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Objectives: To examine the postnatal course of ophthalmic artery (OA) Doppler in women with hypertensive disorders of pregnancy (HDP) and to evaluate the correlation between OA Doppler parameters and poor postnatal blood pressure control and renal dysfunction at 2–3 weeks and 6–9 weeks postnatally. Methods: This was a prospective cohort study of women with a singleton pregnancy and HDP seen at a tertiary pregnancy hypertension clinic between 2019 and 2021. Three visits were included: Visit 1, the last visit to the antenatal hypertension clinic within 2 weeks prior to delivery; Visit 2, at 2–3 weeks postnatally; and Visit 3, at 6–9 weeks postnatally. At each visit, maternal demographic characteristics, medical history, blood pressure and OA Doppler were obtained. In addition, fetal growth and fetal Dopplers were examined antenatally and, at 6–9 weeks postnatally, estimated glomerular filtration rate and proteinuria were quantified. Study participants were divided into four hypertension groups, according to longitudinal changes in blood pressure at the three visits. For the postnatal visits, hypertension was defined as systolic blood pressure (SBP) ≥ 140 mmHg and/or diastolic blood pressure (DBP) ≥ 90 mmHg in the absence of antihypertensive medication, and SBP ≥ 130 mmHg and/or DBP ≥ 80 mmHg whilst taking antihypertensives. Group 1 was hypertensive at all three visits; Group 2 was hypertensive at Visits 1 and 2 but normotensive at Visit 3; Group 3 was hypertensive at Visits 1 and 3 but normotensive at Visit 2; and Group 4 was hypertensive at Visit 1 but normotensive at Visits 2 and 3. The longitudinal changes in mean arterial pressure (MAP), peak systolic velocity (PSV) 1, PSV2 and the ratio of PSV2/PSV1 over the three timepoints were examined by a repeated‐measures, multilevel, linear mixed‐effects analysis, controlling for maternal age, weight at presentation and use of antihypertensive medication. In addition, we examined the longitudinal change in OA Doppler parameters in women with different degrees of postnatal blood pressure control and in those with and those without renal dysfunction at 6–9 weeks postnatally. Results: A total of 108 women were recruited to the study, of whom 86 had new‐onset hypertension and 22 had chronic hypertension. When controlling for maternal age, weight at presentation and use of antihypertensive medication, a significant decline in log10 MAP (P < 0.001), log10 PSV1 (P < 0.001) and log10 PSV2 (P = 0.01) was seen between Visits 1 and 3. Log10 PSVR did not change with time. When assessing OA Doppler against hypertension group, log10 PSV1 and log10 PSV2 did not differ between the hypertension groups, whilst Group 4 had a lower log10 PSVR compared with Group 1 (P < 0.01), Group 2 (P = 0.03) and Group 3 (P < 0.01). At 6–9 weeks postnatally, log10 PSVR was lower in those without compared to those with renal dysfunction (−0.021, P = 0.01), whilst log10 MAP, log10 PSV1 and log10 PSV2 values did not differ. Log10 PSVR did not change with time and remained at −0.12 (95% CI, −0.13 to −0.11) across the three visits. Conclusions: In women with HDP, the OA‐PSVR was significantly higher in those with labile or persistently raised blood pressure postnatally compared to women whose blood pressure normalized. Similarly, the OA‐PSVR at 6–9 weeks postnatally was significantly higher in women with renal dysfunction vs those without dysfunction. © 2023 International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

Objective: To compare the predictive performance for delivery with pre‐eclampsia (PE) within 2 weeks of assessment in women with chronic hypertension at 24–41 weeks' gestation between serum glycosylated fibronectin (GlyFn) concentration, serum placental growth factor (PlGF) concentration and soluble fms‐like tyrosine kinase‐1 (sFlt‐1) to PlGF concentration ratio. Methods: This was a prospective study of 104 women with a singleton pregnancy and chronic hypertension presenting at 24–41 weeks' gestation. Twenty‐six (25.0%) cases developed superimposed PE within 2 weeks of sampling. We compared the predictive performance for superimposed PE between GlyFn, PlGF and the sFlt‐1/PlGF ratio at a fixed screen‐positive rate of approximately 10%. Results: The median gestational age at sampling was 34.1 (interquartile range, 31.5–35.6) weeks and 84.6% (88/104) of cases were sampled at < 36 weeks. The predictive performance for superimposed PE of the three methods of screening was similar, with detection rates of about 23–27%, at a screen‐positive rate of 11% and a false‐positive rate of about 5%. Conclusions: Measurement of GlyFn is a simple point‐of‐care test that can be carried out without need for a laboratory and provide results within 10 min of testing. In this respect, it could potentially replace the angiogenic markers that are used currently in the prediction of imminent PE in high‐risk women. However, neither GlyFn nor angiogenic factors are likely to improve the management of women with chronic hypertension because their predictive performance for superimposed PE is poor. © 2023 International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

