0000000000269697
AUTHOR
Inés Roger
The Role of JAK/STAT Molecular Pathway in Vascular Remodeling Associated with Pulmonary Hypertension
Pulmonary hypertension is defined as a group of diseases characterized by a progressive increase in pulmonary vascular resistance (PVR), which leads to right ventricular failure and premature death. There are multiple clinical manifestations that can be grouped into five different types. Pulmonary artery remodeling is a common feature in pulmonary hypertension (PH) characterized by endothelial dysfunction and smooth muscle pulmonary artery cell proliferation. The current treatments for PH are limited to vasodilatory agents that do not stop the progression of the disease. Therefore, there is a need for new agents that inhibit pulmonary artery remodeling targeting the main genetic, molecular,…
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 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…
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…
Lung Fibrosis and Fibrosis in the Lungs: Is It All about Myofibroblasts?
In the lungs, fibrosis is a growing clinical problem that results in shortness of breath and can end up in respiratory failure. Even though the main fibrotic disease affecting the lung is idiopathic pulmonary fibrosis (IPF), which affects the interstitial space, there are many fibrotic events that have high and dangerous consequences for the lungs. Asthma, chronic obstructive pulmonary disease (COPD), excessive allergies, clearance of infection or COVID-19, all are frequent diseases that show lung fibrosis. In this review, we describe the different kinds of fibrosis and analyse the main types of cells involved—myofibroblasts and other cells, like macrophages—and review the main fibrotic mec…
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 …
DPP-4 is overexpressed in lung tissue from idiopathic pulmonary patients and activates lung fibroblasts
Background: Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible form of fibrotic interstitial lung disease, characterized by uncontrolled fibroblast invasion. Dipeptidyl peptidase-4 (DPP-4)/ glucagon-like peptide 1 (GLP-1) system is involved in multiple effects, including cardiac, liver or kidney fibrosis. However, its implication in IPF has not been described. Objective: To analyse the implication of DPP4/GLP1 system in IPF. Methods: Protein expression of DPP4, GLP-1 and GLP-1 receptor was analyzed in lung tissues from 7 IPF patients. TGFβ1-induced fibroblast to myofibroblast transition (FMT), epithelial to mesenchymal transition (EMT) and mesothelial to mesenchymal trans…
Role of JAK/STAT in Interstitial Lung Diseases; Molecular and Cellular Mechanisms
Interstitial lung diseases (ILDs) comprise different fibrotic lung disorders characterized by cellular proliferation, interstitial inflammation, and fibrosis. The JAK/STAT molecular pathway is activated under the interaction of a broad number of profibrotic/pro-inflammatory cytokines, such as IL-6, IL-11, and IL-13, among others, which are increased in different ILDs. Similarly, several growth factors over-expressed in ILDs, such as platelet-derived growth factor (PDGF), transforming growth factor β1 (TGF-β1), and fibroblast growth factor (FGF) activate JAK/STAT by canonical or non-canonical pathways, which indicates a predominant role of JAK/STAT in ILDs. Between the different JAK/STAT iso…
IL-11 promotes pulmonary vascular remodeling and lung fibrosis through the activation of endothelial to mesenchymal transition
Background: Pulmonary hypertension (PH) in idiopathic pulmonary fibrosis (IPF) portends a poor prognosis and currently there is no approved therapy for hypoxemic PH. IL-11 is a novel lung fibrosis mediator but its role on vascular function is unknown. Objective: To analyze the role of IL-11 on pulmonary artery remodeling and lung fibrosis in vitro and in vivo. Methods: IL-11 expression was evaluated in pulmonary arteries and lung sections of control subjects and patients with IPF, IPF+PH and idiopathic PH (PAH). Human pulmonary artery endothelial cells and smooth muscle cells were stimulated with IL-11. Endothelial to mesenchymal transition was evaluated measuring the increase of mesenchyma…
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 …
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)