Impact of probiotics on the lung development of Bama minipig after premature birth / 中华儿科杂志

Objectives: To examine the impact of probiotics on the lung development of preterm birth of Bama pig. Methods: From April 2020 to October 2021, this animal experimental research was performed by setting up preterm (birth at gestation 104 d), full-term (birth at gestation 113 d), preterm with probiotics (birth at gestation 104 d treated with probiotics given at 3 d after birth), and full-term with probiotics (birth at gestation 113 d treated with probiotics given at 3 d after birth) groups and using the preterm Bama minipig model, the body weights were recorded and lung, ileum, and intestinal content samples were collected at birth, 4 days, 9 days, and 21 days after births of the piglets in preterm and full-term groups, the same samples were collected on 9 days after births of the piglets in preterm with probiotics and full-term with probiotics groups. The body weight and radial alveolar counts (RAC) were compared to evaluate the lung development of the piglets. The lengths of ileal villus were compared to evaluate the development of ileum. The composition structures of bacteria in ileum were analyzed by 16 S rRNA sequencing. The statistical analyses between different groups were performed by t test. Results: There were totally 30 piglets (16 female piglets and 14 male piglets) involving 12 piglets in preterm and full-term groups respectively and 3 piglets in preterm with probiotics and full-term with probiotics groups respectively. The body weights of the piglets in preterm group were lower than those in full-term group at 4, 9 and 21 d after birth ((507±27) vs. (694±56) g, (620±35) vs. (1 092±154) g, (1 660±210) vs. (2 960±418) g,t=2.96, 2.99, 2.78, all P<0.05). The alveolarization of the preterm piglets at 9 days after birth was significantly lower than that of the full-term piglets at the equivalent time point (4.00±0.29 vs. 6.11±0.35, t=4.64, P<0.01). The bacteria genus with the highest abundance in ileum were all different between the preterm and the full-term groups at 4, 9 and 21 d after birth (4 d Escherichia-Shigella (26.63%) and Enterococcus (30.48%) respectively;9 d Turicibacter (35.94%) and Lactobacillus (27.33%) respectively;21 d Escherichia-Shigella (28.02%) and Lactobacillus (46.29%) respectively). The heights of ileal villus of the preterm piglets at 9 d after birth were significantly lower than those of the full-term minipigs at the equivalent time point ((297±21) vs. (411±32) μm, t=3.01, P=0.007).There were both no differences in the body weight and alveolarization ((692±36) vs. (767±67) g, 5.44±0.34 vs. 5.89±0.26, t=0.74, 1.04, both P>0.05) between the piglets in preterm with probiotics group and those in full-term with probiotics group. Turicibacter was the dominant genus in the piglets of both preterm with probiotics and the full-term with probiotics groups. The heights of ileal villus of the piglets in preterm with probiotics group were significantly longer that those of the piglets in preterm group ((371±13) vs. (297±21) μm, t=3.04, P=0.006), and were both not significantly different from those of the piglets in full-term with probiotics group and full-term group ((371±13) vs. (338±12) and (411±32) μm, t=1.90, 1.15, both P>0.05). Conclusions: Premature birth could impact the lung alveolarization of piglets. The probiotics could improve the lung alveolarization of preterm minipigs by promoting the development of ileum.

Geographic variations in the incidence of congenital hypothyroidism in China: a retrospective study based on 92 million newborns screened in 2013-2018 / 中华医学杂志(英文版)

BACKGROUND@#Although congenital hypothyroidism (CH) has been widely studied in Western countries, CH incidence at different administrative levels in China during the past decade remains unknown. This study aimed to update the incidence and revealed the spatial pattern of CH incidence in the mainland of China, which could be helpful in the planning and implementation of preventative measures.@*METHODS@#The data used in our study were derived from 245 newborns screening centers that cover 30 provinces of the Chinese Newborn Screening Information System. Spatial auto-correlation was analyzed by Global Moran I and Getis-Ord Gi statistics at the provincial level. Kriging interpolation methods were applied to estimate a further detailed spatial distribution of CH incidence at city level throughout the mainland of China, and Kulldorff space scanning statistical methods were used to identify the spatial clusters of CH cases at the city level.@*RESULTS@#A total of 91,921,334 neonates were screened from 2013 to 2018 and 42,861 cases of primary CH were identified, yielding an incidence of 4.66 per 10,000 newborns screened (95% confidence interval [CI]: 4.62-4.71). Neonates in central (risk ratio [RR] = 0.84, 95% CI: 0.82-0.85) and western districts (RR = 0.71, 95% CI: 0.69-0.73) had lower probability of CH cases compared with the eastern region. The CH incidence indicated a moderate positive global spatial autocorrelation (Global Moran I value = 0.394, P  < 0.05), and the CH cases were significantly clustered in spatial distribution. A most likely city-cluster (log-likelihood ratio [LLR] = 588.82, RR = 2.36, P  < 0.01) and 25 secondary city-clusters of high incidence were scanned. The incidence of each province and each city in the mainland of China was estimated by kriging interpolation, revealing the most affected province and city to be Zhejiang Province and Hangzhou city, respectively.@*CONCLUSION@#This study offers an insight into the space clustering of CH incidence at provincial and city scales. Future work on environmental factors need to focus on the effects of CH occurrence.