BACKGROUND The widespread adoption of electric scooters (e-scooters) as a mode of urban transportation has led to a notable upsurge in e-scooter-related injuries globally. Variations in e-scooter regulations across countries contribute to differences in injury patterns. This study sought to investigate the healthcare burden posed by e-scooter-related injuries on emergency departments (EDs) in Poland, and to delineate the epidemiological and clinical features of these injuries. MATERIAL AND METHODS Medical records of patients who presented to 2 distinct EDs - in Poznań and Bydgoszcz, Poland - with injuries directly linked to e-scooter use were collected and retrospectively analyzed. RESULTS A total of 633 patients were admitted to the EDs due to e-scooter injuries during the study period, and 413 of these patients were further analyzed. The majority were males (64.65%), with a median age of 27 years. Most admissions occurred in the afternoon and nighttime (71.94%), with a higher incidence in the summer (46.73%). Falls were the most frequent mechanism of injury (74.09%), with the head and upper and lower extremities being the most frequently affected locations (36.08%, 29.78%, and 21.07%, respectively). Twelve patients (2.91%) confirmed recent alcohol consumption. Hospitalization costs were higher in cases involving alcohol use and among males. CONCLUSIONS The findings of this study underscore the significant strain exerted by e-scooter-related injuries on EDs in Poland. Injuries, notably to the head and limbs, carry significant long-term implications and strain healthcare resources. Collaboration with policymakers is crucial to ensure the safety of e-scooter users and appropriate healthcare resource allocation.

The mitochondrial adaptor protein p66Shc has been suggested to control life span in mice via the release of hydrogen peroxide. However, the role of p66Shc in lung aging remains unsolved. Thus, we investigated the effects of p66Shc -/- on the aging of the lung and pulmonary circulation. In vivo lung and cardiac characteristics were investigated in p66Shc -/- and wild type (WT) mice at 3, 12, and 24 months of age by lung function measurements, micro-computed tomography (µCT), and echocardiography. Alveolar number and muscularization of small pulmonary arteries were measured by stereology and vascular morphometry, respectively. Protein and mRNA levels of senescent markers were measured by western blot and PCR, respectively. Lung function declined similarly in WT and p66Shc -/- mice during aging. However, µCT analyses and stereology showed slightly enhanced signs of aging-related parameters in p66Shc -/- mice, such as a decline of alveolar density. Accordingly, p66Shc -/- mice showed higher protein expression of the senescence marker p21 in lung homogenate compared to WT mice of the corresponding age. Pulmonary vascular remodeling was increased during aging, but aged p66Shc -/- mice showed similar muscularization of pulmonary vessels and hemodynamics like WT mice. In the heart, p66Shc -/- prevented the deterioration of right ventricular (RV) function but promoted the decline of left ventricular (LV) function during aging. p66Shc -/- affects the aging process of the lung and the heart differently. While p66Shc -/- slightly accelerates lung aging and deteriorates LV function in aged mice, it seems to exert protective effects on RV function during aging.

