Implications de la voie RhoA/Rho-kinases dans la physiopathologie des atteintes vasculaires et interstitielles pulmonaires des maladies respiratoires chroniques (études humaines et expérimentales chez la souris)

La voie RhoA/Rho-kinases (ROCK) joue un rôle important dans la physiopathologie de l hypertension pulmonaire (HTP) par son implication dans le dysfonctionnement endothélial, la constriction et le remodelage des vaisseaux pulmonaires. Selon les classifications internationales, la bronchopneumopathie chronique obstructive (BPCO) et la pneumopathie infiltrante diffuse (PID) sont deux causes fréquentes d HTP ayant en commun plusieurs mécanismes physiopathologiques dont le dysfonctionnement endothélial, le remodelage vasculaire et la fibrose parenchymateuse. Les objectifs de ce travail étaient d étudier le rôle de la voie RhoA/ROCK dans la physiopathologie de la BPCO et de la PID avec ou sans HTP et de préciser les anomalies moléculaires liées à la perturbation de la signalisation de cette voie dans chacune de ces situations.Le dysfonctionnement endothélial est un événement essentiel dans l initiation et la progression de la BPCO. L activation de la voie RhoA/ROCK dans le dysfonctionnement endothélial systémique et pulmonaire a été mise en évidence chez les tabagiques avec ou sans BPCO. Les résultats de notre première étude montrent l existence d une activation de la voie RhoA/ROCK au niveau des artères pulmonaires chez les patients BPCO ayant un dysfonctionnement endothélial, et une corrélation entre l activité de la RhoA et l expression génique et l activité de la NO synthase endothéliale (NOS-3).L HTP est une complication grave des PID. Nous avons montré dans notre deuxième étude l implication de la voie RhoA/ROCK dans la réponse inflammatoire et la fibrose pulmonaire (FP) dans un modèle murin de PID induite par injection intratrachéale de bléomycine (BLM). Nous avons ensuite testé l effet préventif du fasudil, un inhibiteur des ROCK, sur l apparition de la FP et l HTP expérimentales induites par la BLM. Les résultats de cette deuxième étude montrent que la FP et l HTP sont associées à une activation de la voie RhoA/ROCK dans ce modèle murin et que le fasudil inhibe la réponse inflammatoire, la FP et l HTP, via l inhibition de la phosphorylation de Smad2/3 de la voie de signalisation par le TGF-b1.La FP et l HTP représentent deux causes principales de mortalité liée à la sclérodermie systémique (ScS). Nous avons étudié le rôle de la voie RhoA/ROCK dans la physiopathologie de la fibrose cutanée et l atteinte pulmonaire dans un modèle murin de ScS induite par injection intradermique d acide hypochloreux (HOCl). Les résultats de cette troisième étude montrent l association entre la fibrose cutanée induite par l HOCl et l activation de la voie RhoA/ROCK au niveau de la peau, et l effet préventif du fasudil sur la fibrose cutanée et pulmonaire, en partie via l inhibition de la phosphorylation de Smad2/3 et de l activation des protéines ERK1/2. Ces résultats suggèrent l implication de la voie RhoA/ROCK dans la physiopathologie de la BPCO et de la PID avec ou sans HTP. La voie RhoA/ROCK pourrait de ce fait représenter une nouvelle cible thérapeutique dans la BPCO et la PID avec ou sans HTP.Mots-clés : RhoA, Rho-kinases, fasudil, BPCO, fibrose pulmonaire, hypertension pulmonaire.The RhoA/Rho-kinases (ROCK) pathway plays a pivotal role in the pathophysiology of pulmonary hypertension (PH) as its abnormal activation leads to endothelial dysfunction, sustained vasoconstriction and pulmonary vascular remodeling. According to the international classification of PH, chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD) represent two main causes of PH associated with chronic respiratory diseases. These two causes have in common major pathophysiological mechanisms such as endothelial dysfunction, vascular remodeling and interstitial fibrosis. The aims of the present study were to investigate the role of the RhoA/ROCK pathway in the pathophysiology of lung vascular and interstitial injuries in COPD and ILD with or without development of PH, and to study the molecular mechanisms associated with regulation of the RhoA/ROCK pathway in each of these situations.The pulmonary endothelial dysfunction is an essential event in the initiation and progression of COPD. Although the role of the RhoA/Rho-kinase pathway in pulmonary endothelial dysfunction has been demonstrated in smokers with normal lung function, little is known about its role in patients with COPD. The results of our first study demonstrated an increase in RhoA and ROCK activity in pulmonary arteries of patients with COPD, simultaneously with an altered pulmonary endothelial-dependent vasodilation. The increased RhoA activity in patients with COPD was correlated with an impairment of the gene expression and activity of endothelial NO synthase (eNOS).PH associated with pulmonary fibrosis (PF) considerably worsens prognosis of ILD. The results of our second study showed an activation of the RhoA/ROCK pathway in lung tissues of mice intoxicated by intratracheal instillation of bleomycin (BLM). BLM induced severe PF and PH in mice, associated with an increased RhoA and ROCK activity in the lung. We further demonstrated that long-term treatment with fasudil, a selective ROCK inhibitor, reduced BLM-induced lung inflammation, lung fibrosis and PH in mice, at least in part, via inhibition of Smad2/3 phosphorylation in TGF-b1 signaling.PF and PH represent two leading causes of death in patients with systemic sclerosis (SSc). In our third study, we investigated the role of the RhoA/ROCK pathway in the pathophysiology of skin fibrosis and lung injuries in a murine model of SSc induced by intradermal injection of hypochlorous acid (HOCl). We demonstrated that HOCl-induced skin fibrosis was associated with an activation of the RhoA/ROCK pathway in the fibrotic skin, and that long-term treatment with fasudil reduced both skin and lung fibrosis through inhibition of the phosphorylation of Smad2/3 and ERK1/2 in the fibrotic skin.These results suggest the implications of the RhoA/ROCK pathway in the pathophysiology of lung vascular and interstitial injuries in COPD and ILD with and without development of PH. The RhoA/ROCK pathway might be a promising therapeutic target for patients with COPD or ILD with and without PH.PARIS5-Bibliotheque electronique (751069902) / SudocSudocFranceF