Epidemiological features and mechanism of coronavirus disease 2019 in children / 中国当代儿科杂志

Compared with adults, children tend to have lower incidence rate, hospitalization rate, and mortality rate of coronavirus disease 2019 (COVID-19), while the cause of such age-based differences in disease severity remains unclear. An investigation of pathogenesis in children may help to analyze the therapies for the high-risk population. Human angiotensin-converting enzyme Ⅱ is the main receptor of severe acute respiratory syndrome coronavirus 2 and can limit pulmonary capillary leakage and inflammation mediated by angiotensin 2 and exert a protective effect against acute lung injury. Its expression decreases with age. Regular vaccination and frequent upper respiratory virus infection in children can lead to regular immune activation, and its combination with strong innate immunity can help to achieve virus clearance in the early stage of infection in children with COVID-19. Meanwhile, there are strong regeneration and repair abilities of alveolar epithelial cells in children, which may help with the early recovery of infection. In addition, risk factors, such as underlying cardiopulmonary diseases, obesity, and smoking, are relatively uncommon in children. Social factors, including home quarantine and timely closure of schools, may help to reduce the infection rate in children. However, children with immunodeficiency are a high-risk population and should be closely monitored. Further studies are needed to investigate the immune and protection mechanisms against COVID-19 in children.

Effect of low-concentration paclitaxel on collagen deposition outside rat pulmonary artery smooth muscle cells and related mechanism / 中国当代儿科杂志

OBJECTIVE@#To study the effect of low-concentration paclitaxel (PTX) on transforming growth factor-β1 (TGF-β1)-induced collagen deposition outside rat pulmonary artery smooth muscle cells (PASMCs) and related mechanism.@*METHODS@#Primary rat PASMCs were divided into a blank control group (n=3), a model group (n=3), and a drug intervention group (n=3). No treatment was given for the blank control group. The model group was treated with TGF-β1 with a final concentration of 10 ng/mL. The drug intervention group was treated with PTX with a final concentration of 100 nmol/L in addition to the treatment in the model group. MTT colorimetry was used to measure cell proliferation. Quantitative real-time PCR was used to measure the relative mRNA expression of collagen type I (COL-I) and collagen type III (COL-III). ELISA was used to measure the OD value of COL-I and COL-III proteins. Western blot was used to measure the relative protein expression of COL-I, COL-III, and the key proteins of the TGF-β1/Smad3 signaling pathway (Smad3 and p-Smad3).@*RESULTS@#Compared with the blank control group, the model group had significant increases in proliferation ability, relative mRNA and protein expression of COL-I and COL-III, and relative protein expression of p-Smad3 (P0.05).@*CONCLUSIONS@#Low-concentration PTX exerts a marked inhibitory effect on TGF-β1-induced collagen deposition outside PASMCs, possibly by regulating the phosphorylation of Smad3 protein.

Effect of NF-κB on proliferation of rat pulmonary artery smooth muscle cells inhibited by simvastatin / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To explore the effects of NF-κB on proliferation of rat pulmonary artery smooth muscle cells (PASMC) inhibited by simvastatin.</p><p><b>METHODS</b>PASMC isolated from rats and cultured in vitro were randomly divided into four groups (n=6 each): control, platelet-derived growth factor (PDGF) treatment, PDGF+simvastatin treatment, and PDGF+simvastatin+parthenolide (NF-κB inhibitor) treatment. MTT colorimetric assay and flow cytometry were performed to detect cell proliferation and cell cycle distribution. Immunohistochemistry was performed to detect the expression of NF-κB protein. Real-Time PCR was performed to detect NF-κB mRNA expression.</p><p><b>RESULTS</b>Compared with the control group, MTT values of PASMC at all time points, cell proportion at the S phase and G2+M phase, NF-κB protein and mRNA expression increased significantly in the PDGF group (P<0.05). With the intervention of simvastatin, the levels of above indexes decreased compared with the PDGF group (P<0.05). With the intervention of simvastatin and parthenolide, the levels of above indexes decreased more obviously, but were not significantly different from those in the simvastatin intervention group.</p><p><b>CONCLUSIONS</b>Simvastatin can inhibit proliferation of PASMC and cell cycle process. NF-κB may play an important role in the inhibitory effect of simvastatin on the proliferation of PASMC.</p>