Background: COPD is an incurable disease and a leading cause of death worldwide. In mice, fibroblast growth factor (FGF)10 is essential for lung morphogenesis, and in humans, polymorphisms in the human FGF10 gene correlate with an increased susceptibility to develop COPD., Methods: We analysed FGF10 signalling in human lung sections and isolated cells from healthy donor, smoker and COPD lungs. The development of emphysema and PH was investigated in Fgf10 +/- and Fgfr2b +/- (FGF receptor 2b) mice upon chronic exposure to cigarette smoke. In addition, we overexpressed FGF10 in mice following elastase- or cigarette smoke-induced emphysema and pulmonary hypertension (PH)., Results: We found impaired FGF10 expression in human lung alveolar walls and in primary interstitial COPD lung fibroblasts. In contrast, FGF10 expression was increased in large pulmonary vessels in COPD lungs. Consequently, we identified impaired FGF10 signalling in alveolar walls as an integral part of the pathomechanism that leads to emphysema and PH development: mice with impaired FGF10 signalling ( Fgf10 +/- and Fgfr2b +/- ) spontaneously developed lung emphysema, PH and other typical pathomechanistic features that generally arise in response to cigarette smoke exposure., Conclusion: In a therapeutic approach, FGF10 overexpression successfully restored lung alveolar and vascular structure in mice with established cigarette smoke- and elastase-induced emphysema and PH. FGF10 treatment triggered an initial increase in the number of alveolar type 2 cells that gradually returned to the basal level when the FGF10-mediated repair process progressed. Therefore, the application of recombinant FGF10 or stimulation of the downstream signalling cascade might represent a novel therapeutic strategy in the future., Competing Interests: Conflict of interest: The authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2023.)

We demonstrate in this work the practical use of uniform mixtures of a bioresin shellac and four natural clays, i.e. montmorillonite, sepiolite, halloysite and vermiculate as dielectrics in organic field effect transistors (OFETs). We present a thorough characterization of their processability and film forming characteristic, surface characterization, elaborate dielectric investigation and the fabrication of field effect transistors with two classic organic semiconductors, i.e. pentacene and fullerene C60. We show that low operating voltage of approximately 4 V is possible for all the OFETs using several combinations of clays and shellac. The capacitance measurements show an improvement of the dielectric constant of shellac by a factor of 2, to values in excess of 7 in the uniform mixtures of sepiolite and montmorillonite with this bioresin., (© TÜBİTAK.)

Surface-enhanced Raman scattering (SERS) is a sensitive and fast technique for sensing applications such as chemical trace analysis. However, a successful, high-throughput practical implementation necessitates the availability of simple-to-use and economical SERS substrates. In this work, we present a robust, reproducible, flexible and yet cost-effective SERS substrate suited for the sensitive detection of analytes at near-infrared (NIR) excitation wavelengths. The fabrication is based on a simple dropcast deposition of silver or gold nanomaterials on an aluminium foil support, making the design suitable for mass production. The fabricated SERS substrates can withstand very high average Raman laser power of up to 400 mW in the NIR wavelength range while maintaining a linear signal response of the analyte. This enables a combined high signal enhancement potential provided by (i) the field enhancement via the localized surface plasmon resonance introduced by the noble metal nanomaterials and (ii) additional enhancement proportional to an increase of the applicable Raman laser power without causing the thermal decomposition of the analyte. The application of the SERS substrates for the trace detection of melamine and rhodamine 6G is demonstrated, which shows limits of detection smaller than 0.1 ppm and analytical enhancement factors on the order of 10 4 as compared to bare aluminium foil., Competing Interests: There are no conflicts of interest to declare., (© 2023 The Authors. Analytical Science Advances published by Wiley‐VCH GmbH.)

Four pinaceae pine resins analyzed in this study: black pine, shore pine, Baltic amber, and rosin demonstrate excellent dielectric properties, outstanding film forming, and ease of processability from ethyl alcohol solutions. Their trap-free nature allows fabrication of virtually hysteresis-free organic field effect transistors operating in a low voltage window with excellent stability under bias stress. Such green constituents represent an excellent choice of materials for applications targeting biocompatibility and biodegradability of electronics and sensors, within the overall effort of sustainable electronics development and environmental friendliness., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors. Global Challenges published by Wiley‐VCH GmbH.)