A Status Data Transmitting System for Vessel Monitoring

This paper presents a status data transmitting system suitable for vessel monitoring. The system consists of four main parts, which are a status data module, a frequency synthesizer, a power amplifier and a horn antenna. The status data module packs information of the identification, longitude, latitude and state of the vessel into data frames. FSK/MSK/GMSK schemes were used to modulate the data. The frequency synthesizer was designed with very high stability over temperature and very low frequency tolerance. The power amplifier provides 130 W output power at S band. The impedance bandwidth of the horn antenna can be controlled using the beveling technique

Multiobjective Logistics Optimization for Automated ATM Cash Replenishment Process

In the digital transformation era, integrating digital technology into every aspect of banking operations improves process automation, cost efficiency, and service level improvement. Although logistics for ATM cash is a crucial task that impacts operating costs and consumer satisfaction, there has been little effort to enhance it. Specifically, in Vietnam, with a market of more than 20,000 ATMs nationally, research and technological solutions that can resolve this issue remain scarce. In this paper, we generalized the vehicle routing problem for ATM cash replenishment, suggested a mathematical model and then offered a tool to evaluate various situations. When being evaluated on the simulated dataset, our proposed model and method produced encouraging results with the benefits of cutting ATM cash operating costs

A Simple Procedure to Measure the Tidal Volume Delivered by Mechanical Ventilators: A Tool for Bedside Verification and Quality Control