Mechanisms for reversal of pulmonary hypertension by rapamycin in rats / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To investigate the effects of rapamycin (RAP) on pulmonary hypertension (PH) in rats, and to provide new insights into medication selection for the clinical treatment of PH.</p><p><b>METHODS</b>Fifty male Sprague-Dawley rats were randomly divided into blank control, PH model, solvent control, RAP 1, and RAP 2 groups. A rat model of PH was induced by left pneumonectomy (PE) and monocrotaline (MCT). At 5 days after PH model establishment, the solvent control group and the RAP 1 group received an intramuscular injection of solvent and RAP, respectively. At 35 days after PH model establishment, the RAP 2 group received an intramuscular injection of RAP. The mean pulmonary artery pressure (mPAP) and the right ventricle/left ventricle plus septum weight ratio (RV/LV+S) were measured in each group. Histopathological changes in the right lung were evaluated by hematoxylin-eosin (HE) staining. The relative expression of alpha-smooth muscle actin (α-SMA) and smooth muscle protein 22-alpha (SM22α) in each group was determined using real-time PCR.</p><p><b>RESULTS</b>At 35 days after surgery, the PH model and the solvent control groups had significantly higher mPAP and RV/LV+S than the blank control group, while the RAP 1 and the RAP 2 groups had significantly lower mPAP than the solvent control group (P<0.05). The RV/LV+S in the RAP 1 group was significantly lower than that in the solvent control group (P<0.05); however, there was no significant difference in RV/LV+S between the RAP 2 and the solvent control groups (P>0.05). HE staining in the right lung showed the substantially thickened pulmonary artery wall and narrowed arterial lumen in the PH model and the solvent control groups compared with the blank control group. Different degrees of reversal of the pulmonary artery wall thickening were observed after RAP administration. The results of real-time PCR revealed that the relative expression of α-SMA and SM22α in the PH model and the solvent control groups was significantly lower than in the blank control group, while the relative expression of α-SMA and SM22α in the RAP 1 and the RAP 2 groups was significantly higher than in the solvent control group (P<0.05).</p><p><b>CONCLUSIONS</b>RAP can reverse the increase in pulmonary artery pressure and the right ventricular hypertrophy probably by regulation of the phenotypic conversion of vascular smooth muscle cells.</p>

Relationship between Hes-1 and airway inflammation and remodeling in a rat model of asthma / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To study the changes of Hes-1, the target gene of Notch signaling pathway, and its relationship with airway inflammation and remodeling in a rat model of asthma.</p><p><b>METHODS</b>Forty-eight rats were randomly divided into an asthma group and a control group. The rats in the asthma group were sensitized and challenged by ovalbumin (OVA), and normal saline was used in the control group. Two groups were further divided into 3 subgroups according to time points after challenging, i.e. 4 weeks, 8 weeks and 12 weeks (n=8 rats each). Pathological changes of lungs were observed by light microscopy and the thickness of bronchial smooth muscle layer (Wam) was measured. The levels of IL-4 and INF-γ in rat serum and bronchoalveolar lavage fluids (BALF) were measured using ELISA. Expression levels of Hes-1 protein and mRNA were determined by immunohistochemistry and quantitative real-time PCR respectively.</p><p><b>RESULTS</b>Together with the extension of challenging, the Wam of rats in the asthma group increased, a decrease of INF-γ level and an increase of IL-4 level in serum and BALF were also observed, and the differences were statistically significant compared with those in the corresponding control group (P<0.05). Hes-1 protein and mRNA levels also increased gradually after OVA challenging and were higher than those in the control group (P<0.05). The levels of Hes-1 protein and mRNA were positively correlated with Wam and IL-4 in serum and BALF, but were inversely correlated with INF-γ in serum and BALF (P<0.05).</p><p><b>CONCLUSIONS</b>Levels of Hes-1 protein and mRNA increased, which were closely related with the levels of airway inflammatory factors and remodeling of airway smooth muscle. Hes-1 may play an important role in the pathogenesis of asthma.</p>

Pulmonary vascular remodeling in congenital cardiovascular abnormalities: an eternal topic / 中国当代儿科杂志