Background: Electronic cigarette (e-cigarette) vapour is gaining popularity as an alternative to tobacco smoking and can induce acute lung injury. However, the specific role of nicotine in e-cigarette vapour and its long-term effects on the airways, lung parenchyma and vasculature remain unclear., Results: In vitro exposure to nicotine-containing e-cigarette vapour extract (ECVE) or to nicotine-free e-cigarette vapour extract (NF ECVE) induced changes in gene expression of epithelial cells and pulmonary arterial smooth muscle cells (PASMCs), but ECVE in particular caused functional alterations ( e.g. a decrease in human and mouse PASMC proliferation by 29.3±5.3% and 44.3±8.4%, respectively). Additionally, acute inhalation of nicotine-containing e-cigarette vapour (ECV) but not nicotine-free e-cigarette vapour (NF ECV) increased pulmonary endothelial permeability in isolated lungs. Long-term in vivo exposure of mice to ECV for 8 months significantly increased the number of inflammatory cells, in particular lymphocytes, compared to control and NF ECV in the bronchoalveolar fluid (BALF) (ECV: 853.4±150.8 cells·mL -1 ; control: 37.0±21.1 cells·mL -1 ; NF ECV: 198.6±94.9 cells·mL -1 ) and in lung tissue (ECV: 25.7±3.3 cells·mm -3 ; control: 4.8±1.1 cells·mm -3 ; NF ECV: 14.1±2.2 cells·mm -3 ). BALF cytokines were predominantly increased by ECV. Moreover, ECV caused significant changes in lung structure and function ( e.g. increase in airspace by 17.5±1.4% compared to control), similar to mild tobacco smoke-induced alterations, which also could be detected in the NF ECV group, albeit to a lesser degree. In contrast, the pulmonary vasculature was not significantly affected by ECV or NF ECV., Conclusions: NF ECV components induce cell type-specific effects and mild pulmonary alterations, while inclusion of nicotine induces significant endothelial damage, inflammation and parenchymal alterations., Competing Interests: Conflict of interest: All authors have nothing to disclose., (Copyright ©The authors 2023.)

This work reports a reversible braking system for micromotors that can be controlled by small temperature changes (≈5 °C). To achieve this, gated-mesoporous organosilica microparticles are internally loaded with metal catalysts (to form the motor) and the exterior (partially) grafted with thermosensitive bottle-brush polyphosphazenes to form Janus particles. When placed in an aqueous solution of H 2 O 2 (the fuel), rapid forward propulsion of the motors ensues due to decomposition of the fuel. Conformational changes of the polymers at defined temperatures regulate the bubble formation rate and thus act as brakes with considerable deceleration/acceleration observed. As the components can be easily varied, this represents a versatile, modular platform for the exogenous velocity control of micromotors., (© 2020 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Background and Purpose: Chronic obstructive pulmonary disease, encompassing chronic airway obstruction and lung emphysema, is a major worldwide health problem and a severe socio-economic burden. Evidence previously provided by our group has shown that inhibition of inducible NOS (iNOS) prevents development of mild emphysema in a mouse model of chronic tobacco smoke exposure and can even trigger lung regeneration. Moreover, we could demonstrate that pulmonary hypertension is not only abolished in cigarette smoke-exposed iNOS -/- mice but also precedes emphysema development. Possible regenerative effects of pharmacological iNOS inhibition in more severe models of emphysema not dependent on tobacco smoke, however, are hitherto unknown., Experimental Approach: We have established a mouse model using a single dose of porcine pancreatic elastase or saline, intratracheally instilled in C57BL/6J mice. Emphysema, as well as pulmonary hypertension development was determined by both structural and functional measurements., Key Results: Our data revealed that (i) emphysema is fully established after 21 days, with the same degree of emphysema after 21 and 28 days post instillation, (ii) emphysema is stable for at least 12 weeks and (iii) pulmonary hypertension is evident, in contrast to smoke models, only after emphysema development. Oral treatment with the iNOS inhibitor N(6)-(1-iminoethyl)-l-lysine (L-NIL) was started after emphysema establishment and continued for 12 weeks. This resulted in significant lung regeneration, evident in the improvement of emphysema and reversal of pulmonary hypertension., Conclusion and Implications: Our data indicate that iNOS is a potential new therapeutic target to treat severe emphysema and associated pulmonary hypertension., Linked Articles: This article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.1/issuetoc., (© 2020 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and death worldwide. Peroxynitrite, formed from nitric oxide, which is derived from inducible nitric oxide synthase, and superoxide, has been implicated in the development of emphysema, but the source of the superoxide was hitherto not characterized. Here, we identify the non-phagocytic NADPH oxidase organizer 1 (NOXO1) as the superoxide source and an essential driver of smoke-induced emphysema and pulmonary hypertension development in mice. NOXO1 is consistently upregulated in two models of lung emphysema, Cybb (also known as NADPH oxidase 2, Nox2)-knockout mice and wild-type mice with tobacco-smoke-induced emphysema, and in human COPD. Noxo1-knockout mice are protected against tobacco-smoke-induced pulmonary hypertension and emphysema. Quantification of superoxide, nitrotyrosine and multiple NOXO1-dependent signalling pathways confirm that peroxynitrite formation from nitric oxide and superoxide is a driver of lung emphysema. Our results suggest that NOXO1 may have potential as a therapeutic target in emphysema.