Mechanical ventilation is the most extensively employed life support intervention among patients with severe respiratory fail ure of different etiologies. In this context, consistent delivery of the most suitable tidal volume (VT) to the patientis criticalto achieving personalized mechanical ventilation. Indeed, in addition to its con tribution to minute volume for optimization of blood gas exchange,appropriate VT strategies are critical to avoid ventilator-induced lung injury in the general context of lung-protective ventilation and when specifically applying ultra-low tidal volume ventilation. Additionally, VT is required to compute respiratory system com pliance or ventilatory ratio, useful indices in the classification of patient phenotype and estimation of prognosis

Some preliminary results of paleo-tsunami study in the coastal region of the Nghe An province, Vietnam

In the coastal region of the Nghe An province, the geomorphology is characterized by appearances of fields of arca granosa with placura placenta and hills of placura placenta with arca granosa, namely: The hills of placura placenta with the arca granosa shells in the Quynh Van and Nghi Tien communes; the fields of arca granosa with the placura placenta: deep-seated in the Quynh Nghia, Dien Chau and along the Nghi Yen coast  which have age of 4,500 - 4,300 yrs.; The appearance of the placura placenta-arca granosa shell’s fields and hills which do not originate from either marine transgression in the Holocene epoch, tectonic movement or artificiality; Our results suggest that there were three tsunami events occurring in the past during the periods of 4,500 - 4,300; 4,100 - 3,900 and 900 - 600 yrs., respectively in the region

OPTICAL BISTABILITY IN A DEGENERATE TWO-LEVEL EIT MEDIUM UNDER THE INFLUENCE OF AN EXTERNAL MAGNETIC FIELD: AN ANALYTICAL APPROACH

We investigate the behavior of optical bistability in a degenerate two-level atomic medium using an external magnetic field to separate the lower level into two distinct levels that both connect to an upper level by the probe and coupling laser fields. Based on analytical solutions, the absorption spectrum and behavior of optical bistability in an electromagnetically induced transparency regime under an external magnetic field are investigated. By controlling the external magnetic field, we find that the appearance and disappearance of the optical bistability can be easily controlled according to the strength of the magnetic field in the transparent window domain. Furthermore, the effects of the intensity of the coupling laser field and the parameters of the system on the behavior of optical bistability are also considered. The proposed model is useful for applications in all-optical switches and magneto-optic storage devices.We investigate the behavior of optical bistability in a degenerate two-level atomic medium using an external magnetic field to separate the lower level into two distinct levels that both connect to an upper level by the probe and coupling laser fields. Based on analytical solutions, the absorption spectrum and behavior of optical bistability in an electromagnetically induced transparency regime under an external magnetic field are investigated. By controlling the external magnetic field, we find that the appearance and disappearance of the optical bistability can be easily controlled according to the strength of the magnetic field in the transparent window domain. Furthermore, the effects of the intensity of the coupling laser field and the parameters of the system on the behavior of optical bistability are also considered. The proposed model is useful for applications in all-optical switches and magneto-optic storage devices

Evaluating the shoreline and bottom terrain variations in the naval port of zone 5, Phu Quoc, Kien Giang by using multi - temporal remote sensing images

In this study, the authors aim to study two major contents: (1) Evaluating the shoreline variation in the naval port of zone 5 (in the years of 1999, 2006, 2009 and 2016); (2) Evaluating the bottom terrain variation in the naval port of zone 5 (in the years of 2007 and 2010). Three main research methodologies were applied: (i) Band rationing method for the shoreline extraction; (ii) Shoreline change analysis method using GPS data; (iii) Digital elevation model integrated with bottom terrain analysis method. The most obvious change in shoreline is in the An Thoi port from Mui Den to Mui Ong Doi. In the shoreline from Mui Den to Mui Con Duong, a backward shoreline evolution (erosion) mainly occurred with an average width of about 40–50 m, while some other places had a forward shoreline evolution (accumulation), especially in Mui Con Duong with a width of 60 m. These sediment materials are sent to conductor and accumulation, making the bottom terrain raised. As on the sections AA’, BB’, CC’, DD’, we could see that the bottom terrain at the channel of naval port of zone 5 has the depth variation only from 2 m to 4 m. The accumulation rate is up to 1 m/year in this period