Pulmonary arterial hypertension (PAH) is one of the most severe complications of congenital heart defects with left to right shunt. Pulmonary vascular remodeling (PVR) is extremely essential in PAH. Therefore, prevention and reversion of PVR is one of the most important factors for improving quality of life for children suffering from PAH. In this article we reviewed the emerging research views on PVR from the disciplines of oncology and anti-tumor pharmacy. Two main sections were included. On the one hand, we introduced the "ATM signal turning point hypothesis" from the DNA damage response (DDR) mechanism research in oncology. The hypothesis suggests that the tumor-like proliferation of vascular smooth muscle cells might be the pathological basis of obstructive PAH. On the other hand, a new lung-targeted drug delivery system based on the fact that low concentration of anti-tumor drugs can inhibit angiogenesis without cellular toxicity was introduced. These new research directions could extend current practice in PVR therapy.

Effect of inhibition of Notch signal on pulmonary vascular remodeling induced by angiotensin Ⅱ / 中国当代儿科杂志

<p><b>OBJECTIVE</b>It is known that Notch signal is very important to vascular remodeling during the process of embryonic development, vessel repair and tumor growth, but there are few studies about pulmonary vascular remodeling in pulmonary hypertension. This study was to explore the effect of inhibiting Notch signal on pulmonary vascular remodeling induced by angiotensin II.</p><p><b>METHODS</b>Vessel strips taken from healthy Wistar rats were co-cultured with extrogenous angiotensin II and the potent smooth muscle cell proliferation stimulators for 7 days. Vascular wall thickness, proliferating cell nuclear antigen (PCNA) positive cell rate and caspase-3 positive cell rate were examined in vessel strips. Then some vessel strips were cultured with angiotensin II and γ-secretase inhibitor DAPT, a Notch signaling inhibitor for 7 days. The levels of Notch 1 to 4 receptor and HERP1/2 mRNA were ascertained by FQ-PCR.</p><p><b>RESULTS</b>Angiotensin II stimulation in the cultured normal pulmonary arteries resulted in an increase in the vascular medial thickness by nearly 50%, and a significant increase in the PCNA positive cell rate and a decrease in the caspase-3 positive cell rate. DAPT treatment did not result in the alterations of Notch 1 to 4 receptor levels, but decreased remarkably HERP1 and HERP2 mRNA expression. DAPT treatment also decreased angiotensin II-induced vascular medial thickness and PCNA positive cell rate and increased caspase-3 positive cell rate.</p><p><b>CONCLUSIONS</b>Inhibiting Notch signal by γ-secretase inhibitor may lead to the suppression of pulmonary vascular remodeling induced by angiotensin II, suggesting that the inhibition of Notch signal pathway might be a novel strategy for the treatment of pulmonary hypertension.</p>

Effects of endogenous carbon monoxide on gene expression profiles associated with the apoptosis of pulmonary arterial smooth muscle cells / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To identify the gene expression profiles associated with the apoptosis of pulmonary arterial smooth muscle cells stimulated by carbon monoxide (CO).</p><p><b>METHODS</b>Primary cultured Sprague-Dawley rat pulmonary arterial smooth muscle cells (PASMC) were stimulated by platelet-derived growth factor (PDGF, 20 ng/mL) and hemin (20 μmol/L). Cells were harvested after 2 hrs and Affymetrix microarrays were used to detect the gene expression profile.</p><p><b>RESULTS</b>Some genes associated with Map2k3 (P38) signal pathway, such as CyclinD1, CyclinH, CyclinL1, MAP2K3, Kras and Nras, were upregulated, but P27 expression was downregulated after PDGF treatment. After endogenous CO treatment, some genes associated with P53 pathway, such as Gadd45α, P21 and Trp53inp1, were upregulated.</p><p><b>CONCLUSIONS</b>P53 pathway probably plays an important role in apoptosis of pulmonary arterial smooth muscle cells treated with endogenous CO.</p>

Effect of spleen tyrosine kinase on the proliferation of pulmonary vascular smooth muscle cells in rats / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To investigate the role of spleen tyrosine kinase (Syk) in rat pulmonary vascular smooth muscle cells (PVSMCs) proliferation induced by platelet-derived growth factor-BB (PDGF-BB).</p><p><b>METHODS</b>PVSMCs from male Sprague-Dawley rats were cultured in vitro and the cells of passages 3-5 were used in the experiment. PVSMCs were stimulated by PDGF-BB and were treated with three different doses of piceatannol, a Syk selective inhibitor. Cell proliferation was assessed by methyl thiazolyl tetrazolium (MTT) assay. DNA synthesis was measured by ³H-thymidine incorporation (³H-TdR). Cellular cycle was observed by flow cytometry. Syk mRNA and protein expression were detected using real-time quantitative PCR and Western blot, respectively.</p><p><b>RESULTS</b>The expression of Syk protein of PVSMCs was significantly up-regulated following PDGF-BB stimulation. PDGF-BB stimulation dramatically increased PVSMCs proliferation. After piceatannol treatment, both Syk mRNA and protein expression decreased and the proliferation of PVSMCs was inhibited in a dose-dependent manner.</p><p><b>CONCLUSIONS</b>Syk may promote PVSMCs proliferation induced by PDGF-BB.</p>