Chronic obstructive pulmonary disease (COPD), which comprises the phenotypes of chronic bronchitis and emphysema, is often associated with pulmonary hypertension (PH). However, currently, no approved therapy exists for PH-COPD. Signalling of the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) axis plays an important role in PH and COPD.We investigated the treatment effect of riociguat, which promotes the NO-cGMP pathway, in the mouse model of smoke-induced PH and emphysema in a curative approach, and retrospectively analysed the effect of riociguat treatment on PH in single patients with PH-COPD.In mice with established PH and emphysema (after 8 months of cigarette smoke exposure), riociguat treatment for another 3 months fully reversed PH. Moreover, histological hallmarks of emphysema were decreased. Microarray analysis revealed involvement of different signalling pathways, e.g. related to matrix metalloproteinases (MMPs). MMP activity was decreased in vivo by riociguat. In PH-COPD patients treated with riociguat (n=7), the pulmonary vascular resistance, airway resistance and circulating MMP levels decreased, while oxygenation at rest was not significantly changed.Riociguat may be beneficial for treatment of PH-COPD. Further long-term prospective studies are necessary to investigate the tolerability, efficacy on functional parameters and effect specifically on pulmonary emphysema in COPD patients., Competing Interests: Conflict of interest: A. Pichl has nothing to disclose. Conflict of interest: N. Sommer has nothing to disclose. Conflict of interest: M. Bednorz has nothing to disclose. Conflict of interest: M. Seimetz has nothing to disclose. Conflict of interest: S. Hadzic has nothing to disclose. Conflict of interest: S. Kuhnert reports nonfinancial (travel) support from Teva, Bayer and Astellas, personal fees for advisory board work from Chiesi, personal fees for advisory board work and nonfinancial (travel) support from GSK, personal fees for advisory board work, honoraria and nonfinancial (travel) support from Novartis, honoraria from Berlin-Chemie Menarini and AstraZeneca, outside the submitted work. Conflict of interest: S. Kraut has nothing to disclose. Conflict of interest: E.T. Roxlau has nothing to disclose. Conflict of interest: B. Kojonazarov has nothing to disclose. Conflict of interest: J. Wilhelm has nothing to disclose. Conflict of interest: M. Gredic has nothing to disclose. Conflict of interest: H. Gall reports grants and personal fees from Actelion, AstraZeneca, Bayer, BMS, GSK, Janssen Cilag, Lilly, MSD, Novartis, Pfizer, and United Therapeutics/OMT, outside the submitted work. Conflict of interest: K. Tello has nothing to disclose. Conflict of interest: M.J. Richter reports grants from United Therapeutics, grants and personal fees for consultancy and lecturing from Bayer, personal fees for lecturing from Actelion, Mundipharma, Roche and OMT, outside the submitted work. Conflict of interest: O. Pak has nothing to disclose. Conflict of interest: A. Petrovic has nothing to disclose. Conflict of interest: M. Hecker has nothing to disclose. Conflict of interest: R.T. Schermuly has nothing to disclose. Conflict of interest: F. Grimminger has nothing to disclose. Conflict of interest: W. Seeger has received honoraria for consultant activities from Bayer, United Therapeutics and Liquidia, outside the submitted work. Conflict of interest: H.A. Ghofrani reports personal fees for advisory board work from Actelion, Bayer, GSK, Novartis and Pfizer, personal fees for consultancy from Actelion, Bayer, GSK, MSD, Novartis and Pfizer, personal fees for lecturing from Actelion, Bayer, GSK, Novartis and Pfizer, personal fees for meeting attendance from Actelion, Bayer, GSK, MSD, Novartis and Pfizer, and grants from Deutsche Forschungsgemeinschaft (DFG), outside the submitted work. Conflict of interest: N. Weissmann has nothing to disclose., (Copyright ©ERS 2019.)

