Effects of phosphodiesterase 4 inhibition on bleomycin-induced pulmonary fibrosis in mice

Pulmonary fibrosis (PF) is an irreversible and largely untreatable human disease with the causes often remaining unknown. Phosphodiesterase 4 (PDE4) is involved in the processes of inflammation, cell proliferation, differentiation and migration that are known to play an important role in tissue fibrosis. The aim of the study was, therefore, to determine the expression of PDE4 under conditions of PF and to investigate the effects of PDE4 inhibition on functional, histological and biochemical parameters in experimental PF. Pulmonary fibrosis was induced by cytostatic and profibrotic agent bleomycin in C57BL/6N mice. Expression profiles of the different PDE4 isoforms were analyzed at mRNA and protein levels in lungs with both experimental and human PF. Animals were treated with the selective PDE4 inhibitor cilomilast and/or vehicle and treatment effects were examined by means of bronchoalveolar lavage fluid (BALF) differential cell count, mRNA analysis for lung tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL6, pulmonary compliance measurement, quantified pathological examination of the lungs, collagen assay and survival analysis. Analysis of PDE4 expression showed significant upregulation of inflammation-related PDE4 isoform in lungs with both human and experimental PF. Treatment of mice with cilomilast resulted in significant reduction in total number of cells, number of macrophages and lymphocytes, but not neutrophils, in BALF at early inflammatory fibrosis stage (days 4 and 7). Lung TNFalpha, but not IL1beta, level was also significantly reduced by cilomilast while level of IL6 was significantly elevated. At later stage (days 14 and 21) cilomilast-treated mice demonstrated improved lung function and lesser fibrosis degree compared to non-treated group. Lung collagen content and overall survival were also partially restored by treatment with cilomilast. Our results suggest that selective PDE4 inhibition suppresses early inflammatory stage and has the potential to attenuate the late stage of pulmonary fibrosis in experimental fibrosis and thus may offer a new therapeutic option for patients with PF.Die Lungenfibrose ist eine progressive und meistens tödliche Erkrankung, für die es noch immer keine effektive Behandlung gibt. Die Phosphodiesterase 4 (PDE4) spielt bei verschiedenen zellulären Prozessen wie Entzündung, Proliferation, Differenzierung und Migration eine wichtige Rolle. Das Ziel der vorliegenden Arbeit war die Untersuchung der Rolle der PDE4 in der experimentellen Fibrose. Dazu erfolgten Untersuchungen zur Expression der PDE4 in fibrotischen Lungen und Überprüfung des Effektes einer PDE4-Hemmung auf funktionelle, histologische und biochemische Parameter in einem experimentellen Modell der Fibrose. Dazu wurde eine Lungenfibrose in C57BL/6N Mäusen durch eine einmalige Gabe von Bleomycin induziert und die Expression der verschiedene PDE4 Isoformen auf mRNA- und Proteinebene bestimmt. Die Versuchstiere wurden weiterhin mit dem selektivem PDE4-Hemmstoff Cilomilast oder mit dem Placebo behandelt. Anschließend wurden die Behandlungseffekte durch Zellzählung der bronchoalveolären Lavage (BAL), Genexpressionsanalyse der Zytokine Tumor-Nekrose-Faktor (TNF) alpha, Interleukin (IL) 1beta, IL6, pulmonale Compliance-Messung, quantifizierte pathologische Lungenuntersuchung, Kollagenanalyse und die Überlebensdauer untersucht. Begleitende Untersuchungen zur Expression der PDE4 Isoformen erfolgten am explantierten Gewebe von Patienten mit Lungenfibrose. Die Genexpressionsanalyse der PDE4 zeigte eine signifikant erhöhte Expression der entzündungsbedingten Isoformen in Maus- und Humanlunge mit Lungenfibrose. Die Behandlung mit Cilomilast führte zu einer signifikanten Reduktion der totalen Zellnummer, der Nummer von Makrophagen und Lymphozyten, nicht aber der Neutrophilien, in der BAL in der frühen Krankheitsphase (Tage 4 und 7). Der Zytokinspiegel von TNFalpha wurde signifikant gesenkt, während die Spiegel von IL1beta und IL6 unverändert blieben. In der späteren Krankheitsphase (Tage 14 und 24) zeigten die Cilomilast-behandelten Mäuse eine verbesserte Lungenfunktion und weniger Fibrose, im Verglech mit unbehandelte Tieren. Zusammenfassend kann man sagen, dass im experimentellen Modell der Lungenfibrose eine selektive Hemmung der PDE4 die frühe Entzündungsreaktion unterdrückt und möglicherweise die spätere Krankheitsphase abschwächt. Dies könnte daher eine neue Behandlungsmöglichkeit zur Therapie der Lungenfibrose darstellen