Role of spleen tyrosine kinase in phenotypic modulation of vascular smooth muscle cell induced by platelet-derived growth factor-BB / 中华儿科杂志

<p><b>OBJECTIVE</b>To investigate the role of spleen tyrosine kinase (syk) in the phenotypic modulation induced by platelet-derived growth factor (PDGF-BB) in rat pulmonary vascular smooth muscle cells (VSMC).</p><p><b>METHODS</b>Vascular smooth muscles were isolated from pulmonary media of SD rats, cultured, adopted, and divided into 3 groups: blank control group, control group and medicine intervention group. The changes of proliferation and ultrastructure of vascular smooth muscle cells by using [(3)H] thymidine incorporation and electron microscopy. The mRNA and protein expression level of syk, alpha-smooth muscle-actin (α-SM-actin) and smooth muscle protein 22alpha (SM22α) were detected by RT-PCR and Western blotting. The change of fluorescence intensity was detected by laser scanning confocal microscope.</p><p><b>RESULTS</b>Treatment with PDGF-BB for 24 h resulted in a significant increase in [(3)H] thymidine incorporation (2429.25 ± 253.36 vs. 242.75 ± 14.33,P < 0.01) and marked change in phenotype and cytoskeleton, the level of average optical density decreased significantly (263.75 ± 19.21 vs.1146.23 ± 62.61, P < 0.01). Meanwhile, the mRNA (1.70 ± 0.25 vs. 1.01 ± 0.12, P < 0.05) and protein level of syk significantly increased, the mRNA and protein expression of α-SM-actin (0.10 ± 0.00 vs. 1.00 ± 0.00, P < 0.01) and SM22α (0.18 ± 0.00 vs. 1.00 ± 0.01, P < 0.01) significantly decreased in VSMC induced by PDGF-BB. Piceatannol could inhibit significantly these biological effects. Compared with control group, the level of [(3)H] thymidine incorporation (527.00 ± 27.76 vs. 2429.25 ± 253.36,P < 0.01) was significantly down-regulated and the VSMC presented an apoptotic status in medicine intervention group, the level of average optical density increased significantly (810.65 ± 37.94 vs. 263.75 ± 19.21,P < 0.01) in medicine intervention group. Meanwhile, the mRNA (0.36 ± 0.07 vs. 1.70 ± 0.25, P < 0.01) and protein level of syk significantly decreased. The mRNA and protein levels of α-SM-actin (0.22 ± 0.00 vs. 0.10 ± 0.00, P < 0.01) and SM22α (0.31 ± 0.00 vs. 0.18 ± 0.00, P < 0.01) were significantly higher in medicine intervention group than in control group. The level of average optical density increased significantly (810.65 ± 37.94 vs. 263.75 ± 19.21, P < 0.01).</p><p><b>CONCLUSION</b>Syk plays an important role in vascular remodeling by changing the phenotypes and cytoskeleton of VSMC stimulated by PDGF-BB.</p>

Effect of doxycycline on the development of pulmonary hypertension induced by four methods in rats / 中华儿科杂志