It remains a mystery why HIV-associated end-organ pathologies persist in the era of combined antiretroviral therapy (ART). One possible mechanism is the continued production of HIV-encoded proteins in latently HIV-infected T cells and macrophages. The proapoptotic protein HIV-Nef persists in the blood of ART-treated patients within extracellular vesicles (EVs) and peripheral blood mononuclear cells. Here we demonstrate that HIV-Nef is present in cells and EVs isolated from BAL of patients on ART. We hypothesize that HIV-Nef persistence in the lung induces endothelial apoptosis leading to endothelial dysfunction and further pulmonary vascular pathologies. The presence of HIV-Nef in patients with HIV correlates with the surface expression of the proapoptotic endothelial-monocyte-activating polypeptide II (EMAPII), which was implicated in progression of pulmonary emphysema via mechanisms involving endothelial cell death. HIV-Nef protein induces EMAPII surface expression in human embryonic kidney 293T cells, T cells, and human and mouse lung endothelial cells. HIV-Nef packages itself into EVs and increases the amount of EVs secreted from Nef-expressing T cells and Nef-transfected human embryonic kidney 293T cells. EVs from BAL of HIV + patients and Nef-transfected cells induce apoptosis in lung microvascular endothelial cells by upregulating EMAPII surface expression in a PAK2-dependent fashion. Transgenic expression of HIV-Nef in vascular endothelial-cadherin + endothelial cells leads to lung rarefaction, characterized by reduced alveoli and overall increase in lung inspiratory capacity. These changes occur concomitantly with lung endothelial cell apoptosis. Together, these data suggest that HIV-Nef induces endothelial cell apoptosis via an EMAPII-dependent mechanism that is sufficient to cause pulmonary vascular pathologies even in the absence of inflammation.

Epidemiological evidence demonstrates a strong link between postnatal cigarette smoke (CS) exposure and increased respiratory morbidity in young children. However, how CS induces early onset airway disease in young children, and how it interacts with endogenous risk factors, remains poorly understood. We, therefore, exposed 10-day-old neonatal wild-type and β-epithelial sodium ion channel (β-ENaC)-transgenic mice with cystic fibrosis-like lung disease to CS for 4 days. Neonatal wild-type mice exposed to CS demonstrated increased numbers of macrophages and neutrophils in the bronchoalveolar lavage fluid (BALF), which was accompanied by increased levels of Mmp12 and Cxcl1 BALF from β-ENaC-transgenic mice contained greater numbers of macrophages, which did not increase following acute CS exposure; however, there was significant increase in airway neutrophilia compared with filtered air transgenic and CS-exposed wild-type controls. Interestingly, wild-type and β-ENaC-transgenic mice demonstrated epithelial airway and vascular remodeling following CS exposure. Morphometric analysis of lung sections revealed that CS exposure caused increased mucus accumulation in the airway lumen of neonatal β-ENaC-transgenic mice compared with wild-type controls, which was accompanied by an increase in the number of goblet cells and Muc5ac upregulation. We conclude that short-term CS exposure 1) induces acute airway disease with airway epithelial and vascular remodeling in neonatal wild-type mice; and 2) exacerbates airway inflammation, mucus hypersecretion, and mucus plugging in neonatal β-ENaC-transgenic mice with chronic lung disease. Our results in neonatal mice suggest that young children may be highly susceptible to develop airway disease in response to tobacco smoke exposure, and that adverse effects may be aggravated in children with underlying chronic lung diseases., (Copyright © 2016 the American Physiological Society.)

