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PDE4 inhibitors and oxidative stress
No full textPDE4 belongs to the PDE1-11 superfamily, specifically degrades cAMP and is present in almost all cells with the exception of platelets. Selective inhibition of PDE4 augments cellular cAMP content that improves chronic inflammation or tissue remodeling. Consequently, over almost three decades industry endeavored to develop PDE4 inhibitors. Roflumilast has now been approved in EU/US as the first PDE4 inhibitor for treatment in severe chronic obstructive pulmonary disease (COPD).
In COPD an enhanced burden of oxidative stress is likely promoting key disease mechanisms such as COPD-related inflammation, lung remodeling or mucociliary malfunction. Neutrophils, which are considered as primary effectors cells in COPD almost exclusively express PDE4. That PDE4 inhibitors such as rolipram or Ro20-1724 suppress fMLP-induced superoxide radical release from neutrophils was described in 1990. These findings were probably the first demonstration that PDE4 inhibitors may mitigate oxidative stress. Such initial observations in neutrophils were now extended to numerous other cells involved in COPD, specifically structural cells. Indeed, PDE4 inhibitors reduce ROS formation in airway epithelial cells, lung fibroblasts, endothelial cells or pulmonary artery smooth muscle cells. Mechanistically, PDE4 inhibitors may act by (i) reducing NADPH oxidase (NOX) activity secondary to inactivating Rac, (ii) attenuating the expression levels of some NOX isoforms. Cellular ROS levels may result from the balance between ROS formation mainly attributed to the NOX system and ROS quenching secondary to the Nrf2-dependent anti-oxidative machinery. Aside from its potential to reduce ROS formation more recently an increase in cAMP was related to enhanced Nrf2 nuclear accumulation, which may support the anti-oxidative machinery. Evidence for this concept was first generated in dermal fibroblasts. Preliminary data from human umbilical vein endothelial cells showed that inhibition of PDE4 (1μM roflumilast N-oxide) when PDE3 was blocked (10μM motapizone) resulted in an about 1.9-fold increase in nuclear Nrf2 following a 3 hours incubation time (roflumilast N-oxide or motapizone on their own were ineffective). Thus, the notion may be raised that PDE4 inhibitors potentially attack excessive ROS twofold, by inhibiting generation and accelerating degradation. More studies are required to further support such a concept.
Lung fibrotic remodeling has been related to oxidative stress and indeed N-acetyl cysteine (NAC) may have some clinical benefit in idiopathic pulmonary fibrosis. In vivo, NAC partly suppresses the bleomycin-induced lung fibrotic response indicating a critical role of ROS to mediate fibrosis. The PDE4 inhibitor roflumilast was shown to mitigate lung fibrosis following bleomycin in preventive but also therapeutic protocols in mice and rats that was paralleled by a partial reduction of lipid hydroperoxides (markers of oxidative stress) in BAL.
Taken together, there is firm evidence that PDE4 inhibitors suppress oxidative stress in vitro that is also reflected in vivo. One may postulate that reducing the burden of oxidative stress may be one of the mechanisms translating into the therapeutic success of roflumilast in severe COPD although this notion remains to be specifically addressed in clinical investigations
Roflumilast, a Targeted Phosphodiesterase 4 Inhibitor, Fully Prevents the Development of Emphysema Induced by Cigarette Smoke Exposure
No full textRationale: As indicated in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, there is a pressing need to develop new agents capable of suppressing the inflammatory response in chronic obstructive pulmonary disease (COPD). Methods: Since cigarette smoke is the major risk factor for the development of COPD, we investigated the effects of roflumilast, a novel targeted phosphodiesterase 4 (PDE4) inhibitor, given orally either at 1 mg/kg or at 5 mg/kg, in an acute and in a chronic model of cigarette smoke exposure in mice (C57Bl/6J). Control mice were exposed to air. Results: Acute exposure to the smoke of 5 cigarettes resulted in an increase (+404%) of bronchoalveolar lavage fluid (BALF) neutrophils within 24 hours. Both roflumilast doses significantly inhibited (by 37%) this increase. Additionally, roflumilast 1mg/kg and 5 mg/kg increased the levels of the anti-inflammatory cytokine interleukin-10 by 79% (p<0.05) and 129% (0.05), respectively, in BALF. Chronic exposure to cigarette smoke for 7 months resulted in disseminated foci of emphysema mirrored by an increase of the mean linear intercept (+21%, p<0.05), a decrease of the internal surface area (–13%, p<0.05), and a drop (-13%, p<0.05) in lung desmosine content. Roflumilast at a dose of 1 mg/kg did not have any effect, while at 5 mg/kg roflumilast fully prevented the morphological, morphometrical, and the biochemical changes. Conclusions: This is the first study to show that administration of a targeted PDE4 inhibitor ameliorates lung inflammation induced by acute exposure to cigarette smoke and fully prevents elastolytic parenchymal destruction induced by chronic cigarette smoke exposure
Effect of roflumilast on inflammatory cell volume density in lungs of mice chronically exposed to cigarette smoke
No full textRationale: The phosphodiesterase 4 (PDE4) inhibitor roflumilast was previously shown to fully prevent emphysematous-like changes in lungs of mice that were chronically exposed to cigarette smoke. This study assessed the effect of roflu- milast on inflammatory cell volume density (VV) changes in lung tissue of mice chronically exposed to cigarette smoke.