Increased expression of 5-hydroxytryptamine(2A/B) receptors in idiopathic pulmonary fibrosis: a rationale for therapeutic intervention

Background Idiopathic pulmonary fibrosis (IPF) has a poor prognosis and limited responsiveness to available treatments. It is characterised by epithelial cell injury, fibroblast activation and proliferation and extracellular matrix deposition. Serotonin (5-hydroxytryptamine; 5-HT) induces fibroblast proliferation via the 5-HTR2A and 5-HTR2B receptors, but its pathophysiological role in IPF remains unclear. A study was undertaken to determine the expression of 5-HT receptors in IPF and experimental lung fibrosis and to investigate the effects of therapeutic inhibition of 5-HTR2A/B signalling on lung fibrosis in vivo and in vitro. Methods and results Quantitative RT-PCR showed that the expression of 5-HTR1A/B and 5-HTR2B was significantly increased in the lungs of patients with IPF (n = 12) and in those with non-specific interstitial pneumonia (NSIP, n = 6) compared with transplant donors (n = 12). The expression of 5-HTR2A was increased specifically in IPF lungs but not in NSIP lungs. While 5-HTR2A protein largely localised to fibroblasts, 5-HTR2B localised to the epithelium. To assess the effects of 5HTR(2A/B) inhibition on fibrogenesis in vivo, mice were subjected to bleomycin-induced lung fibrosis and treated with the 5-HTR2A/B antagonist terguride (or vehicle) in a therapeutic approach (days 14-28 after bleomycin). Terguride-treated mice had significantly improved lung function and histology and decreased collagen content compared with vehicle-treated mice. Functional in vitro studies showed that terguride is a potent inhibitor of transforming growth factor beta(1)- or WNT3a-induced collagen production. Conclusion The studies revealed an increased expression of 5-HTR2A specifically in IPF. Blockade of 5-HTR2A/B signalling by terguride reversed lung fibrosis and is thus a promising therapeutic approach for IPF

A clinical case of successful application of a new treatment method for severe COVID-19

COVID-19, formerly coronavirus infection 2019-nCoV, is a potentially severe acute respiratory infection caused by the SARS-CoV-2 coronavirus (2019-nCoV). It is a dangerous disease that can occur both in the form of a mild acute respiratory viral infection and in a severe form with the development of bilateral polysegmental viral pneumonia, specific complications of which may include acute respiratory distress syndrome, resulting in the respiratory failure with a high risk of death. Due to the absence of etiotropic therapy for the coronavirus infection, pathogentic treatment becomes of primary importance. We present a clinical case of a severe form of COVID-19 in a 33-year-old man to whom we administered a new method of pathogenetic treatment of this disease based on immunosuppresiive therapy followed by therapeutic plasma exchange and infusion of non-specific human immunoglobulin

Effects of phosphodiesterase 4 inhibition on bleomycin-induced pulmonary fibrosis in mice

<p>Abstract</p> <p>Background</p> <p>Pulmonary fibrosis (PF) is a group of devastating and largely irreversible diseases. Phosphodiesterase (PDE) 4 is involved in the processes of remodeling and inflammation, which play key role in tissue fibrosis. The aim of the study was, therefore, to investigate the effect of PDE4 inhibition in experimental model of PF.</p> <p>Methods</p> <p>PF was induced in C57BL/6N mice by instillation of bleomycin. Pharmacological inhibition of PDE4 was achieved by using cilomilast, a selective PDE4 inhibitor. Changes in either lung inflammation or remodeling were evaluated at different stages of experimental PF. Lung inflammation was assessed by bronchoalveolar lavage fluid (BALF) differential cell count and reverse transcription quantitative polymerase chain reaction (RT-qPCR) for inflammatory cytokines. Changes in tissue remodeling were evaluated by pulmonary compliance measurement, quantified pathological examination, measurement of collagen deposition and RT-qPCR for late remodeling markers. Survival in all groups was analyzed as well.</p> <p>Results</p> <p>PDE4 inhibition significantly reduced the total number of alveolar inflammatory cells in BALF of mice with bleomycin-induced PF at early fibrosis stage (days 4 and 7). Number of macrophages and lymphocytes, but not neutrophils, was significantly reduced as well. Treatment decreased lung tumor necrosis factor (TNF)-α mRNA level and increased mRNA level of interleukin (IL)-6 but did not influence IL-1β. At later stage (days 14 and 24) cilomilast improved lung function, which was shown by increase in lung compliance. It also lowered fibrosis degree, as was shown by quantified pathological examination of Hematoxilin-Eosin stained lung sections. Cilomilast had no significant effect on the expression of late remodeling markers such as transforming growth factor (TGF)-β1 and collagen type Ia1 (COL(I)α1). However, it tended to restore the level of lung collagen, assessed by SIRCOL assay and Masson's trichrome staining, and to improve the overall survival.</p> <p>Conclusions</p> <p>Selective PDE4 inhibition suppresses early inflammatory stage and attenuates the late stage of experimental pulmonary fibrosis.</p