Background: Chronic obstructive lung disease (COPD) is a common cause of death in industrialized countries often induced by exposure to tobacco smoke. A substantial number of patients with COPD also suffer from pulmonary hypertension that may be caused by hypoxia or other hypoxia-independent stimuli - inducing pulmonary vascular remodeling. The Ca(2+) binding protein, S100A4 is known to play a role in non-COPD-driven vascular remodeling of intrapulmonary arteries. Therefore, we have investigated the potential involvement of S100A4 in COPD induced vascular remodeling., Methods: Lung tissue was obtained from explanted lungs of five COPD patients and five non-transplanted donor lungs. Additionally, mice lungs of a tobacco-smoke-induced lung emphysema model (exposure for 3 and 8 month) and controls were investigated. Real-time RT-PCR analysis of S100A4 and RAGE mRNA was performed from laser-microdissected intrapulmonary arteries. S100A4 immunohistochemistry was semi-quantitatively evaluated. Mobility shift assay and siRNA knock-down were used to prove hypoxia responsive elements (HRE) and HIF binding within the S100A4 promoter., Results: Laser-microdissection in combination with real-time PCR analysis revealed higher expression of S100A4 mRNA in intrapulmonary arteries of COPD patients compared to donors. These findings were mirrored by semi-quantitative analysis of S100A4 immunostaining. Analogous to human lungs, in mice with tobacco-smoke-induced emphysema an up-regulation of S100A4 mRNA and protein was observed in intrapulmonary arteries. Putative HREs could be identified in the promoter region of the human S100A4 gene and their functionality was confirmed by mobility shift assay. Knock-down of HIF1/2 by siRNA attenuated hypoxia-dependent increase in S100A4 mRNA levels in human primary pulmonary artery smooth muscle cells. Interestingly, RAGE mRNA expression was enhanced in pulmonary arteries of tobacco-smoke exposed mice but not in pulmonary arteries of COPD patients., Conclusions: As enhanced S100A4 expression was observed in remodeled intrapulmonary arteries of COPD patients, targeting S100A4 could serve as potential therapeutic option for prevention of vascular remodeling in COPD patients.

Rationale: Chronic obstructive pulmonary disease (COPD) is a widespread disease, with no curative therapies available. Recent findings suggest a key role of NO and sGC-cGMP signaling for the pathogenesis of the disease. Previous data suggest a downregulation/inactivation of the cGMP producing soluble guanylate cyclase, and sGC stimulation prevented cigarette smoke-induced emphysema and pulmonary hypertension (PH) in mice. We thus aimed to investigate if the inhibition of the cGMP degrading phosphodiesterase (PDE)5 has similar effects. Results were compared to the effects of a PDE 4 inhibitor (cAMP elevating) and a combination of both., Methods: C57BL6/J mice were chronically exposed to cigarette smoke and in parallel either treated with Tadalafil (PDE5 inhibitor), Piclamilast (PDE4 inhibitor) or both. Functional measurements (lung compliance, hemodynamics) and structural investigations (alveolar and vascular morphometry) as well as the heart ratio were determined after 6 months of tobacco smoke exposure. In addition, the number of alveolar macrophages in the respective lungs was counted., Results: Preventive treatment with Tadalafil, Piclamilast or a combination of both almost completely prevented the development of emphysema, the increase in lung compliance, tidal volume, structural remodeling of the lung vasculature, right ventricular systolic pressure, and right ventricular hypertrophy induced by cigarette smoke exposure. Single, but not combination treatment prevented or reduced smoke-induced increase in alveolar macrophages., Conclusion: Cigarette smoke-induced emphysema and PH could be prevented by inhibition of the phosphodiesterases 4 and 5 in mice.

