scholarly journals Apoptosis signal-regulating kinase 1 inhibition attenuates human airway smooth muscle growth and migration in chronic obstructive pulmonary disease

2018 ◽  
Vol 132 (14) ◽  
pp. 1615-1627 ◽  
Author(s):  
Mathew S. Eapen ◽  
Anudeep Kota ◽  
Howard Vindin ◽  
Kielan D. McAlinden ◽  
Dia Xenaki ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Smooth Muscle ◽  
Pulmonary Disease ◽  
Airway Smooth Muscle ◽  
Airway Remodeling ◽  
Mitogen Activated Protein Kinase ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Copd Patients

Increased airway smooth muscle (ASM) mass is observed in chronic obstructive pulmonary disease (COPD), which is correlated with disease severity and negatively affects lung function in these patients. Thus, there is clear unmet clinical need for finding new therapies which can target airway remodeling and disease progression in COPD. Apoptosis signal-regulating kinase 1 (ASK1) is a ubiquitously expressed mitogen-activated protein kinase (MAPK) kinase kinase (MAP3K) activated by various stress stimuli, including reactive oxygen species (ROS), tumor necrosis factor (TNF)-α, and lipopolysaccharide (LPS) and is known to regulate cell proliferation. ASM cells from COPD patients are hyperproliferative to mitogens in vitro. However, the role of ASK1 in ASM growth is not established. Here, we aim to determine the effects of ASK1 inhibition on ASM growth and pro-mitogenic signaling using ASM cells from COPD patients. We found greater expression of ASK1 in ASM bundles of COPD lung when compared with non-COPD. Pre-treatment of ASM cells with highly selective ASK1 inhibitor, TC ASK 10 resulted in a dose-dependent reduction in mitogen (FBS, PDGF, and EGF; 72 h)-induced ASM growth as measured by CyQUANT assay. Further, molecular targetting of ASK1 using siRNA in ASM cells prevented mitogen-induced cell growth. In addition, to anti-mitogenic potential, ASK1 inhibitor also prevented TGFβ1-induced migration of ASM cells in vitro. Immunoblotting revealed that anti-mitogenic effects are mediated by C-Jun N-terminal kinase (JNK) and p38MAP kinase-signaling pathways as evident by reduced phosphorylation of downstream effectors JNK1/2 and p38MAP kinases, respectively, with no effect on extracellular signal-regulated kinase (ERK) 1/2 (ERK1/2). Collectively, these findings establish the anti-mitogenic effect of ASK1 inhibition and identify a novel pathway that can be targetted to reduce or prevent excessive ASM mass in COPD.

Platelet-Derived Growth Factors (PDGFs) are Key Players in the Stimulation of Airway Smooth Muscle Cells (ASMCs) Alteration in Asthma and Chronic Obstructive Pulmonary Disease (COPD) with Multifarious Inhibitors at an Early Stage of Development

2020 ◽  
Vol 17 (4) ◽  
pp. 324-332
Author(s):  
Xiaodong Shi ◽  
Kwaku Appiah-Kubi
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Smooth Muscle ◽  
Growth Factors ◽  
Smooth Muscle Cells ◽  
Pulmonary Disease ◽  
Airway Smooth Muscle ◽  
Muscle Cells ◽  
Chronic Obstructive ◽  
Airway Smooth Muscle Cells ◽  
Obstructive Pulmonary Disease

Background: Alterations in airway smooth muscle cells cause an increase in their mass and result in a significant impact on airway remodeling diseases such as asthma and chronic obstructive pulmonary disease. Several studies have used platelet-derived growth factors to stimulate the alterations of airway smooth muscle cells. Objective: This review discusses the platelet-derived growth factor-stimulated alterations of airway smooth muscle cells, diversity of inhibitors and inhibitory actions against these alterations and their related mechanisms, and how this diversity presents an avenue for the development of multifarious therapeutic targets for airway remodeling diseases especially asthma and chronic obstructive pulmonary disease. Methods: A comprehensive search of PubMed and Medscape database for studies that investigated the stimulation of the alterations of airway smooth muscle cells in asthma and chronic obstructive pulmonary disease by platelet-derived growth factors and inhibitions of these alterations. Results: Marked platelet-derived growth factor-stimulated alterations of airway smooth muscle cells are proliferation, migration and proliferative phenotype with diverse inhibitors and inhibitory actions against these alterations. Inhibitory actions are the result of the activation of protein kinase, overexpression of Tripartite motif protein, human transporter sub-family ABCA1 protein and miRNAs, knockdown of an isoform of reticulon 4 and follistatin protein, exogenous applications of recombinant proteins, supplements and active metabolite of retinoic acid, flavonoid extracts and polysaccharides extract. Conclusion: The multifarious inhibitors and inhibitory actions with varied mechanisms in platelet-derived growth factors-stimulated alterations of airway smooth muscle cells present a potential for diverse therapeutic targets for the treatment of airway remodeling diseases.

scholarly journals Quadriceps miR-542-3p and -5p are elevated in COPD and reduce function by inhibiting ribosomal and protein synthesis

2019 ◽  
Vol 126 (6) ◽  
pp. 1514-1524 ◽  
Author(s):  
Roser Farre-Garros ◽  
Jen Y. Lee ◽  
S. Amanda Natanek ◽  
Martin Connolly ◽  
Avan A. Sayer ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Protein Synthesis ◽  
Mitochondrial Dysfunction ◽  
Pulmonary Disease ◽  
Physical Performance ◽  
Quadriceps Muscle ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Copd Patients

Reduced physical performance reduces quality of life in patients with chronic obstructive pulmonary disease (COPD). Impaired physical performance is, in part, a consequence of reduced muscle mass and function, which is accompanied by mitochondrial dysfunction. We recently showed that miR-542-3p and miR-542-5p were elevated in a small cohort of COPD patients and more markedly in critical care patients. In mice, these microRNAs (miRNAs) promoted mitochondrial dysfunction suggesting that they would affect physical performance in patients with COPD, but we did not explore the association of these miRNAs with disease severity or physical performance further. We therefore quantified miR-542-3p/5p and mitochondrial rRNA expression in RNA extracted from quadriceps muscle of patients with COPD and determined their association with physical performance. As miR-542-3p inhibits ribosomal protein synthesis its ability to inhibit protein synthesis was also determined in vitro. Both miR-542-3p expression and -5p expression were elevated in patients with COPD (5-fold P < 0.001) and the degree of elevation associated with impaired lung function (transfer capacity of the lung for CO in % and forced expiratory volume in 1 s in %) and physical performance (6-min walk distance in %). In COPD patients, the ratio of 12S rRNA to 16S rRNA was suppressed suggesting mitochondrial ribosomal stress and mitochondrial dysfunction and miR-542-3p/5p expression was inversely associated with mitochondrial gene expression and positively associated with p53 activity. miR-542-3p suppressed RPS23 expression and maximal protein synthesis in vitro. Our data show that miR-542-3p and -5p expression is elevated in COPD patients and may suppress physical performance at least in part by inhibiting mitochondrial and cytoplasmic ribosome synthesis and suppressing protein synthesis. NEW & NOTEWORTHY miR-542-3p and -5p are elevated in the quadriceps muscle of patients with chronic obstructive pulmonary disease (COPD) in proportion to the severity of their lung disease. These microRNAs inhibit mitochondrial and cytoplasmic protein synthesis suggesting that they contribute to impaired exercise performance in COPD.

Sign in / Sign up

Export Citation Format

Share Document