Theoretical investigation of the effect of the taper angle of the deforming roller on the limiting degrees of deformation in the process of flow forming

The conditions for the application of taper angles of deforming rollers are considered in the article, which ensure a steady flow of the flow forming. With the help of the developed engineering technique, analytical and graphical dependences of the boundary values of the deformation degrees on the cone angle of the deforming roller are obtained. The results of the theoretical study are in good agreement with the known experimental data. The developed engineering technique can be used in designing the flow forming on the direct and reverse method, as well as for any process of pressure treatment with a local focus of deformation

Theoretical investigation of the effect of the taper angle of the deforming roller on the limiting degrees of deformation in the process of flow forming

The conditions for the application of taper angles of deforming rollers are considered in the article, which ensure a steady flow of the flow forming. With the help of the developed engineering technique, analytical and graphical dependences of the boundary values of the deformation degrees on the cone angle of the deforming roller are obtained. The results of the theoretical study are in good agreement with the known experimental data. The developed engineering technique can be used in designing the flow forming on the direct and reverse method, as well as for any process of pressure treatment with a local focus of deformation

Simulation of Wind Speed in the Problems of Wind Power

The article is devoted to research of mathematical models of wind speed and development a way to improve the efficiency of wind power plants based on fuzzy logic using fuzzy model of the wind speed. Simulation of the wind speed is a fairly difficult task, since this source of energy is constantly changing in time and space. Four basic models of wind speed were identified at the end of research work: determinate, probability, spectral and fuzzy. Every one finds their own field of application. Thus, from the energy point of view, the model probabilistic distribution of Weibull is most applicable at the level of technical and economic development. Deterministic model allows to determine the power generated by wind turbines at a given average wind speed. The spectral model should apply in those studies where necessary to account for gusts of wind and sudden changes. Fuzzy model of the wind is the most convenient and relevant for modeling of wind turbine control, it is allows to form a flexible control system.Статья посвящена исследованию математических моделей скорости ветра и разработке способа повышения эффективности выработки ветроэнергетической установки на основе нечеткой логики с использованием нечеткой модели скорости ветра. Моделирование скорости ветра представляет собой достаточно сложную задачу, так как данный источник энергии постоянно изменяется во времени и пространстве. В результате исследований было выделено четыре основных модели скорости ветра: детерминированная, вероятностная, спектральная и нечеткая. Каждая из них находит свою область применения. Так, с энергетической точки зрения, на уровне технико-экономических разработок наиболее применима вероятностная модель или распределение Вэйбулла. Детерминированная модель позволяет определить мощность, вырабатываемую ветроустановкой при заданной средней скорости ветра. В тех исследованиях, где необходим учет порывов и резких изменений ветра, следует обратиться к спектральной модели. Нечеткая же модель ветра удобна и наиболее актуальна при моделировании процессов управления ВЭУ, так как позволяет сформировать достаточно гибкую систему управления

Исследование средств повышения регулирования мощности ветровой турбины

Today, wind power is the fastest-growing renewable energy source. Wind power is free, clean and endless. Furthermore, the cost of the electricity produced by wind turbines already reached the point where it is comparable with that of electricity produced by some of the conventional, fossil based power plants. However, it is still important to improve upon the technology in order to keep wind energy economically competitive with traditional and other renewable energy sources. In this paper, the idea of a variable-length blades, microdevices, and plasma jet drives are offered as a means of improving energy generation wind turbinesСегодня энергия ветра является самым быстрорастущим источником возобновляемой энергии. Ветровая энергия доступна, экологически чистая и бесконечна. Кроме того, стоимость электроэнергии, производимой ВЭУ, уже достигла точки, где она сравнима со стоимостью электроэнергии, производимой некоторыми электростанциями на основе ископаемых видов топлива. Тем не менее по-прежнему важно улучшать технологии для того, чтобы сохранить энергию ветра экономически конкурентноспособной по отношению к традиционным и другим возобновляемым источниками энергии. В этой статье представлена идея переменной длины лопасти, микроустройств и плазменных приводов, которые предлагаются в качестве средства улучшения производимой энергии ветровых турби