Rationale: Chronic obstructive pulmonary disease (COPD) is a major cause of death worldwide. No therapy stopping progress of the disease is available., Objectives: To investigate the role of the soluble guanylate cyclase (sGC)-cGMP axis in development of lung emphysema and pulmonary hypertension (PH) and to test whether the sGC-cGMP axis is a treatment target for these conditions., Methods: Investigations were performed in human lung tissue from patients with COPD, healthy donors, mice, and guinea pigs. Mice were exposed to cigarette smoke (CS) for 6 hours per day, 5 days per week for up to 6 months and treated with BAY 63-2521. Guinea pigs were exposed to CS from six cigarettes per day for 3 months, 5 days per week and treated with BAY 41-2272. Both BAY compounds are sGC stimulators. Gene and protein expression analysis were performed by quantitative real-time polymerase chain reaction and Western blotting. Lung compliance, hemodynamics, right ventricular heart mass alterations, and alveolar and vascular morphometry were performed, as well as inflammatory cell infiltrate assessment. In vitro assays of cell adhesion, proliferation, and apoptosis have been done., Measurements and Main Results: The functionally essential sGC β1-subunit was down-regulated in patients with COPD and in CS-exposed mice. sGC stimulators prevented the development of PH and emphysema in the two different CS-exposed animal models. sGC stimulation prevented peroxynitrite-induced apoptosis of alveolar and endothelial cells, reduced CS-induced inflammatory cell infiltrate in lung parenchyma, and inhibited adhesion of CS-stimulated neutrophils., Conclusions: The sGC-cGMP axis is perturbed by chronic exposure to CS. Treatment of COPD animal models with sGC stimulators can prevent CS-induced PH and emphysema.

Background: The N-methyl-D-aspartate receptors are key mediators of excitatory transmission and are implicated in many forms of synaptic plasticity. These receptors are heterotetrameres consisting of two obligatory NR1 and two regulatory subunits, usually NR2A or NR2B. The NR2B subunits are abundant in the early postnatal brain, while the NR2A/NR2B ratio increases during early postnatal development. This shift is driven by NMDA receptor activity. A functional interplay of the Low Density Lipoprotein Receptor Related Protein 1 (LRP1) NMDA receptor has already been reported. Such abilities as interaction of LRP1 with NMDA receptor subunits or its important role in tPa-mediated NMDA receptor signaling were already demonstrated. Moreover, mice harboring a conditional neuronal knock-out mutation of the entire Lrp1 gene display NMDA-associated behavioral changes. However, the exact role of LRP1 on NMDA receptor function remains still elusive., Results: To provide a mechanistic explanation for such effects we investigated whether an inactivating knock-in mutation into the NPxY2 motif of LRP1 might influence the cell surface expression of LRP1 and NMDA receptors in primary cortical neurons. Here we demonstrate that a knock-in into the NPxY2 motif of LRP1 results in an increased surface expression of LRP1 and NR2B NMDA receptor subunit due to reduced endocytosis rates of LRP1 and the NR2B subunit in primary neurons derived from LRP1ΔNPxY2 animals. Furthermore, we demonstrate an altered phosphorylation pattern of S1480 and Y1472 in the NR2B subunit at the surface of LRP1ΔNPxY2 neurons, while the respective kinases Fyn and casein kinase II are not differently regulated compared with wild type controls. Performing co-immunoprecipitation experiments we demonstrate that binding of LRP1 to NR2B might be linked by PSD95, is phosphorylation dependent and this regulation mechanism is impaired in LRP1ΔNPxY2 neurons. Finally, we demonstrate hyperactivity and changes in spatial and reversal learning in LRP1ΔNPxY2 mice, confirming the mechanistic interaction in a physiological readout., Conclusions: In summary, our data demonstrate that LRP1 plays a critical role in the regulation of NR2B expression at the cell surface and may provide a mechanistic explanation for the behavioral abnormalities detected in neuronal LRP1 knock-out animals reported earlier.

The authors report on the fabrication of a silicon/organic heterojunction based IR photodetector. It is demonstrated that an Al/ p -Si/perylene-derivative/Al heterostructure exhibits a photovoltaic effect up to 2.7 μm (0.46 eV), a value significantly lower than the bandgap of either material. Although the devices are not optimized, at room temperature a rise time of 300 ns, a responsivity of ≈0.2 mA/W with a specific detectivity of D ∗  ≈ 7 × 10 7 Jones at 1.55 μm is found. The achieved responsivity is two orders of magnitude higher compared to our previous efforts [1,2]. It will be outlined that the photocurrent originates from an absorption mechanism involving excitation of an electron from the Si valence band into the extended LUMO state in the perylene-derivative, with possible participation of intermediate localized surface state in the organic material. The non-invasive deposition of the organic interlayer onto the Si results in compatibility with the CMOS process, making the presented approach a potential alternative to all inorganic device concepts.