<p><b>OBJECTIVE</b>Based on establishment of four rat models of experimental pulmonary hypertension (PH), the authors examined the inhibition of matrix metalloproteinases (MMPs) by doxycycline and its effect on the development of PH and associated pulmonary vascular remodeling.</p><p><b>METHOD</b>Healthy male Sprague-Dawley rats (weight 350 g to 400 g) were randomly divided into nine groups: Normal control group (N), four model groups (H, M, P, PM) and their corresponding drug intervention groups (HD, MD, PD, PMD) in which doxycycline was given by gavage at a 20 mg/kg daily dosage. On day 28 (day 35 for PM and PMD models), the animals were catheterized to record mean pulmonary arterial pressure (mPAP) and then sacrificed. Fulton Index [RV/(LV + S)] was measured immediately. Morphometric parameters, including percent vascular wall thickness and muscularization of non-muscularized peripheral pulmonary arterioles were determined microscopically. The activity of MMPs was measured by gelatin zymography in the lung tissue.</p><p><b>RESULTS</b>(1) Rats in all model groups (H, M, P, PM) developed significant pulmonary arterial hypertension and right ventricular hypertrophy in comparison with their corresponding drug intervention groups (HD, MD, PD, PMD) and normal control group (N) (P < 0.01). For example, mPAP (mm Hg)(1 mm Hg = 0.133 kPa):N: 18.10 +/- 1.45, H: 27.20 +/- 1.55, HD: 23.90 +/- 2.13; Fulton Inedx(%):N: 23.41 +/- 1.84, H: 34.44 +/- 2.70, HD: 27.55 +/- 2.45. (2) The percent vascular wall thickness (WT%) and percentage of muscularization of non-muscular pulmonary arterioles were significantly increased in all model groups compared with drug intervention groups and normal group (P < 0.01). For example, WT%:N: 10.90 +/- 3.11, H:41.41 +/- 5.21, HD: 17.73 +/- 3.12; Muscularization(%):N: 13.83 +/- 3.72, H: 44.93 +/- 2.43, HD: 29.89 +/- 4.45. (3) The activity of MMPs was inhibited by doxycycline effectively as assessed by gelatin zymography (P < 0.01). For example, the activity of MMP2 (A x 10(3)):N: 1.43 +/- 0.24, H: 3.58 +/- 0.28, HD: 2.29 +/- 0.31.</p><p><b>CONCLUSION</b>Doxycycline attenuated PH and associated pulmonary vascular remodeling in all rat PH models. The study suggests that high expression and enhanced activity of MMPs may play a brutial role in the development of PH. Such phenomenon seems to be common in a variety of PH models of different etiology.</p>

Expression of connective tissue growth factor and its down-regulation by simvastatin administration in pulmonary hypertensive rats / 中华儿科杂志

<p><b>OBJECTIVE</b>To explore the role of expression of connective tissue growth factor (CTGF) in pulmonary vascular remodeling of pulmonary hypertensive rats, and investigate the regulation of CTGF expression by simvastatin in this animal model.</p><p><b>METHODS</b>Eighty male Sprague-Dawley rats (350 to 400 g) were randomized to 7 groups. The rats in group PM(1 - 21) (n = 10) and PM(1 - 35) (n = 12) were treated with pneumonectomy + monocrotaline (MCT), and sacrificed at the 21st or 35th experimental day;those in groups PMS(1 - 35) (n = 12), PMS(21 - 35) (n = 12), PMV(1 - 35) (n = 12) and PMV(21 - 35) (n = 12) were given daily lavage of simvastatin (or vehicle) as intervention measure which began from the 1st and 21st experimental days, respectively; additional 10 rats were used as control without any intervention. The animals were sacrificed at the end of experiment (35 th day) as hemodynamic measurements and study on the morphological parameters relevant to pulmonary vascular remodeling were performed on each group of rats. The expression of ET-1 mRNA, CTGF mRNA and protein, and synthesis of collagen in these pneumonectomized, MCT-treated rats were compared between control and rats treated with simvastatin.</p><p><b>RESULTS</b>Rats in PM(1 - 35) Group developed severe PAH (mPAP = 39.75 +/- 3.62 mm Hg) (1 mm Hg = 0.133 kPa), right ventricular hypertrophy [RV/(LV + S) ratio = 0.627 +/- 0.040], and arterial medial hypertrophy (WT% = 61.73 +/- 5.39), these parameters of the control animals were 17.10 +/- 1.20 mm Hg, 0.262 +/- 0.018 and 14.71 +/- 1.16, respectively. CTGF mRNA and protein were mainly located in pulmonary arterial smooth muscle cells and interstitial macrophage shown by in situ hybridization and immunohistochemistry, respectively. The expression of ET-1 mRNA and CTGF mRNA detected by fluorescent quantitative RT-PCR in Group PM(1 - 35) were significantly increased in comparison with controls, and so did the CTGF protein expression determined by Western blotting in these diseased rats. The content of hydroxyproline (1.30 +/- 0.19 microg/mg wet lung) was remarkably higher than that of control animals (0.56 +/- 0.10 microg/mg wet lung). The up-regulation of ET-1 and CTGF gene expression, and elevated synthesis of hydroxyproline were reversed in rats intervened with simvastatin. The pulmonary hypertension, right ventricular hypertrophy and medial hypertrophy were attenuated in all simvastatin-treated rats no matter the intervention was initiated from the beginning or midway of the study.</p><p><b>CONCLUSION</b>The up-regulation of CTGF gene expression may play an important role in the development of pulmonary vascular remodeling in PAH. Simvastatin can prevent and, to some extent, reverse the vascular remodeling via down-regulation of CTGF gene expression.</p>

