Intrauterine life represents a window of phenotypic plasticity which carries consequences for later health in adulthood as well as health of subsequent generations. Intrauterine growth-restricted fetuses (intrauterine growth restriction [IUGR]) have a higher risk of pulmonary arterial hypertension in adulthood. Endothelial dysfunction, characterized by hyperproliferation, invasive migration, and disordered angiogenesis, is a hallmark of pulmonary arterial hypertension pathogenesis. Growing evidence suggests that intergenerational transmission of disease, including metabolic syndrome, can be induced by IUGR. Epigenetic modification of the paternal germline is implicated in this transmission. However, it is unclear whether offspring of individuals born with IUGR are also at risk of developing pulmonary arterial hypertension and endothelial dysfunction. Using a model of maternal caloric restriction to induce IUGR, we found that first and second generations of IUGR exhibited elevated pulmonary arterial pressure, myocardial, and vascular remodeling after prolonged exposure to hypoxia. Primary pulmonary vascular endothelial cells (PVECs) from both first and second generations of IUGR exhibited greater proliferation, migration, and angiogenesis. Moreover, in 2 generations, PVECs-derived ET-1 (endothelin-1) was activated by IUGR and hypoxia, and its knockdown mitigated PVECs dysregulation. Most interestingly, within ET-1 first intron, reduced DNA methylation and enhanced tri-methylation of lysine 4 on histone H3 were observed in PVECs and sperm of first generation of IUGR, with DNA demethylation in PVECs of second generation of IUGR. These results suggest that IUGR permanently altered epigenetic signatures of ET-1 from the sperm and PVECs in the first generation, which was subsequently transferred to PVECs of offspring. This mechanism would yield 2 generations with endothelial dysfunction and pulmonary arterial hypertension–like pathophysiological features in adulthood.
Background Increasing evidence revealed that airway microbial dysbiosis was associated with increased risk of asthma, or persistent wheezing (PW). However, the role of lung microbiota in PW or wheezing recurrence remains poorly understood. Methods In this prospective observational study, we performed a longitudinal 16S rRNA-based microbiome survey on bronchoalveolar lavage (BAL) samples collected from 35 infants with PW and 28 age-matched infants (control group). A 2-year follow-up study on these PW patients was conducted. The compositions of lower airway microbiota were analyzed at the phylum and genus levels. Results Our study showed a clear difference in lower airway microbiota between PW children and the control group. Children with PW had a higher abundance of Elizabethkingia and Rothia, and lower abundance of Fusobacterium compared with the control group. At the end of the 2-year follow-up, 20 children with PW (57.1%) experienced at least one episode of wheezing, and 15 (42.9%) did not suffer from wheezing episodes. Furthermore, PW children with recurrence also had increased abundances of Elizabethkingia and Rothia relative to those who had no recurrence. Additionally, wheezing history, different gender, and caesarean section demonstrated a greater impact in airway microbiota compositions. Conclusion This study suggests that the alterations of lower airway microbiota could be strongly associated with the development of wheezing, and early airway microbial changes could also be associated with wheezing recurrence later in life.
Background Intrauterine growth retardation ( IUGR ) is related to pulmonary artery hypertension in adults, and mi croRNA ‐206 (miR‐206) is proposed to affect the proliferation and apoptosis of pulmonary artery smooth muscle cells ( PASMC s) via post‐transcriptional regulation. Methods and Results In an IUGR rat model, we found that the expression and function of potassium voltage‐gated channel subfamily A member 5 (Kv1.5) in PASMC s was inhibited, and pulmonary artery hypertension was exaggerated after chronic hypoxia ( CH ) treatment as adults. micro RNA expression was investigated in PASMC s from 12‐week‐old male IUGR rats with CH by microarray, polymerase chain reaction, and in situ hybridization. The expression levels of Kv1.5 in primary cultured PASMC s and pulmonary artery smooth muscle from IUGR or control rats were evaluated with and without application of an miR‐206 inhibitor. Right ventricular systolic pressure, cell proliferation, luciferase reporter assay, and I K v were also calculated. We found increased expression of miR‐206 in resistance pulmonary arteries of IUGR rats at 12 weeks compared with newborns. Application of an miR‐206 inhibitor in vivo or in vitro increased expression of Kv1.5 α‐protein and KCNA 5. Also, decreased right ventricular systolic pressure and cell proliferation were observed in PASMC s from 12‐week‐old control and IUGR rats after CH , while inhibitor did not significantly affect control and IUGR rats. Conclusions These results suggest that expression of Kv1.5 and 4‐aminopyridine (Kv channel special inhibitor)‐sensitive Kv current were correlated with the inhibition of miR‐206 in PA rings of IUGR ‐ CH rats and cultured IUGR PASMC s exposed to hypoxia. Thus, miR‐206 may be a trigger for induction of exaggerated CH–pulmonary artery hypertension of IUGR via Kv1.5.
