0000000000262686
AUTHOR
Anselm Morell
Additional file 1: of The JAK2 pathway is activated in idiopathic pulmonary fibrosis
Supplementary data. (DOCX 1218 kb)
Roflumilast improves corticosteroid resistance COPD bronchial epithelial cells stimulated with toll like receptor 3 agonist
Chronic obstructive pulmonary disease (COPD) is characterised by chronic pulmonary inflammation punctuated by periods of viral exacerbations. Recent evidence suggests that the combination of roflumilast with corticosteroids may improve the compromised anti-inflammatory properties of corticosteroids in COPD. We analyzed differential and combination anti-inflammatory effects of dexamethasone and roflumilast N-oxide in human bronchial epithelial cells (HBECs) stimulated with viral toll like receptor (TLR) agonists. Lung tissue and HBECs were isolated from healthy (n = 15), smokers (n = 12) and smokers with COPD (15). TLR3 expression was measured in lung tissue and in HBECs. IL-8 secretion was …
β2-adrenoreceptors control human skin microvascular reactivity.
Topical α1- and α2-adrenoreceptor (ADRA1 and 2) agonists are effective in alleviating permanent vasodilation and facial erythema associated with rosacea by inducing skin vasoconstriction. Although β-adrenoreceptor (ADRB) antagonists are used off-label for rosacea, pharmacological and pharmacodynamic data pertaining to these receptors in skin micro-vessels are lacking. Objectives: To analyse the expression of different adrenergic receptors and their contribution to vasoreactivity in skin micro-vessels. Small arteries (500-800 μm) and arterioles (<200 μm) were studied in human foreskin tissue. Specifically, ADR-A1, -A2, -B1 and -B2 expression was assayed by immunofluorescence, polymerase chai…
MUC4 overexpression correlates corticoid resistance in chronic rhinosinusitis with nasal polyps
Background: Some patients with chronic rhinosinusitis with nasal polyps (CRSwNP) are resistant to corticoids. Mucin 4 (MUC4) is a membrane anchored protein with a nuclear translocation domain which is modulated by corticoids. Because glucocorticoid receptor (GR) nuclear translocation is key to the anti-inflammatory effect of corticoids, we hypothesized that MUC4 is involved in the effectiveness of these drugs Objective: To analyze the role of MUC4 in corticoid effectiveness in different cohorts of patients with CRSwNP and elucidate the possible mechanisms involved Methods: 73 patients with CRSwNP took oral corticoids for 15 days. Corticoid resistance was evaluated by nasal endoscopy. The ex…
Role of JAK2/STAT3 pathway in vascular function of pulmonary fibrosis patients
Background: Idiopathic Pulmonary Fibrosis (IPF) is a chronic progressive lung disease with a life expectancy of 2-5 years. A proportion of IPF patients develop pulmonary hypertension (PH), characterized by vasoconstriction and remodeling of pulmonary arteries. Currently, no therapy can improve survival of patients diagnosed with this disease. JAK2/STAT3 molecular route is overexpressed in proliferative disorders, however, its role in PH- associated IPF is unknown. Objective: To analyze the role of JAK2/STAT3 in vascular function of IPF patients with PH. We hypothesized that inhibition of JAK2, STAT3 or JAK2/STAT3 may improve vascular function. Methods: Human precision cut lung slices and ar…
JAK2 mediates lung fibrosis, pulmonary vascular remodelling and hypertension in idiopathic pulmonary fibrosis: an experimental study
BackgroundPulmonary hypertension (PH) is a common disorder in patients with idiopathic pulmonary fibrosis (IPF) and portends a poor prognosis. Recent studies using vasodilators approved for PH have failed in improving IPF mainly due to ventilation (V)/perfusion (Q) mismatching and oxygen desaturation. Janus kinase type 2 (JAK2) is a non-receptor tyrosine kinase activated by a broad spectrum of profibrotic and vasoactive mediators, but its role in PH associated to PH is unknown.ObjectiveThe study of JAK2 as potential target to treat PH in IPF.Methods and resultsJAK2 expression was increased in pulmonary arteries (PAs) from IPF (n=10; 1.93-fold; P=0.0011) and IPF+PH (n=9; 2.65-fold; P<0.00…
Mucin 1 deficiency mediates corticosteroid insensitivity in asthma