Interventional approach to the treatment of aneurysms of the perimembranous ventricular septal defects / 中华儿科杂志

<p><b>OBJECTIVES</b>To explore applicable protocol for the positioning of ventricular septal defect (VSD) occluder and the selection of the device by retrospective analysis of transcatheter closure approach to the aneurysms of the perimembranous VSD.</p><p><b>METHODS</b>Thirty-five cases of perimembranous VSD with septal aneurysm (19 males and 16 females) from May, 2004 to May, 2005 were included, with a mean age of 5.3 y and mean weight of 17.6 kg. Their angiographic and ultrasound data, and interventional processes were analyzed. Seven segments of the aneurysms were assessed: the diameter of the defect on the left ventricle, the diameter of the defect on the right ventricle, the thickness of ventricular septum, the distance from the farthest end of the aneurysm to the defect, the diameter of the widest part of the aneurysm and the distance between the two farthest orifices on the aneurysm.</p><p><b>RESULTS</b>Sixteen cystiform aneurysms and nineteen tubiform ones were identified with left ventricular angiography. The diameters of the orifices of aneurysms and the diameters of the VSDs ranged from 1.5 mm to 4.1 mm and 2.7 mm to 11.9 mm, separately, with the mean of 2.9 mm and 4.3 mm. From the echocardiography, the distances of the rim of defect to the aortic valve ranged from 2.0 mm to 7.0 mm, with the mean of 4.3 mm. All the interventions were successfully done with symmetrical devices from 4 mm to 14 mm. The left disc of the device was positioned at the defect surface from the left ventricle in 29 cases, and was released at the left side of the orifice in 3 cases.</p><p><b>CONCLUSIONS</b>The positioning of the left disc is mostly determined by the condition for the correct formation of the right disc in the right ventricle after deploying. Generally the defect surface in the left ventricle is most ideal to release the left disc of the device. If the body of aneurysm was too long for the right disc to restore its configuration, the left disc should be released on the left side of the orifice. The selection of device size is determined by the placement of the left disc. When the left disc is to be released at the defect surface in the left ventricle, the device size should be equal to or 1 to 2 mm larger than the diameter of the defect on the left ventricle. When the left disc is to be deployed on the left side of an orifice, the device size should be equal to or 1 mm larger than the defect diameter on the left ventricle when there is a single orifice. In the case of multiple orifices, the minimal size of the device which can cover all the orifices should be selected.</p>

Study on GATA-6 Gene on Inhibition of Endogenous Carbon Monoxide on Pulmonary Vascular Smooth Muscle Cells Proliferation / 实用儿科临床杂志

Objective To investigate the effect of GATA-6 on endogenous carbon monoxide(CO) inhibited pulmonary vascular smooth muscle cells(PVSMCs) proliferation induced by platelet-derived growth factor(PDGF).Methods Tissue mass culture was done to get PVSMCs artery in SD rats.The PVSMCs were stimulated to proliferation by PDGF(20 ?g/L),and the 3 different concentrations of hemin[a substrate and inducer of heme oxygenase-1(HO-1)] add into the cultures to induce CO production.The PVSMC cell proli-feration was detected by 3-(4,5-dimethyl-2-thiazoly1)-2,5-diphenyl-2H-tetrazolium bromide(MTT) method,DNA synthesis was detected by thymidine incorporation,and GATA-6 mRNA expression was detected by reverse transcription polymerase chain reaction(RT-PCR).Results CO inhibited the PVSMCs proliferation induced by PDGF in a dose-dependent and time-dependent manner.Hemin with high concentration markedly inhibited the proliferation and DNA synthesis of PVSMCs.After 2 hours with PDGF,the expression of(GATA-6) mRNA markedly down-regulated,and began returned after 6 hours.However,CO could reversed this down-regulation.Conclusions CO can inhibit the proliferation of PVSMCs induced by PDGF.PDGF can result in the expression of GATA-6 mRNA down-regulated;the down-regulation is reversed by CO.This study suggested that CO maybe inhibit PVSMCs proliferation by regulating expression of GATA-6.