Background Nurses in tertiary hospitals are at high risk for depression. Understanding sleep quality and perceived stress may contribute to nurses’ mental health and health-related nursing productivity. The aim of this study was to investigate the role of sleep quality and perceived stress on depressive symptoms among nurses in tertiary hospitals. Methods A total of 2,780 nurses (overall response rate = 91.1%) were recruited through a cross-sectional survey in 23 tertiary hospitals in China. Questionnaires included the Self-Rating Depression Scale, the Pittsburgh Sleep Quality Index, and the Chinese Perceived Stress Scale. Variables that were significant in Chi-square tests were further entered into binary logistic stepwise regression. Results The prevalence of depressive symptoms was 60.3% (n = 1,676), of which 97.4% (n = 1,633) were female, and 77.8% were younger than 35 years (n = 1,304). Nurses who had moderate, poor, severe sleep quality and poor perceived pressure were more likely to be depressed. Master’s degree, 6–10 years of work, and physical activity were protective factors, while the opposite was the case for shift work and high dissatisfaction. Conclusions More than half of nurses working in tertiary care hospitals reported depressive symptoms, and lower sleep quality and higher perceived stress were more associated with this. Perceived stress is an interesting concept, which may provide a new entry point for the well-known idea that there is a relationship between poor sleep quality and depression. It is possible to reduce depressive symptoms among public hospital nurses by providing information on sleep health and stress relief.
Background Recent studies have demonstrated the important role of metabolomics in the pathogenesis of asthma. However, the role of lung metabolomics in childhood persistent wheezing (PW) or wheezing recurrence remains poorly understood. Methods In this prospective observational study, we performed a liquid chromatography/mass spectrometry-based metabolomic survey on bronchoalveolar lavage samples collected from 30 children with PW and 30 age-matched infants (control group). A 2-year follow-up study on these PW children was conducted. Results Children with PW showed a distinct characterization of respiratory metabolome compared with control group. Children with PW had higher abundances of choline, oleamide, nepetalactam, butyrylcarnitine, l-palmitoylcarnitine, palmitoylethanolamide, and various phosphatidylcholines. The glycerophospholipid metabolism pathway was the most relevant pathway involving in PW pathophysiologic process. Additionally, different gender, prematurity, and systemic corticoids use demonstrated a greater impact in airway metabolite compositions. Furthermore, for PW children with recurrence during the follow-up period, children who were born prematurely had an increased abundance of butyrylcarnitine relative to those who were carried to term. Conclusions This study suggests that the alterations of lung metabolites could be associated with the development of wheezing, and this early alteration could also be correlated with wheezing recurrence later in life.
Background Intrauterine growth restriction (IUGR) is closely related to systemic or pulmonary hypertension (PH) in adulthood. Aberrant crosstalk between pulmonary vascular endothelial cells (PVECs) and pulmonary arterial smooth muscle cells (PASMCs) that is mediated by exosomes plays an essential role in the progression of PH. FoxM1 (Forkhead box M1) is a key transcription factor that governs many important biological processes. Methods and Results IUGR‐induced PH rat models were established. Transwell plates were used to coculture PVECs and PASMCs. Exosomes were isolated from PVEC‐derived medium, and a microRNA (miRNA) screening was proceeded to identify effects of IUGR on small RNAs enclosed within exosomes. Dual‐Luciferase assay was performed to validate the predicted binding sites of miRNAs on FoxM1 3’ untranslated region. FoxM1 inhibitor thiostrepton was used in IUGR‐induced PH rats. In this study, we found that FoxM1 expression was remarkably increased in IUGR‐induced PH, and PASMCs were regulated by PVECs through FoxM1 signaling in a non‐contact way. An miRNA screening showed that miR‐214‐3p, miR‐326‐3p, and miR‐125b‐2‐3p were downregulated in PVEC‐derived exosomes of the IUGR group, which were associated with overexpression of FoxM1 and more significant proliferation and migration of PASMCs. Dual‐Luciferase assay demonstrated that the 3 miRNAs directly targeted FoxM1 3’ untranslated region. FoxM1 inhibition blocked the PVECs‐PASMCs crosstalk and reversed the abnormal functions of PASMCs. In vivo, treatment with thiostrepton significantly reduced the severity of PH. Conclusions Transmission of exosomal miRNAs from PVECs regulated the functions of PASMCs via FoxM1 signaling, and FoxM1 may serve as a potential therapeutic target in IUGR‐induced PH.
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