BACKGROUND: The loss of corticosteroid efficacy is an important issue in severe asthma management and may lead to poor asthma control and deterioration of airflow. Recent data indicate that Mucin 1 (MUC1) membrane mucin can mediate corticosteroid efficacy in chronic rhinosinusitis, but the role of MUC1 in uncontrolled severe asthma is unknown. The objective was to analyze the previously unexplored role of MUC1 on corticosteroid efficacy in asthma. METHODS: Mucin 1 expression was evaluated by real-time PCR in human bronchial epithelial cells (HBEC) and blood neutrophils from uncontrolled severe asthma (n=27), controlled mild asthma (n=16), and healthy subjects (n=13). IL-8, MMP9, and GM-CSF …
MUC4 impairs the anti-inflammatory effects of corticosteroids in patients with chronic rhinosinusitis with nasal polyps
Background Current evidence suggests that membrane-tethered mucins could mediate corticosteroid efficacy, interacting with glucocorticoid receptor (GR) in patients with chronic rhinosinusitis with nasal polyps (CRSwNP). Mucin 4 (MUC4)–tethered mucin is expressed in nasal polyp (NP) epithelial cells and upregulated under inflammatory conditions. Moreover, MUC4β has the capacity to interact with other intracellular proteins. We hypothesized that MUC4 modulates corticosteroid efficacy of patients with CRSwNP. Objective We sought to analyze the role of MUC4 in corticosteroid effectiveness in different cohorts of patients with CRSwNP and elucidate the possible mechanisms involved. Methods Eighty…
LATE-BREAKING ABSTRACT: MUC1 downregulation induces corticosteroid resistance in asthma'sin vitroandin vivomodels
Background: Corticosteroids are in the first-line of Asthma treatment. However a subset of asthmatic patients is insensitive to anti-inflammatory effects of corticosteroids. Our previous data demonstrated that MUC1 downregulation correlates corticosteroid resistance in Nasal Polyposis and COPD. We hypothesized that MUC1 is also involved in corticosteroid resistance in Asthma. Objective: To analyze the role of MUC1 in the corticosteroid effectiveness in Asthma9s in vitro and in vivo models. Methods: 20 patients with steroid resistant Asthma were recruited. The expression of MUC1 was determined by real-time PCR in inflammatory cells from peripheral blood. HMVEC-L and U937 cells knockdown with…
Roflumilast N- oxide combined with sildenafil reverses cellular remodeling on IPF models
Background: Idiopathic pulmonary fibrosis (IPF) is characterized by a rapid progressive lung decline and premature death after its diagnosis. Roflumilast displayed anti-fibrotic effects in animal and cellular models. Recent studies indicate that the combination of PDE4 and PDE5 inhibitors (sildenafil) potentiates anti-fibrotic properties of each drug, suggesting potential beneficts of this combination. Objectives: To study the effects from adding sildenafil to roflumilast N-oxide (RNO) inhibiting TGFβ1-induced human alveolar type II (AECII) epithelial-to-mesenchymal transition (EMT) and human fibrocyte to myofibroblast transition in vitro. Methods: AECII and fibrocytes were isolated from he…
The JAK2 pathway is activated in idiopathic pulmonary fibrosis
Background: Idiopathic pulmonary fibrosis (IPF) is the most rapidly progressive and fatal fibrotic disorder, with no curative therapies. The signal transducer and activator of transcription 3 (STAT3) protein is activated in lung fibroblasts and alveolar type II cells (ATII), thereby contributing to lung fibrosis in IPF. Although activation of Janus kinase 2 (JAK2) has been implicated in proliferative disorders, its role in IPF is unknown. The aim of this study was to analyze JAK2 activation in IPF, and to determine whether JAK2/STAT3 inhibition is a potential therapeutic strategy for this disease. Methods and results: JAK2/p-JAK2 and STAT3/pSTAT3 expression was evaluated using quantitative …
Mucin 1 downregulation associates with corticosteroid resistance in chronic rhinosinusitis with nasal polyps
Background A number of patients with chronic rhinosinusitis with nasal polyps (CRSwNP) are resistant to oral corticosteroids. Mucin 1 (MUC1) shows anti-inflammatory properties, and its cytoplasmic tail (CT) interacts with transcription factors, facilitating their nuclear translocation. Because glucocorticoid receptor (GR) nuclear translocation is key to the anti-inflammatory effect of corticosteroids, we hypothesized that MUC1 is involved in the effectiveness of corticosteroids. Objective To analyze the role of MUC1 in corticosteroid effectiveness in different cohorts of patients with CRSwNP and elucidate the possible mechanisms involved. Methods Seventy-three patients with CRSwNP took oral…