8 research outputs found
Aquaporin 1 controls the functional phenotype of pulmonary smooth muscle cells in hypoxia-induced pulmonary hypertension
Benralizumab: Cibler le récepteur de l’IL-5 dans l’asthme sévère éosinophile
Zusammenfassung. Für Patienten mit schwierig kontrollierbarem, schwerem Asthma bronchiale stehen heute neben der inhalativen Medikation hochwirksame, gezielte Behandlungsmöglichkeiten zur Verfügung. Bei Vorliegen einer deutlichen Eosinophilie verspricht die Hemmung der Interleukin-5-Achse (IL-5) mit spezifischen, monoklonalen Antikörpern eine wirksame und nebenwirkungsarme Alternative zur dauerhaften systemischen Steroidtherapie. In diesem Übersichtsartikel werden die Daten zu Benralizumab, einem spezifischen Antikörper gegen den IL-5-Rezeptor Alpha, zusammengefasst. Dieser Angriffspunkt verhindert die Rezeptorstimulation durch IL-5 und aktiviert eine NK-zellvermittelte zytotoxische Reaktion, die zur Apoptose der eosinophilen Granulozyten führt. Die s.c.-Applikation von Benralizumab führt innerhalb von Tagen zur nahezu vollständigen Depletion der Eosinophilen im Blut mit konsekutiver Verbesserung der Lungenfunktion und Stabilisierung des Asthmas. Für ausgewählte Patienten mit schwerem Asthma eröffnet sich hier eine vielversprechende Therapie-Optio
Benralizumab: Der IL-5-Rezeptor als Ziel bei schwerem eosinophilem Asthma
Benralizumab: Targeting the IL-5 Receptor in Severe Eosinophilic Asthma For patients with difficult-to-control, severe bronchial asthma, highly effective, targeted treatment options are available in addition to inhaled medication. In the presence of eosinophilia, inhibition of the interleukin-5 (IL‑5) axis with specific monoclonal antibodies promises to be an effective alternative to continuous systemic steroid therapy with few side effects. This review summarizes the data on benralizumab, a specific antibody against the IL-5 receptor alpha preventing receptor stimulation by IL-5 and activating a NK-cell mediated cytotoxic reaction with apoptosis of eosinophils. The s.c.-application of benralizumab leads within days to a virtually complete depletion of blood eosinophils with consecutive improvement in lung function and stabilization of asthma. For selected severe asthmatics, this is a promising therapy option
Aquaporin 1 controls the functional phenotype of pulmonary smooth muscle cells in hypoxia-induced pulmonary hypertension
Analysis of hypoxia-induced noncoding RNAs reveals metastasis-associated lung adenocarcinoma transcript 1 as an important regulator of vascular smooth muscle cell proliferation
Vascular remodeling, a pathogenic hallmark in pulmonary hypertension, is mainly driven by a dysbalance between proliferation and apoptosis of human pulmonary artery smooth muscle cells. It has previously been shown that microRNAs are involved in the pathogenesis of pulmonary hypertension. However, the role of long noncoding RNAs has not been evaluated. long noncoding RNA expression was quantified in human pulmonary artery smooth muscle cells using PCR arrays and quantitative PCR. Knockdown of genes was performed by transfection of siRNA or GapmeR. Proliferation and migration were measured using BrdU incorporation and wound healing assays. The mouse model of hypoxia-induced PH was used to determine the physiological meaning of identified long noncoding RNAs. The expression of 84 selected long noncoding RNAs was assessed in hypoxic human pulmonary artery smooth muscle cells and the levels of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) were significantly increased. Depletion of hypoxia-inducible factor 1α abolished the hypoxia-induced upregulation of metastasis-associated lung adenocarcinoma transcript 1 expression. Silencing of MALAT1 significantly decreased proliferation and migration of human pulmonary artery smooth muscle cells. In vivo, MALAT1 expression was significantly increased in lungs of hypoxic mice. Of note, targeting of MALAT1 by GapmeR ameliorated heart hypertrophy in mice with pulmonary hypertension. This is the first report on functional characterization of MALAT1 in the pulmonary vasculature. Our data provide evidence that MALAT1 expression is significantly increased by hypoxia, probably by hypoxia-inducible factor 1α. Intervention experiments confirmed that MALAT1 regulates the proliferative phenotype of smooth muscle cells and silencing of MALAT1 reduced heart hypertrophy in mice with pulmonary hypertension. These data indicate a potential role of MALAT1 in the pathogenesis of pulmonary hypertension. IMPACT STATEMENT: Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a long noncoding RNA that mediates several biological processes. In the context of vascular biology, MALAT1 has been shown to be inducible by hypoxia and to control cell proliferation. These processes are of major importance for the pathophysiology of hypoxia-induced pulmonary hypertension (PH). Until now, the physiological role of MALAT1 in PH remains unclear. By using smooth muscle cells and by employing an established PH mouse model, we provide evidence that hypoxia induces MALAT1 expression. Moreover, depletion of MALAT1 inhibited migration and proliferation of smooth muscle cells, probably by the induction of cyclin-dependent kinase inhibitors. Of note, MALAT1 was significantly increased in mice exposed to hypoxia and silencing of MALAT1 ameliorated heart hypertrophy in mice with hypoxia-induced PH. Since vascular remodeling and right heart failure as a consequence of pulmonary pressure overload is a major problem in PH, these data have implications for our pathogenetic understanding
MicroRNA-223 controls the expression of histone deacetylase 2: a novel axis in COPD
Reduced activity of histone deacetylase 2 (HDAC2) has been described in patients with chronic obstructive pulmonary disease (COPD), but the mechanisms resulting in decreased expression of this important epigenetic modifier remain unknown. Here, we employed several in vitro experiments to address the role of microRNAs (miRNAs) on the regulation of HDAC2 in endothelial cells. Manipulation of miRNA levels in human pulmonary artery endothelial cells (HPAEC) was achieved by using electroporation with anti-miRNAs and miRNA mimics. Target prediction software identified miR-223 as a potential repressor of HDAC2. In subsequent stimulation experiments using inflammatory cytokines known to be increased in patients with COPD, miR-223 was found to be significantly induced. Functional analysis demonstrated that overexpression of miR-223 decreased HDAC2 expression and activity in HPAEC. Conversely, HDAC2 expression and activity was preserved in anti-miR-223-treated cells. Direct miRNA-target interaction was confirmed by reporter gene assay. In a next step, reduced expression of HDAC2 was found to increase the levels of the chemokine fractalkine (CX3CL1). In vivo studies confirmed elevated expression levels of miR-223 in mice exposed to cigarette smoke and in emphysematous lung tissue from LPS-treated mice. Moreover, a significant inverse correlation of miR-223 and HDAC2 expression was found in two independent cohorts of COPD patients. These data emphasize that miR-223, the most prevalent miRNA in COPD, controls expression and activity of HDAC2 in pulmonary cells, which, in turn, might alter the expression profile of chemokines. This pathway provides a novel pathogenic link between dysregulated miRNA expression and epigenetic activity in COPD.
KEY MESSAGES: Histone deacetylase 2 is directly targeted by miR-223. Levels of miR-223 are induced by interleukin-1β and tumor necrosis factor-α. miR-223 controls the expression of fractalkine by targeting histone deacetylase 2. miR-223 levels are increased in COPD mouse models. miR-223 levels inversely correlate with HDAC2 expression in COPD patients