0000000000002757
AUTHOR
Sonia Contreras
MUC1 deficiency mediates corticosteroid resistance in chronic obstructive pulmonary disease.
Background Lung inflammation in COPD is poorly controlled by inhaled corticosteroids (ICS). Strategies to improve ICS efficacy or the search of biomarkers who may select those patients candidates to receive ICS in COPD are needed. Recent data indicate that MUC1 cytoplasmic tail (CT) membrane mucin can mediate corticosteroid efficacy in chronic rhinosinusitis. The objective of this work was to analyze the previously unexplored role of MUC1 on corticosteroid efficacy in COPD in vitro and in vivo models. Methods MUC1-CT expression was measured by real time PCR, western blot, immunohistochemistry and immunofluorescence. The inflammatory mediators IL-8, MMP9, GM-CSF and MIP3α were measured by EL…
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…
In vitro anti-inflammatory effects of AZD8999, a novel bifunctional muscarinic acetylcholine receptor antagonist /β2-adrenoceptor agonist (MABA) compound in neutrophils from COPD patients.
Recent evidence indicates that AZD8999 (LAS190792), a novel muscarinic acetylcholine receptor antagonist and β2-adrenoceptor agonist (MABA) in development for chronic respiratory diseases, induces potent and sustained relaxant effects in human bronchi by adressing both muscarinic acetylcholine receptors and β2-adrenoceptor. However, the anti-inflammatory effects of the AZD8999 monotherapy or in combination with corticosteroids are unknown. This study investigates the anti-inflammatory effects of AZD8999 in monotherapy and combined with fluticasone propionate in neutrophils from healthy and chronic obstructive pulmonary disease (COPD) patients. Peripheral blood neutrophils from healthy and C…
Roflumilast N-oxide combined with PI3Kδ inhibitor improves the phenotype of early-onset COPD
Background: Severe, early-onset COPD (Chronic Obstructive Pulmonary Disease) is characterized by a rapid decline in lung function at an early age with neutrophil over-activation. Roflumilast is approved as treatment for moderate and severe COPD at risk of exacerbation as add on therapy. Recent evidence indicates that the combination of PDE4 and PI3Kδ inhibitors show synergic anti-inflammatory properties. Objectives: To explore the effects from adding a selective PI3Kδ inhibitor to roflumilast N-oxide (RNO) in neutrophils isolated from peripheral blood of severe, early-onset COPD patients in in vitro models. Methods: Neutrophils were isolated from peripheral blood of 20 severe, early-onset C…
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…
Role of MUC1 in idiopathic pulmonary fibrosis: mechanistic insights
Background: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and irreversible form of fibrotic interstitial lung disease. MUC1, a membrane-bound O-glycoprotein, is considered as oncogenic molecule by altering signaling pathways involved in cellular processes related to IPF. In previous studies we have observed an up-regulation of MUC1 and its phosphorylated forms in IPF lung tissue. However the exact participation of MUC1 in IPF is currently unknown. Objective: To analyze the mechanism of MUC1-induced lung fibrosis in different cellular and animal models of IPF. Methods: The intracellular mechanism of MUC1 was evaluated by western blot, immunoprecipation and immunofluorescence …
Selective Inhibition of Phosphodiesterases 4A, B, C and D Isoforms in Chronic Respiratory Diseases: Current and Future Evidences
Chronic respiratory diseases affect millions of people every day. According to the World Health Organization estimates, ~235 million people suffer from asthma, ~64 million suffer from chronic obstructive pulmonary disease (COPD), and millions more suffer from allergic rhinitis around the world. In recent last years, the first phosphodiesterase 4 (PDE4) inhibitor, roflumilast, was approved as a treatment to reduce the risk of exacerbations in stable and severe COPD associated with chronic bronchitis and a history of exacerbations. PDE4 exists as four subtypes (A, B, C, and D) each with a capacity to degrade cAMP, a second messenger involved in inflammatory responses. PDE4 inhibitors inhibit …
The combination of PDE4 and PDE5 inhibitors reduces YAP expression in IPF
Background: Pathological fibrosis is associated with repeated episodes of injury to alveolar epithelial cells of largely. Yes-associated protein (YAP) is prominently expressed in fibrotic lung. Roflumilast has demonstrated to exhibit anti-fibrosis effects, while PDE5 inhibitors (sildenafil) combinated with PDE4 inhibitors reduce fibrotic-effects secondary to TGFs1. Apparently, no studies of PDE4 and PDE5 inhibitors on YAP expression there are. Objectives: To study the effects from adding a sildenafil to Roflumilast N- oxide (RNO) on TGF-β/SMAD3/YAP pathway in IPF in vitro models. Methods: A549 cells were pre-incubated with therapeutical concentrations of RNO (2nM) and/or sildenafil (10nM) a…
Additional file 1: of MUC1 deficiency mediates corticosteroid resistance in chronic obstructive pulmonary disease
Figure S1. Acute cigarette smoke/ lipopolysaccharide lung inflammatory animal model showed resistance to dexamethasone improving lung resistance and bronchoalveolar inflammatory cell extravasation in Muc1 KO animals. Figure S2. IL-8 and IL-13 bronchoalveolar fluid content in Muc1 KO mice exposed to acute cigarette smoke/ lipopolysaccharide is resistant to dexamethasone. Figure S3. Inflammatory lung cell infiltration secondary to acute lipopolysaccharide/ cigarette smoke exposure is resistant to dexamethasone in MUC1 KO mice. (DOCX 1611 kb)