Clinical value of serum matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 for the prediction and early diagnosis of coronary artery lesion in patients with Kawasaki disease / 中华儿科杂志

<p><b>OBJECTIVE</b>Kawasaki disease (KD) complicated with coronary artery lesion (CAL) seriously threatens survival quality and life of patients, suggesting that it is very important to early predict the risk of CAL and to early diagnose the disease. Nevertheless, up to now there has been no specific clinical biochemical marker for it because of the poor understanding of the pathological process of KD with CAL. Matrix metalloproteinases (MMPs) and their specific tissue inhibitor of metalloproteinases (TIMPs) play an important role in arterial wall extracellular matrix breakdown and remodeling and are involved in CAL in other diseases. In the present study the practical value of serum MMP-9 and TIMP-1 levels in the prediction and early diagnosis of CAL in KD patients was investigated.</p><p><b>METHODS</b>All subjects were from Chinese population. Serum levels of MMP-9 and TIMP-1 were measured by rapid one-step sandwich enzyme immunoassay in 59 KD patients including 15 with CAL and 44 without CAL by 2 D-echocardiography and coronary angiography, and 20 normal healthy children as controls. Blood samples of patients were obtained before and after intravenous immunoglobulin (IVIG) treatment in acute stage, subacute stage and convalescent stage as well. Serum MMP-9 and TIMP-1 levels and the ratio of MMP-9/TIMP-1 were compared by statistical method in KD patients and controls, as well as in KD with CAL and without CAL.</p><p><b>RESULTS</b>In acute stage serum MMP-9 and TIMP-1 levels and the ratio of MMP-9/TIMP-1 were higher (P < 0.01) in patients with KD than those in healthy children. After IVIG treatment in KD patients serum MMP-9 level and the ratio of MMP-9/TIMP-1 decreased (P < 0.01). Before IVIG treatment serum MMP-9 level and the ratio of MMP-9/TIMP-1 were higher (P < 0.01) in patients with CAL than those in patients without CAL, and in acute stage after IVIG treatment serum MMP-9 level of KD patients with CAL was still higher than that of KD patients without CAL.</p><p><b>CONCLUSION</b>In acute stage of KD serum MMP-9 level and the ratio of MMP-9/TIMP-1 were higher in patients with CAL than those in patients without CAL, suggesting that during acute phase of KD the great increase in serum MMP-9 and the imbalance of the MMP-9/TIMP-1 ratio might be high risk factors of KD coronary artery lesion. Therefore, the measurement of serum MMP-9 and TIMP-1 might be of important clinical value in the prediction and the early diagnosis of KD with coronary artery lesion.</p>

Effect of truncated platelet-derived growth factor-alpha receptor on apoptosis and expression of c-sis mRNA of pulmonary artery smooth muscle cells / 中华儿科杂志

<p><b>OBJECTIVE</b>Platelet-derived growth factor (PDGF) plays an important role during the pathophysiological changes in vascular remodeling. The study aimed to investigate the effect of truncated PDGF-alpha receptor on apoptosis and expression of c-sis mRNA of pulmonary artery smooth muscle cells (VSMCs).</p><p><b>METHODS</b>Tissue mass culture was done to get vascular smooth muscle cells of pulmonary artery in newborn pigs. Two methods were used to interfere VSMCs: adding adenoviral recombined body (Ad5CMV-PalphaRtr, ACP) with three different concentrations of truncated PDGF-alpha receptor into the cultures, or adding three concentrations of PDGF-BB after the treatment with mid-concentration of ACP. VSMC apoptosis, cellular cycle and expression of c-sis were observed using flow-cytometry, and the expression of c-sis mRNA was detected by reverse transcription polymerase chain reaction (RT-PCR).</p><p><b>RESULTS</b>ACP with mid- to- high concentrations could restrain the proliferation of VSMCs apparently with the increase of G(0)/G(1) cells. The apoptotic rate presented an ascending tendency. The differences among the groups were of statistically significant. Affected by mid- concentration of ACP, PDGF-BB did not exhibit a significantly accelerating effect on the changes of cellular cycle and VSMC apoptosis. The expression of c-sis mRNA was up-regulated under the effect of ACP. Affected by mid-concentration of ACP and PDGF-BB, c-sis mRNA expressed was down-regulated.</p><p><b>CONCLUSION</b>Mid- to- high concentration of ACP is a powerful inhibitor of cellular proliferation for pulmonary artery VSMCs. It can significantly increase cells in number in G(0)/G(1) phase, apoptosis and c-sis mRNA expression.</p>

Advances in Bosentan Treatment for Pediatric Pulmonary Arterial Hypertension / 实用儿科临床杂志

Bosentan is a non-selective endothelin receptor antagonist,which plays an important role in the treatment of children with pulmonary arterial hypertension.Bosentan has shown to improve exercise capacity,hemodynamics and reduce pulmonary vascular resistance in pediatric patients.The main adverse effect is less severely comparing with the adult.The combination of bosentan with other drugs can improve the life quality furtherly.Further study of large-scale trials needs focus on the long-effects of bosentan,the ideal period of therapy and the effects of combination therapy in children.