Methods: C57BL/6J mice were either exposed to room air (N=5) or cigarette smoke for 7 months (N = 5). Another group of animals (N = 5) exposed to cigarette smoke received roflumilast 5 mg/kg per os on 5 days/week for 7 months. VV was assessed immunohistochemically and by point counting in lung sections. Cells were labeled with specific antibodies: neutrophils with myeloperoxidase, macrophages with Mac-3, dendritic cells with fascin, B-lymphocytes with B220, CD4+ T-cells with CD4+ antibody.
Results: In mice chronically exposed to cigarette smoke, VV of neutrophils, macrophages, dendritic cells, B-lymphocytes, and CD4+ T-cells increased 1.8- to more than 6-fold as compared to air exposure (all p < 0.01). Roflumilast did not affect baseline VV but prevented VV increases of neutrophils by 78% (p < 0.05), macrophages by 70%, dendritic cells by 48%, B-lymphocytes by 100%, and CD4+ T-cells by 98% (all p < 0.01).
Conclusions: In this mouse model of chronic cigarette smoke exposure, increases in broad inflammatory cell populations involved in both the innate and adaptive immune responses were demonstrated. This study suggests that roflumilast may prevent cigarette smoke-induced emphysema development through inhibition of the recruitment of neutrophils, macrophages, and cells of the adaptive immune system
Roflumilast fully prevents emphysema in mice chronically exposed to cigarette smoke
No full textThere is a need for new agents capable of suppressing the inflammatory response in chronic obstructive pulmonary disease.
OBJECTIVES:
This study evaluated the effects of roflumilast, a phosphodiesterase 4 (PDE4) inhibitor on acute lung inflammation and chronic lung changes in models of cigarette exposure in mice.
METHODS:
Roflumilast was given orally either at 1 mg/kg (R1) or at 5 mg/kg (R5). In the acute model (five cigarettes for 20 minutes), bronchoalveolar lavage fluid (BALF) changes were investigated at 4 and 24 hours. In the chronic model (three cigarettes/day for 7 months), morphometric and biochemical parameters were assessed at 7 months.
MEASUREMENTS AND MAIN RESULTS:
Acute exposure caused a fivefold increase in BALF neutrophils. Both doses of roflumilast partially prevented (by 30%) this increase. In addition, after smoke exposure, R1 increased BALF interleukin-10 by 79% and R5 by 129%. Chronic smoke exposure caused a 1.8-fold increase in lung macrophage density, emphysema, an increase of the mean linear intercept (+21%), a decrease of the internal surface area (-13%), and a drop (-13%) in lung desmosine content. R1 did not have any effect, whereas R5 prevented the increase in lung macrophage density by 70% and fully prevented the other changes. In addition, in the smoke-exposure group, 63% of the mice showed goblet cell metaplasia, and neither of the doses of roflumilast had any effect.
CONCLUSIONS:
This study shows for the first time that a PDE4 inhibitor partially ameliorates lung inflammation and fully prevents parenchymal destruction induced by cigarette smoke
Roflumilast prevents the increase in inflammatory cells in the lungs of mice chronically exposed to cigarette smoke: an immunohistochemical study
No full textRATIONALE We have previously reported that roflumilast, an investigational phosphodiesterase 4 (PDE4) inhibitor, fully prevented the development of emphysema in C57BL/6J mice chronically exposed to cigarette smoke (AJRCCM 2005; 172: 848-53). In the present study, we investigated the effect of roflumilast on changes in inflammatory cell volume density (VV) in mice exposed to cigarette smoke for 7 months. METHODS C57BL/6J mice were either exposed to room air (N=5) or cigarette smoke for 7 months (N=5). Additionally, a group of cigarette smoke exposed animals received roflumilast 5 mg/kg per os (N=5). VV was assessed immunohistochemically and by point counting. Neutrophils were marked with myeloperoxidase antibody, macrophages with Mac-3 antibody, dendritic cells with fascin antibody, B-lymphocytes with B220 antibody, and CD4+ T-cells with CD4+ antibody. RESULTS Chronic cigarette smoke exposure of mice, as compared to air exposure, increased neutrophil VV (2.3±0.3 x 10-4 mL/g vs 1.2±0.2 x 10-4 mL/g, p<0.01), macrophage VV (14.4±0.4 x 10-4 mL/g vs 8.0±0.5 x 10-4 mL/g, p<0.01), dendritic cell VV (6.1±0.4 x 10-4 mL/g vs 1.9±0.3 x 10-4 mL/g, p<0.01), B-lymphocyte VV (3.4±0.4 x 10-4 mL/g vs 0.6±0.3 x 10-4 mL/g, p<0.01), and CD4+ T-cell VV (6.7±1.0 x 10-4 mL/g vs 1.1±0.3 x 10-4 mL/g, p<0.01). Roflumilast prevented the increase in neutrophil VV by 78% (p<0.05), macrophage VV by 70% (p<0.01), dendritic cell VV by 48% (p<0.01), B-lymphocyte VV by 100% (p<0.01), and CD4+ T-cell VV by 98% (p<0.01). CONCLUSIONS These results indicate that chronic cigarette smoke exposure in mice elicits an increase of cells involved in both the innate and adaptive immune responses. Roflumilast administration significantly prevented the recruitment of these cells
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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