0000000001115881
AUTHOR
Beatriz Ballester
Additional file 1: of The JAK2 pathway is activated in idiopathic pulmonary fibrosis
Supplementary data. (DOCX 1218 kb)
Role of IL-11 in vascular function of pulmonary fibrosis patients
Pulmonary hypertension (PH) in idiopathic pulmonary fibrosis (IPF) portends a poor prognosis. Currently, no therapy can improve survival of patients diagnosed with this disease. IL-11 molecular pathway is over-expressed in proliferative disorders, however, its role in PH- associated IPF is unknown. The aim of this study was to evaluated the expression of IL-11 in IPF patients with or without PH. Also we hypothesized that the stimulation of pulmonary artery smooth muscle cells (PASMCs) and human pulmonary artery microvascular endothelial cells (HMVEC-L) with IL-11 induced the transformation into invasive myofibroblast. Human pulmonary artery rings, parenchyma tissue, broncho-alveolar lavage …
MUC1 intracellular bioactivation mediates lung fibrosis
BackgroundSerum KL6/mucin 1 (MUC1) has been identified as a potential biomarker in idiopathic pulmonary fibrosis (IPF), but the role of MUC1 intracellular bioactivation in IPF is unknown.ObjectiveTo characterise MUC1 intracellular bioactivation in IPF.Methods and resultsThe expression and phosphorylation of Thr41 and Tyr46 on the intracellular MUC1-cytoplasmic tail (CT) was increased in patients with IPF (n=22) compared with healthy subjects (n=21) and localised to fibroblasts and hyperplastic alveolar type II cells. Transforming growth factor (TGF)-β1 phosphorylated SMAD3 and thereby increased the phosphorylation of MUC1-CT Thr41 and Tyr46 in lung fibroblasts and alveolar type II cells, ac…
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…
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…
MUC16 Is Overexpressed in Idiopathic Pulmonary Fibrosis and Induces Fibrotic Responses Mediated by Transforming Growth Factor-β1 Canonical Pathway
Several transmembrane mucins have demonstrated that they contribute intracellularly to induce fibrotic processes. The extracellular domain of MUC16 is considered as a biomarker for disease progression and death in IPF patients. However, there is no evidence regarding the signalling capabilities of MUC16 that contribute to IPF development. Here, we demonstrate that MUC16 was overexpressed in the lung tissue of IPF patients (n = 20) compared with healthy subjects (n = 17) and localised in fibroblasts and hyperplastic alveolar type II cells. Repression of MUC16 expression by siRNA-MUC16 transfection inhibited the TGF-β1-induced fibrotic processes such as mesenchymal/ myofibroblast transformati…
MUC4 is overexpressed in idiopathic pulmonary fibrosis and collaborates with transforming growth factor β inducing fibrotic responses.
Several mucins are implicated in idiopathic pulmonary fibrosis (IPF); however, there is no evidence regarding the role of MUC4 in the development of IPF. Here we demonstrated that MUC4 was overexpressed in IPF patients (n = 22) compared with healthy subjects (n = 21) and located in pulmonary arteries, bronchial epithelial cells, fibroblasts, and hyperplastic alveolar type II cells. Decreased expression of MUC4 using siRNA–MUC4 inhibited the mesenchymal/myofibroblast transformations of alveolar type II A549 cells and lung fibroblasts, as well as cell senescence and fibroblast proliferation induced by TGF-β1. The induction of the overexpression of MUC4 increased the effects of TGF-β1 on mesen…
Mucins as a New Frontier in Pulmonary Fibrosis
Idiopathic pulmonary fibrosis (IPF) is the most common idiopathic interstitial pulmonary disease with a median survival of 3–5 years after diagnosis. Recent evidence identifies mucins as key effectors in cell growth and tissue remodeling processes compatible with the processes observed in IPF. Mucins are classified in two groups depending on whether they are secreted (secreted mucins) or tethered to cell membranes (transmembrane mucins). Secreted mucins (MUC2, MUC5AC, MUC5B, MUC6-8 and MUC19) are released to the extracellular medium and recent evidence has shown that a promoter polymorphism in the secreted mucin MUC5B is associated with IPF risk. Otherwise, transmembrane mucins (MUC1, MUC3,…
Activation of nuclear factor erythroid 2-related (Nrf2) system as a novel therapeutic approach in COPD
Background: Chronic Obstructive Pulmonary Disease (COPD) is an inflammatory lung disease caused by chronic exposure to cigarette smoke. Oxidative stress is one of the most important mechanisms involved in the physiopathology of COPD. Nuclear Factor Erythroid 2-related (Nrf2) is critical in protection against oxidative stress by inducing expression of antioxidant genes and a decrease in its expression has been observed in COPD patients. Objective: The aim of this study was to characterise the effects of Bardoxolone, Omavexolone and Obacunone as antioxidant drugs in COPD. Methods: Peripheral blood neutrophils from COPD and healthy volunteers and Primary Human Bronchial Epithelial cells were i…
Idiopathic Pulmonary Fibrosis and Lung Cancer: Mechanisms and Molecular Targets
Idiopathic pulmonary fibrosis (IPF) is the most common idiopathic interstitial pulmonary disease with a median survival of 2–4 years after diagnosis. A significant number of IPF patients have risk factors, such as a history of smoking or concomitant emphysema, both of which can predispose the patient to lung cancer (LC) (mostly non-small cell lung cancer (NSCLC)). In fact, IPF itself increases the risk of LC development by 7% to 20%. In this regard, there are multiple common genetic, molecular, and cellular processes that connect lung fibrosis with LC, such as myofibroblast/mesenchymal transition, myofibroblast activation and uncontrolled proliferation, endoplasmic reticulum stress, alterat…
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…
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 …
Role of MUC1 in idiopathic pulmonary fibrosis
Background: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and irreversible form of fibrotic intersticial lung disease, characterized by uncontrolled fibroblast proliferative processes and alveolar type II epithelial dysfunction. MUC1 is considered as oncogenic molecule by altering signaling pathways involved in cellular proliferation and cell death. Objective: To analyze the implication of MUC1 in IPF Methods: Lung tissue from 14 healthy and 14 IPF patients was obtained. The expression of MUC1 cytoplasmic tail (CT) and its phosphorylation forms in T-1224 and Y-1229 residues were analyzed by western blot and immunohistochemistry. The effect of MUC1 on TGFβ1-Iinduced epithelia…
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 …
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)
The role of mucin 1 in respiratory diseases
Recent evidence has demonstrated that mucin 1 (MUC1) is involved in many pathological processes that occur in the lung. MUC1 is a transmembrane protein mainly expressed by epithelial and hematopoietic cells. It has a receptor-like structure, which can sense the external environment and activate intracellular signal transduction pathways through its cytoplasmic domain. The extracellular domain of MUC1 can be released to the external environment, thus acting as a decoy barrier to mucosal pathogens, as well as serving as a serum biomarker for the diagnosis and prognosis of several respiratory diseases such as lung cancer and interstitial lung diseases. Furthermore, bioactivated MUC1-cytoplasmi…