoxic pulmonary hypertension plays a role of inhibition in the development of hypoxic pulmonary hypertension. Hemin has a therapeutic effect on hypoxic pulmonary hypertension.

Animals ; Carbon Monoxide ; metabolism ; Heme Oxygenase (Decyclizing) ; metabolism ; Hemin ; pharmacology ; Hypertension, Pulmonary ; metabolism ; pathology ; physiopathology ; Hypoxia ; metabolism ; pathology ; Male ; Pulmonary Artery ; metabolism ; physiopathology ; Rats ; Rats, Wistar